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Sample records for chemopreventive agent sulforaphane

  1. Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane.

    PubMed

    Yang, Li; Palliyaguru, Dushani L; Kensler, Thomas W

    2016-02-01

    With the properties of efficacy, safety, tolerability, practicability and low cost, foods containing bioactive phytochemicals are gaining significant attention as elements of chemoprevention strategies against cancer. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate produced by cruciferous vegetables such as broccoli, is found to be a highly promising chemoprevention agent against not only a variety of cancers such as breast, prostate, colon, skin, lung, stomach or bladder, but also cardiovascular disease, neurodegenerative diseases, and diabetes. For reasons of experimental exigency, preclinical studies have focused principally on sulforaphane itself, while clinical studies have relied on broccoli sprout preparations rich in either sulforaphane or its biogenic precursor, glucoraphanin. Substantive subsequent evaluation of sulforaphane pharmacokinetics and pharmacodynamics has been undertaken using either pure compound or food matrices. Sulforaphane affects multiple targets in cells. One key molecular mechanism of action for sulforaphane entails activation of the Nrf2-Keap1 signaling pathway although other actions contribute to the broad spectrum of efficacy in different animal models. This review summarizes the current status of pre-clinical chemoprevention studies with sulforaphane and highlights the progress and challenges for the application of foods rich in sulforaphane and/or glucoraphanin in the arena of clinical chemoprevention. PMID:26970133

  2. Sulforaphane, a cancer chemopreventive agent, induces pathways associated with membrane biosynthesis in response to tissue damage by aflatoxin B1

    PubMed Central

    Techapiesancharoenkij, Nirachara; Fiala, Jeannette L. A.; Navasumrit, Panida; Croy, Robert G.; Wogan, Gerald N.; Groopman, John D.; Ruchirawat, Mathuros; Essigmann, John M.

    2015-01-01

    Aflatoxin B1 (AFB1) is one of the major risk factors for liver cancer globally. A recent study showed that sulforaphane (SF), a potent inducer of phase II enzymes that occurs naturally in widely consumed vegetables, effectively induces hepatic glutathione S-transferases (GSTs) and reduces levels of hepatic AFB1-DNA adducts in AFB1-exposed Sprague Dawley rats. The present study characterized the effects of SF pre-treatment on global gene expression in the livers of similarly treated male rats. Combined treatment with AFB1 and SF caused reprogramming of a network of genes involved in signal transduction and transcription. Changes in gene regulation were observable 4 h after AFB1 administration in SF-pretreated animals and may reflect regeneration of cells in the wake of AFB1-induced hepatotoxicity. At 24 h after AFB1 administration, significant induction of genes that play roles in cellular lipid metabolism and acetyl-CoA biosynthesis was detected in SF-pretreated AFB1-dosed rats. Induction of this group of genes may indicate a metabolic shift toward glycolysis and fatty acid synthesis to generate and maintain pools of intermediate molecules required for tissue repair, cell growth and compensatory hepatic cell proliferation. Collectively, gene expression data from this study provide insights into molecular mechanisms underlying the protective effects of SF against AFB1 hepatotoxicity and hepatocarcinogenicity, in addition to the chemopreventive activity of this compound as a GST inducer. PMID:25450479

  3. Sulforaphane, a cancer chemopreventive agent, induces pathways associated with membrane biosynthesis in response to tissue damage by aflatoxin B{sub 1}

    SciTech Connect

    Techapiesancharoenkij, Nirachara; Fiala, Jeannette L.A.; Navasumrit, Panida; Croy, Robert G.; Wogan, Gerald N.; Groopman, John D.; Ruchirawat, Mathuros; Essigmann, John M.

    2015-01-01

    Aflatoxin B{sub 1} (AFB{sub 1}) is one of the major risk factors for liver cancer globally. A recent study showed that sulforaphane (SF), a potent inducer of phase II enzymes that occurs naturally in widely consumed vegetables, effectively induces hepatic glutathione S-transferases (GSTs) and reduces levels of hepatic AFB{sub 1}-DNA adducts in AFB{sub 1}-exposed Sprague Dawley rats. The present study characterized the effects of SF pre-treatment on global gene expression in the livers of similarly treated male rats. Combined treatment with AFB{sub 1} and SF caused reprogramming of a network of genes involved in signal transduction and transcription. Changes in gene regulation were observable 4 h after AFB{sub 1} administration in SF-pretreated animals and may reflect regeneration of cells in the wake of AFB{sub 1}-induced hepatotoxicity. At 24 h after AFB{sub 1} administration, significant induction of genes that play roles in cellular lipid metabolism and acetyl-CoA biosynthesis was detected in SF-pretreated AFB{sub 1}-dosed rats. Induction of this group of genes may indicate a metabolic shift toward glycolysis and fatty acid synthesis to generate and maintain pools of intermediate molecules required for tissue repair, cell growth and compensatory hepatic cell proliferation. Collectively, gene expression data from this study provide insights into molecular mechanisms underlying the protective effects of SF against AFB{sub 1} hepatotoxicity and hepatocarcinogenicity, in addition to the chemopreventive activity of this compound as a GST inducer. - Highlights: • This study revealed sulforaphane (SF)-deregulated gene sets in aflatoxin B{sub 1} (AFB{sub 1})-treated rat livers. • SF redirects biochemical networks toward lipid biosynthesis in AFB{sub 1}-dosed rats. • SF enhanced gene sets that would be expected to favor cell repair and regeneration.

  4. A review of cancer chemopreventive agents.

    PubMed

    Levi, M S; Borne, R F; Williamson, J S

    2001-09-01

    In the late 20(th) century, the treatment of cancer began to include its prevention. Today, compounds exist that will lower the risk of developing certain types of cancer. This has been demonstrated in studies where chemically induced tumor growth has been slowed or reversed. Anti-inflammatory compounds having chemopreventive activity are piroxicam, sulindac, aspirin, celecoxib and curcumin. The selective estrogen receptor modulators, tamoxifen and raloxifene, are beneficial in the prevention of estrogen dependent tumors. Retinoids, vitamin A derivatives, such as targretin and fenretinide are useful in the prevention of tumors. Compounds containing sulfur, such as sulforaphane and oltipraz, are even useful as radioprotective agents. The steroid dehydroepiandosterone can inhibit experimental carcinogenesis. All of these chemical classes provide a start for the medicinal chemist to design more effective chemopreventive agents. The biomarkers used to determine the chemopreventive activity of new compounds are quite often activities of enzymes. The identification of those individuals at high risk is still in its infancy and presents a troubling dilemma. PMID:11562271

  5. Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition

    PubMed Central

    Tortorella, Stephanie M.; Royce, Simon G.; Licciardi, Paul V.

    2015-01-01

    Abstract Significance: Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. Critical Issues: In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFκB. Future Directions: Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anti-cancer compound alone, and in combination with clinically relevant therapeutic and management strategies. Antioxid. Redox Signal. 22, 1382–1424. PMID:25364882

  6. Chemopreventive Agent Development | Division of Cancer Prevention

    Cancer.gov

    This group promotes and supports research on early chemopreventive agent development, from preclinical studies to phas | Research on early chemopreventive agent development, from preclinical studies to phase I clinical trials.

  7. Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention

    PubMed Central

    Atwell, Lauren L.; Beaver, Laura M.; Shannon, Jackilen; Williams, David E.; Dashwood, Roderick H.; Ho, Emily

    2015-01-01

    Sulforaphane (SFN) is a phytochemical derived from cruciferous vegetables that has multiple molecular targets and anti-cancer properties. Researchers have demonstrated several chemopreventive benefits of SFN consumption, such as reductions in tumor growth, increases in cancer cell apoptosis, and disruption of signaling within tumor microenvironments both in vitro and in vivo. Emerging evidence indicates that SFN exerts several of its chemopreventive effects by altering epigenetic mechanisms. This review summarizes evidence of the impact of SFN on epigenetic events and how they relate to the chemopreventive effects of SFN observed in preclinical and clinical studies of breast and prostate cancers. Specific areas of focus include the role of SFN in the regulation of cell cycle, apoptosis, inflammation, antioxidant defense, and cancer cell signaling and their relationships to epigenetic mechanisms. Finally, remaining challenges and research needs for translating mechanistic work with SFN into human studies and clinical intervention trials are discussed. PMID:26042194

  8. Chemopreventive agents targeting tumor microenvironment.

    PubMed

    Sharma, Sharada H; Thulasingam, Senthilkumar; Nagarajan, Sangeetha

    2016-01-15

    Recent studies have shown that tumor development and progression depend not only on the perturbed genes that govern cell proliferation, but is also highly determined by the non-tumor cells of the stromal compartment surrounding the tumor called tumor microenvironment (TME). These findings highlight the importance of targeting the microenvironment in combination with therapies aimed at tumor cells as a valuable approach. The innate and adaptive immune cells in the TME interact among themselves and also with the endothelial cells, pericytes and mast cells of the stromal compartment through various autocrine and paracrine manner to regulate abnormal cell proliferation. Direct cytotoxic killing of cancer cells and/or reversion of the immunosuppressive TME are to be considered as better strategies for chemoprevention and chemotherapy. With a growing emphasis on a "hallmark targeting" strategy for cancer therapy, the TME now appears as a promising target for cancer prevention using natural products. Clarification on the nontumor stromal cells, the mediators involved, interactions with immune response cells, and immune-evasive mechanisms are needed in order to manipulate the characteristics of the TME by natural pharmacological agents to design effective therapies. This review will provide a glimpse on the roles played by various non-tumor cells in tumor progression and their intervention by pharmacological agents. PMID:26679106

  9. Sulforaphane Bioavailability and Chemopreventive Activity in Women Scheduled for Breast Biopsy.

    PubMed

    Atwell, Lauren L; Zhang, Zhenzhen; Mori, Motomi; Farris, Paige E; Vetto, John T; Naik, Arpana M; Oh, Karen Y; Thuillier, Philippe; Ho, Emily; Shannon, Jackilen

    2015-12-01

    Epidemiologic studies suggest a protective effect of cruciferous vegetables on breast cancer. Sulforaphane (SFN), an active food component derived from crucifers, has been shown to be effective in breast cancer chemoprevention. This study evaluated the chemopreventive effect of SFN on selective biomarkers from blood and breast tissues. In a 2- to 8-week double-blinded, randomized controlled trial, 54 women with abnormal mammograms and scheduled for breast biopsy were randomized to consume a placebo or a glucoraphanin (GFN) supplement providing SFN (n = 27). Plasma and urinary SFN metabolites, peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity, and tissue biomarkers (H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67, p21) were measured before and after the intervention in benign, ductal carcinoma in situ, or invasive ductal carcinoma breast tissues. Within the supplement group, Ki-67 (P = 0.003) and HDAC3 (P = 0.044) levels significantly decreased in benign tissue. Pre-to-postintervention changes in these biomarkers were not significantly different between treatment groups after multiple comparison adjustment. GFN supplementation was associated with a significant decrease in PBMC HDAC activity (P = 0.04). No significant associations were observed between SFN and examined tissue biomarkers when comparing treatment groups. This study provides evidence that GFN supplementation for a few weeks is safe but may not be sufficient for producing changes in breast tissue tumor biomarkers. Future studies employing larger sample sizes should evaluate alternative dosing and duration regimens to inform dietary SFN strategies in breast cancer chemoprevention. PMID:26511489

  10. Organ-specific exposure and response to sulforaphane, a key chemopreventive ingredient in broccoli: implications for cancer prevention.

    PubMed

    Veeranki, Omkara L; Bhattacharya, Arup; Marshall, James R; Zhang, Yuesheng

    2013-01-14

    Naturally occurring sulforaphane (SF) has been extensively studied for cancer prevention. However, little is known as to which organs may be most affected by this agent, which impedes its further development. In the present study, SF was administered to rats orally either in a single dose or once daily for 7 d. Tissue distribution of SF was measured by a HPLC-based method. Glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), two well-known cytoprotective phase 2 enzymes, were measured using biochemical assays to assess tissue response to SF. SF was delivered to different organs in vastly different concentrations. Tissue uptake of SF was the greatest in the stomach, declining rapidly in the descending gastro-intestinal tract. SF was rapidly eliminated through urinary excretion, and urinary concentrations of SF equivalents were 2-4 orders of magnitude higher than those of plasma. Indeed, tissue uptake level of SF in the bladder was second only to that in the stomach. Tissue levels of SF in the colon, prostate and several other organs were very low, compared to those in the bladder and stomach. Moreover, induction levels of GST and NQO1 varied by 3- to 6-fold among the organs of SF-treated rats, though not strictly correlated with tissue exposure to SF. Thus, there is profound organ specificity in tissue exposure and response to dietary SF, suggesting that the potential chemopreventive benefit of dietary SF may differ significantly among organs. These findings may provide a basis for prioritising organs for further chemopreventive study of SF. PMID:22464629

  11. Anticancer Activity of a Broccoli Derivative, Sulforaphane, in Barrett Adenocarcinoma: Potential Use in Chemoprevention and as Adjuvant in Chemotherapy1

    PubMed Central

    Qazi, Aamer; Pal, Jagannath; Maitah, Ma'in; Fulciniti, Mariateresa; Pelluru, Dheeraj; Nanjappa, Puru; Lee, Saem; Batchu, Ramesh B; Prasad, Madhu; Bryant, Christopher S; Rajput, Samiyah; Gryaznov, Sergei; Beer, David G; Weaver, Donald W; Munshi, Nikhil C; Goyal, Raj K; Shammas, Masood A

    2010-01-01

    INTRODUCTION: The incidence of Barrett esophageal adenocarcinoma (BEAC) has been increasing at an alarming rate in western countries. In this study, we have evaluated the therapeutic potential of sulforaphane (SFN), an antioxidant derived from broccoli, in BEAC. METHODS: BEAC cells were treated with SFN, alone or in combination with chemotherapeutic, paclitaxel, or telomerase-inhibiting agents (MST-312, GRN163L), and live cell number determined at various time points. The effect on drug resistance/chemosensitivity was evaluated by rhodamine efflux assay. Apoptosis was detected by annexin V labeling and Western blot analysis of poly(ADP-ribose) polymerase cleavage. Effects on genes implicated in cell cycle and apoptosis were determined by Western blot analyses. To evaluate the efficacy in vivo, BEAC cells were injected subcutaneously in severe combined immunodeficient mice, and after the appearance of palpable tumors, mice were treated with SFN. RESULTS: SFN induced both time- and dose-dependent decline in cell survival, cell cycle arrest, and apoptosis. The treatment with SFN also suppressed the expression of multidrug resistance protein, reduced drug efflux, and increased anticancer activity of other antiproliferative agents including paclitaxel. A significant reduction in tumor volume was also observed by SFN in a subcutaneous tumor model of BEAC. Anticancer activity could be attributed to the induction of caspase 8 and p21 and down-regulation of hsp90, a molecular chaperon required for activity of several proliferation-associated proteins. CONCLUSIONS: These data indicate that a natural product with antioxidant properties from broccoli has great potential to be used in chemoprevention and treatment of BEAC. PMID:21151478

  12. Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane.

    PubMed

    Bauman, Julie E; Zang, Yan; Sen, Malabika; Li, Changyou; Wang, Lin; Egner, Patricia A; Fahey, Jed W; Normolle, Daniel P; Grandis, Jennifer R; Kensler, Thomas W; Johnson, Daniel E

    2016-07-01

    Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547-57. ©2016 AACR. PMID:27339168

  13. Alternate dosing schedules for cancer chemopreventive agents.

    PubMed

    Lazzeroni, Matteo; DeCensi, Andrea

    2016-02-01

    Pharmacologic interventions for cancer risk reduction involve the chronic administration of synthetic or natural agents to reduce or delay the occurrence of malignancy. Despite the strong evidence for a favorable risk-benefit ratio for a number of agents in several common malignancies such as breast and prostate cancer, the public's attitude toward cancer chemoprevention remains ambivalent, with the issue of toxicity associated with drugs being perceived as the main barrier to widespread use of preventive therapy by high-risk subjects. Among the strategies to overcome such obstacles to preventive therapies, two novel and potentially safer modes of administering agents are discussed in this paper. The first strategy is to lower the dose of drugs that are in common use in the adjuvant setting based on the notion that prevention of cancer cells from developing should require a lower dose than eradicating established tumor cells. A second approach is to adopt an intermittent administration similar to what is used in the chemotherapy setting in an attempt to minimize risks while retaining benefits. This article provides a detailed discussion of the principles and future development of these two approaches in the direction of a precision preventive medicine. PMID:26970130

  14. The molecular mechanism of action of aspirin, curcumin and sulforaphane combinations in the chemoprevention of pancreatic cancer

    PubMed Central

    THAKKAR, ARVIND; SUTARIA, DHRUVITKUMAR; GRANDHI, B. KARTHIK; WANG, JEFFREY; PRABHU, SUNIL

    2013-01-01

    Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with ~37,000 deaths each year. The present study evaluated the chemopreventive potential of a combination of aspirin (ASP), curcumin (CUR) and sulforaphane (SFN) in low doses to human pancreatic cancer cells, MIA PaCa-2 and Panc-1. Results demonstrated that low doses of ASP (1 mM), CUR (10 μM) and SFN (5 μM) (ACS) combination reduced cell viability by ~70% (P<0.001), and also induced cell apoptosis by ~51% (P<0.001) accompanied by activation of caspase-3 and Poly(ADP-ribose) polymerase (PARP) proteins. The NF-κB DNA binding activity was inhibited by ~45% (P<0.01) and ~75% (P<0.001) in MIA PaCa-2 and Panc-1 cells, respectively. Mechanistic studies revealed that ACS promoted increase expression of phospho extracellular signal-regulated kinase 1/2 (P-ERK1/2), c-Jun, p38 MAPK and p53 proteins. Furthermore, the cells pretreated with U0126 (ERK1/2 inhibitor) partially abolished the effect of ACS on cell viability. Data from this study demonstrate that a low-dose ACS combination inhibits cell growth by inducing cell apoptosis, and proposes sustained activation of the ERK1/2 signaling pathway as one of the possible mechanisms. PMID:23404329

  15. Expression of MRP1 and GSTP1-1 modulate the acute cellular response to treatment with the chemopreventive isothiocyanate, sulforaphane.

    PubMed

    Sibhatu, Mebrahtu B; Smitherman, Pamela K; Townsend, Alan J; Morrow, Charles S

    2008-04-01

    A major component of the anticarcinogenic activity of the dietary chemopreventive agent sulforaphane (SFN) is attributed to its ability to induce expression of phase II detoxification genes containing the antioxidant response element (ARE) within their promoters. Because SFN is a reactive electrophile--readily forming conjugates with glutathione (GSH)--we asked whether expression of glutathione S-transferase (GST) P1-1 and the GSH conjugate efflux pump, multidrug resistance or resistance-associated protein (MRP) 1, would significantly modify the cellular response to SFN exposure. This was investigated using GST- and MRP1-poor parental MCF7 cells and transgenic derivatives expressing GSTP1-1 and/or MRP1. Compared with parental cells, expression of GSTP1-1 alone enhanced the rate of intracellular accumulation of SFN and its glutathione conjugate, SFN-SG--an effect that was associated with increased ARE-containing reporter gene induction. Expression of MRP1 greatly reduced SFN/SFN-SG accumulation and resulted in significant attenuation of SFN-mediated induction of ARE-containing reporter and endogenous gene expression. Coexpression of GSTP1-1 with MRP1 further reduced the level of induction. Depletion of GSH prior to SFN treatment or the substitution of tert-butylhydroquinone for SFN abolished the effects of MRP1/GSTP1-1 on ARE-containing gene induction-indicating that these effects are GSH dependent. Lastly, analysis of NF-E2-related factor 2 (Nrf2)--a transcription factor operating via binding to the ARE--showed that the increased levels of Nrf2 following SFN treatment were considerably less sustained in MRP1-expressing, especially those coexpressing GSTP1-1, than in MRP1-poor cells. These results suggest that the regulating effects of MRP1 and GSTP1-1 expression on SFN-dependent induction of phase II genes are ultimately mediated by altering nuclear Nrf2 levels. PMID:18204073

  16. Hereditary cancer syndromes as model systems for chemopreventive agent development.

    PubMed

    Walcott, Farzana L; Patel, Jigar; Lubet, Ronald; Rodriguez, Luz; Calzone, Kathleen A

    2016-02-01

    Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings. PMID:26970132

  17. Beer constituents as potential cancer chemopreventive agents.

    PubMed

    Gerhäuser, Clarissa

    2005-09-01

    Beer is a complex alcoholic beverage made from barley (malt), hop, water and yeast. Phenolic constituents of beer are derived from malt (70-80%) and hop (20-30%). Structural classes include simple phenols, benzoic- and cinnamic acid derivatives, coumarins, catechins, di-, tri- and oligomeric proanthocyanidins, (prenylated) chalcones and flavonoids as well as alpha- and iso-alpha-acids derived from hop. Compounds belonging to different structural classes have distinct profiles of biological activity in in vitro test systems, and in combination might lead to enhanced effects. Scientific evidence has accumulated over the past 10 years pointing to the cancer preventive potential of selected hop-derived beer constituents, i.e., prenylflavonoids including xanthohumol and isoxanthohumol, and hop bitter acids. Chemopreventive activities observed with these compounds relevant to inhibition of carcinogenesis at the initiation, promotion and progression phases, as well as results from in vivo studies on metabolism, bioavailability and efficacy are summarised in this review. PMID:15953717

  18. Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents.

    PubMed

    Cragg, Gordon M; Pezzuto, John M

    2016-01-01

    Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. PMID:26679767

  19. Optimizing therapeutic efficacy of chemopreventive agents: A critical review of delivery strategies in oral cancer chemoprevention clinical trials

    PubMed Central

    Holpuch, Andrew S.; Desai, Kashappa-Goud H.; Schwendeman, Steven P.; Mallery, Susan R.

    2011-01-01

    Due to its characterized progression from recognized premalignant oral epithelial changes (i.e., oral epithelial dysplasia) to invasive cancer, oral squamous cell carcinoma represents an optimal disease for chemopreventive intervention prior to malignant transformation. The primary goal of oral cancer chemoprevention is to reverse, suppress, or inhibit the progression of premalignant lesions to cancer. Over the last several decades, numerous oral cancer chemoprevention clinical trials have assessed the therapeutic efficacy of diverse chemopreventive agents. The standard of care for more advanced oral dysplastic lesions entails surgical excision and close clinical follow-up due to the potential (~33%) for local recurrence at a similar or more advanced histological stage. The purpose of this review was to identify prominent oral cancer chemoprevention clinical trials, assess their overall therapeutic efficacy, and delineate effects of local versus systemic drug administration. In addition, these compiled clinical trial data present concepts for consideration in the design and conduction of future clinical trials. PMID:22013393

  20. Chain elongation analog of resveratrol as potent cancer chemoprevention agent.

    PubMed

    Kang, Yan-Fei; Qiao, Hai-Xia; Xin, Long-Zuo; Ge, Li-Ping

    2016-09-01

    Resveratrol is identified as a natural cancer chemoprevention agent. There has been a lot of interest in designing and developing resveratrol analogs with cancer chemoprevention activity superior to that of parent molecule and exploring their action mechanism in the past several decades. In this study, we have synthesized resveratrol analogs of compounds A-C via conjugated chain elongation based on isoprene unit retention strategy. Remarkably, cytotoxic activity analysis results indicated that compound B possesses the best proliferation inhibition activity for NCI-H460 cells in all the test compounds. Intriguingly, compound B displayed a higher cytotoxicity against human non-small cell lung cancer cells (NCI-H460) compared to normal human embryonic lung fibroblasts (MRC-5). Afterward, flow cytometry analysis showed that compound B would induce cell apoptosis. We further researched the action mechanism. When NCI-H460 cells were incubated by compound B for 6 or 9 h, respectively, the intracellular reactive oxygen species (ROS) level was enhanced obviously. With elevation of intracellular ROS level, flow cytometry measurement verified mitochondrial transmembrane potential collapse, which was accompanied by the up-regulation of Bax and down-regulation of Bcl-2. More interestingly, compound B increased the expression of caspase-9 and caspase-3, which induced cell apoptosis. Moreover, compound B arrested cell cycle in G0/G1 phase. These are all to provide useful information for designing resveratrol-based chemoprevention agent and understanding the action mechanism. PMID:27160168

  1. Sulforaphane plays common and different roles in tumorigenic and nontumorigenic colon cell growth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sulforaphane (SFN) is a naturally occurring member of the isothiocyanate family of chemopreventive agents and the induction of cell cycle arrest and apoptosis is a key mechanism by which SFN exerts its colon cancer prevention. However, little is known about the differential effects of SFN on colon c...

  2. The models for assessment of chemopreventive agents: single organ models.

    PubMed

    Das, Sukta; Banerjee, Sarmistha; Saha, Prosenjit

    2004-01-01

    Research in cancer chemoprevention involves a number of activities, the first and foremost of which is acquisition of detailed knowledge concerning the process of carcinogenesis and identification of points of intervention whereby the process can be reversed or stalled. Parallel to this is the search for ideal chemopreventive agents--natural or synthetic--and screening for their activity and efficacy in vitro and in vivo. For ethical reasons it is not possible to test new agents on humans, so preclinical studies are dependent on results first being obtained with suitable animal models. Since it is not possible for a single model to reflect the diversity and heterogeneity of human cancers, it is necessary to have as many different models as possible, depending on the requirement of the studies on different aspects of cancer biology. Advances in research on carcinogenesis and chemoprevention therefore have to be accompanied by development of appropriate laboratory animal models using a variety of carcinogens that produce tumours at different sites. Animal models have contributed significantly to our understanding of carcinogenesis and ways to intervene in the underlying processes. Many animal carcinogenesis and tumour models have been found to mirror corresponding human cancers with respect to cell of origin, morphogenesis, phenotype markers and genetic alteration. In spite of the fact that interpolation of data from animal studies to humans is difficult for various reasons, animal models are widely used for assessment of new compounds with cancer chemopreventive potential and for preclinical trials. So despite the movements of animal rights activists, animal models will continue to be used for biomedical research for saving human lives. In doing so, care should be taken to treat and handle the animals with minimal discomfort to them and ensuring that alternatives are used whenever possible. PMID:15074999

  3. Nuclear factor-kappa B links carcinogenic and chemopreventive agents.

    PubMed

    Ralhan, Ranju; Pandey, Manoj K; Aggarwal, Bharat B

    2009-01-01

    Cancer prevention requires avoidance of tobacco, alcohol, high-fat diet, polluted air and water, sedentary lifestyle, and of mechanical, physical, psychological, or chemical stress. How these factors can cause cancer, is suggested by the transcription nuclear factor-kappa B (NF-kappa B), that is activated by tobacco, alcohol, high-fat diet, environment pollutants, cancer-causing viruses (human papillomavirus, hepatitis B and C viruses, HIV) and bacteria (Helicobacter pylori), ultraviolet light, ionizing radiation, obesity, and stress. Furthermore, NF-kappa B-regulated gene products have been implicated in transformation of cells, and in proliferation, survival, invasion, angiogenesis, and metastasis. Suppression of NF-kappa B activation by the phytochemicals present in fruits and vegetables provides the molecular basis for their ability to prevent cancer. Other agents identified from spices and Ayurvedic and traditional Chinese medicines also been found to suppress NF-kappa B activation and thus may have potential for cancer prevention. The classic chemopreventive agent should offer long-term safety, low cost, and efficacy. The current review discuses in detail numerous agents such as curcumin, resveratrol, silymarin, catechins and others as potential chemopreventive agents. Thus, cancer, an ancient problem, may have an ancient solution. PMID:19482682

  4. Inhibition of AP-1 by Sulforaphane Involves Interaction with Cysteine in the cFos DNA-Binding Domain; Implications for Chemoprevention of UVB-Induced Skin Cancer

    PubMed Central

    Dickinson, Sally E.; Melton, Tania F.; Olson, Erik R.; Zhang, Jian; Saboda, Kathylynn; Bowden, G. Timothy

    2009-01-01

    Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables which has been linked to decreased risk of certain cancers. Although the role of SFN in the induction of the transcription factor Nrf2 has been studied extensively, there is also evidence that inhibition of the transcription factor AP-1 may contribute to the chemopreventive properties of this compound. In this study, we show for the first time that SFN is effective at reducing the multiplicity and tumor burden of UVB-induced squamous cell carcinomas (SCCs) in a mouse model utilizing co-treatment with the compound and the carcinogen. We also show that SFN pretreatment is able to reduce the activity of AP-1 luciferase in the skin of transgenic mice after UVB. Chromatin immunoprecipitation analysis verified that a main constituent of the AP-1 dimer, cFos, is inhibited from binding to the AP-1 DNA binding site by SFN. EMSA analysis of nuclear proteins also show that SFN and diamide, both known to react with cysteine amino acids, are effective at inhibiting AP-1 from binding to its response element. Using truncated recombinant cFos and cJun we show that mutation of critical cysteines in the DNA binding domain of these proteins (Cys154 in cFos and Cys272 in cJun) results in loss of sensitivity to both SFN and diamide in EMSA analysis. Together, these data indicate that inhibition of AP-1 activity may be an important molecular mechanism in chemoprevention of SCC by SFN. PMID:19671797

  5. Pharmacokinetics and pharmacodynamics of phase II drug metabolizing/antioxidant enzymes gene response by anticancer agent sulforaphane in rat lymphocytes.

    PubMed

    Wang, Hu; Khor, Tin Oo; Yang, Qian; Huang, Ying; Wu, Tien-Yuan; Saw, Constance Lay-Lay; Lin, Wen; Androulakis, Ioannis P; Kong, Ah-Ng Tony

    2012-10-01

    This study assesses the pharmacokinetics (PK) and pharmacodynamics (PD) of Nrf2-mediated increased expression of phase II drug metabolizing enzymes (DME) and antioxidant enzymes which represents an important component of cancer chemoprevention in rat lymphocytes following intravenous (iv) administration of an anticancer phytochemical sulforaphane (SFN). SFN was administered intravenously to four groups of male Sprague-Dawley JVC rats each group comprising four animals. Blood samples were drawn at selected time points. Plasma were obtained from half of each of the blood samples and analyzed using a validated LC-MS/MS method. Lymphocytes were collected from the remaining blood samples using Ficoll-Paque Plus centrifuge medium. Lymphocyte RNAs were extracted and converted to cDNA, quantitative real-time PCR analyses were performed, and fold changes were calculated against those at time zero for the relative expression of Nrf2-target genes of phase II DME/antioxidant enzymes. PK-PD modeling was conducted based on Jusko's indirect response model (IDR) using GastroPlus and bootstrap method. SFN plasma concentration declined biexponentially and the pharmacokinetic parameters were generated. Rat lymphocyte mRNA expression levels showed no change for GSTM1, SOD, NF-κB, UGT1A1, or UGT1A6. Moderate increases (2-5-fold) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increases (>5-fold) for GSTT1, GPx1, and Maf. PK-PD analyses using GastroPlus and the bootstrap method provided reasonable fitting for the PK and PD profiles and parameter estimates. Our present study shows that SFN could induce Nrf2-mediated phase II DME/antioxidant mRNA expression for NQO1, GSTT1, Nrf2, GPx, Maf, and HO-1 in rat lymphocytes after iv administration, suggesting that Nrf2-mediated mRNA expression in lymphocytes may serve as surrogate biomarkers. The PK-PD IDR model simultaneously linking the plasma concentrations of SFN and the PD response of lymphocyte mRNA expression is

  6. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

    PubMed Central

    Thoppil, Roslin J; Bishayee, Anupam

    2011-01-01

    Despite significant advances in medicine, liver cancer, predominantly hepatocellular carcinoma remains a major cause of death in the United States as well as the rest of the world. As limited treatment options are currently available to patients with liver cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. Several naturally occurring dietary and non-dietary phytochemicals have shown enormous potential in the prevention and treatment of several cancers, especially those of the gastrointestinal tract. Terpenoids, the largest group of phytochemicals, traditionally used for medicinal purposes in India and China, are currently being explored as anticancer agents in clinical trials. Terpenoids (also called “isoprenoids”) are secondary metabolites occurring in most organisms, particularly plants. More than 40 000 individual terpenoids are known to exist in nature with new compounds being discovered every year. A large number of terpenoids exhibit cytotoxicity against a variety of tumor cells and cancer preventive as well as anticancer efficacy in preclinical animal models. This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors. Both in vitro and in vivo effects of these agents and related cellular and molecular mechanisms are highlighted. Potential challenges and future directions involved in the advancement of these promising natural compounds in the chemoprevention and therapy of human liver cancer are also discussed. PMID:21969877

  7. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer.

    PubMed

    Thoppil, Roslin J; Bishayee, Anupam

    2011-09-27

    Despite significant advances in medicine, liver cancer, predominantly hepatocellular carcinoma remains a major cause of death in the United States as well as the rest of the world. As limited treatment options are currently available to patients with liver cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. Several naturally occurring dietary and non-dietary phytochemicals have shown enormous potential in the prevention and treatment of several cancers, especially those of the gastrointestinal tract. Terpenoids, the largest group of phytochemicals, traditionally used for medicinal purposes in India and China, are currently being explored as anticancer agents in clinical trials. Terpenoids (also called "isoprenoids") are secondary metabolites occurring in most organisms, particularly plants. More than 40 000 individual terpenoids are known to exist in nature with new compounds being discovered every year. A large number of terpenoids exhibit cytotoxicity against a variety of tumor cells and cancer preventive as well as anticancer efficacy in preclinical animal models. This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors. Both in vitro and in vivo effects of these agents and related cellular and molecular mechanisms are highlighted. Potential challenges and future directions involved in the advancement of these promising natural compounds in the chemoprevention and therapy of human liver cancer are also discussed. PMID:21969877

  8. Bowman-Birk inhibitors from legumes as colorectal chemopreventive agents

    PubMed Central

    Clemente, Alfonso; Arques, Maria del Carmen

    2014-01-01

    Aberrant functioning of serine proteases in inflammatory and carcinogenic processes within the gastrointestinal tract (GIT) has prompted scientists to investigate the potential of serine protease inhibitors, both natural and synthetic, as modulators of their proteolytic activities. Protease inhibitors of the Bowman-Birk type, a major protease inhibitor family in legume seeds, which inhibit potently and specifically trypsin- and chymotrypsin-like proteases, are currently being investigated as colorectal chemopreventive agents. Physiologically relevant amounts of Bowman-Birk inhibitors (BBI) can reach the large intestine in active form due to their extraordinary resistance to extreme conditions within the GIT. Studies in animal models have proven that dietary BBI from several legume sources, including soybean, pea, lentil and chickpea, can prevent or suppress carcinogenic and inflammatory processes within the GIT. Although the therapeutic targets and the action mechanism of BBI have not yet been elucidated, the emerging evidence suggests that BBI exert their preventive properties via protease inhibition; in this sense, serine proteases should be considered as primary targets in early stages of carcinogenesis. The validation of candidate serine proteases as therapeutic targets together with the identification, within the wide array of natural BBI variants, of the most potent and specific protease inhibitors, are necessary to better understand the potential of this protein family as colorectal chemopreventive agents. PMID:25132747

  9. About the Chemopreventive Agent Development Research Group | Division of Cancer Prevention

    Cancer.gov

    The Chemopreventive Agent Development Research Group promotes and supports research on early chemopreventive agent development, from preclinical studies to phase I clinical trials. The group’s projects aim to identify and develop prevention agents with the potential to block, reverse, or delay the early stages of cancer. The overarching goal is to determine positive and negative predictive values of preclinical models for clinical development. |

  10. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents

    SciTech Connect

    Higgins, Larry G.; Kelleher, Michael O.; Eggleston, Ian M.; Itoh, Ken; Yamamoto, Masayuki; Hayes, John D.

    2009-06-15

    Sulforaphane can stimulate cellular adaptation to redox stressors through transcription factor Nrf2. Using mouse embryonic fibroblasts (MEFs) as a model, we show herein that the normal homeostatic level of glutathione in Nrf2{sup -/-} MEFs was only 20% of that in their wild-type counterparts. Furthermore, the rate of glutathione synthesis following its acute depletion upon treatment with 3 {mu}mol/l sulforaphane was very substantially lower in Nrf2{sup -/-} MEFs than in wild-type cells, and the rebound leading to a {approx} 1.9-fold increase in glutathione that occurred 12-24 h after Nrf2{sup +/+} MEFs were treated with sulforaphane was not observed in Nrf2{sup -/-} fibroblasts. Wild-type MEFs that had been pre-treated for 24 h with 3 {mu}mol/l sulforaphane exhibited between 1.4- and 3.2-fold resistance against thiol-reactive electrophiles, including isothiocyanates, {alpha},{beta}-unsaturated carbonyl compounds (e.g. acrolein), aryl halides and alkene epoxides. Pre-treatment of Nrf2{sup +/+} MEFs with sulforaphane also protected against hydroperoxides (e.g. cumene hydroperoxide, CuOOH), free radical-generating compounds (e.g. menadione), and genotoxic electrophiles (e.g. chlorambucil). By contrast, Nrf2{sup -/-} MEFs were typically {approx} 50% less tolerant of these agents than wild-type fibroblasts, and sulforaphane pre-treatment did not protect the mutant cells against xenobiotics. To test whether Nrf2-mediated up-regulation of glutathione represents the major cytoprotective mechanism stimulated by sulforaphane, 5 {mu}mol/l buthionine sulfoximine (BSO) was used to inhibit glutathione synthesis. In Nrf2{sup +/+} MEFs pre-treated with sulforaphane, BSO diminished intrinsic resistance and abolished inducible resistance to acrolein, CuOOH and chlorambucil, but not menadione. Thus Nrf2-dependent up-regulation of GSH is the principal mechanism by which sulforaphane pre-treatment induced resistance to acrolein, CuOOH and chlorambucil, but not menadione.

  11. Prolonged sulforaphane treatment activates survival signaling in nontumorigenic NCM460 colon cells but apoptotic signaling in tumorigenic HCT116 colon cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sulforaphane (SFN) is a naturally occurring member of the isothiocyanate family of chemopreventive agents and the induction of cell cycle arrest and apoptosis is a key mechanism by which SFN exerts its colon cancer prevention. However, little is known about the differential effects of SFN on colon c...

  12. Prolonged Sulforaphane Treatment Activates Extracellular-Regulated Kinase 1/2 Signaling in Nontumorigenic Colon Cells but not Colon Cancer Cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sulforaphane (SFN) is a naturally occurring member of the isothiocyanate family of chemopreventive agents and the induction of cell cycle arrest and apoptosis is a key mechanism by which SFN exerts its colon cancer prevention. However, little is known about the differential effects of SFN on colon c...

  13. Big Punches Come in Nanosizes for Chemoprevention

    PubMed Central

    Sharma, Dipali; Sukumar, Saraswati

    2014-01-01

    Literature to support the chemopreventive potential of several bioactive molecules has been prolific and convincing, but the clinical development of these agents has been slow. Major hurdles for development of bioactive chemoprevention approaches include low potency, lack of reliable formulations with high bioavailability that are suitable for oral administration, and relevant preclinical primary prevention models that use meaningful doses that can be translated to humans. The paper presented in this issue (Grandhi and colleagues) is an important step forward in this direction. It shows the efficacy of an oral, low dose, solid-lipid nanoparticles encapsulated curcumin and aspirin combined with free sulforaphane for long-term chemoprevention of pancreatic cancer in a carcinogen-induced hamster model. Reproducing this benefit in multiple cancer models, accompanied by development of intermediate markers of response will allow rapid translation of these findings. It will constitute the first successful multipronged attack at key pathways known to initiate and promote carcinogenesis. PMID:24072677

  14. Determining efficacy of cancer chemopreventive agents using a cell-free system concomitant with DNA adduction.

    PubMed

    Smith, W A; Gupta, R C

    1999-03-10

    The large (>2000) and expanding number of natural and synthetic agents with potential cancer chemopreventive properties renders it economically and physically impossible to test each of these agents for their efficacy in the widely accepted 2-year animal bioassay and clinical trials. Therefore, there is a growing need for relevant short-term screening tests to study these compounds such that only the most efficacious ones undergo extensive long-term studies. We have previously reported in a pilot study that the use of a microsome-mediated test system concomitant with DNA adduction is a pertinent and relevant model for rapidly studying the efficacy and mechanisms of cancer chemopreventive agents. We have extended this study to investigate 26 additional agents for their potential chemopreventive abilities by studying their effects on microsome-mediated benzo[a]pyrene (BP)-DNA adduction. These agents had differential effects on the two major adducts of BP-DNA, i.e., BP-7,8-diol-9,10-epoxide (BPDE)-deoxyguanosine (dG) and 9-OH-BP-dG-derived adducts. These agents were therefore categorized into five classes. Three test agents (ellagic acid, genistein and oltipraz) were strong inhibitors of both adducts. These agents diminished BP-DNA adduction by 65-95% and were categorized as Class I agents. Six other agents (benzyl isocyanate, R(+)-1-phenylethyl isocyanate, linoleic acid ethyl ester, (+)-biotin, indole-3-carboxylic acid and beta-carotene) moderately inhibited both BP-DNA adducts (25-64%); these compounds were identified as Class II agents. Six additional test agents inhibited only one adduct selectively and nine others were ineffective; these agents were categorized as Class III and Class IV, respectively. Interestingly, seven test agents enhanced BPDE-dG or 9-OH-BP-dG or both adducts and were categorized as Class V agents. Four of these Class V agents concomitantly inhibited BPDE-dG while enhancing 9-OH-BP-dG. This emphasizes the importance of studying individual DNA

  15. Development of dietary phytochemical chemopreventive agents: biomarkers and choice of dose for early clinical trials.

    PubMed

    Scott, Edwina N; Gescher, Andreas J; Steward, William P; Brown, Karen

    2009-06-01

    In view of safety concerns surrounding the use of pharmaceuticals such as nonsteroidal anti-inflammatory drugs and tamoxifen as cancer chemopreventive agents, potentially innocuous phytochemicals derived from the diet are considered attractive alternatives. However, results from cancer chemoprevention trials of dietary agents have been disappointing to date, as promising activities observed in rodent models and cells in vitro have not translated into clinical success. This may be partly due to the development process for these agents, which is complex for a number of reasons; the definitive end point, inhibition of carcinogenesis, requires large numbers of individuals followed-up over many years. Furthermore, whereas biomarkers are frequently used as surrogate efficacy end points to expedite the process, biomarker assessment and validation has proven difficult because dietary agents exert multiple actions with an unknown hierarchy of biological importance. These factors have made determining the dose for clinical investigation extremely challenging, and at present, there are no defined strategies for rationally identifying the most appropriate doses. In this commentary, the complexities involved in the development of dietary chemoprevention agents are discussed, and a tentative route towards selection of the optimal clinical dose is proposed. The approach highlights the need to conduct long-term preclinical studies with realistic concentrations that are achievable in human tissues and the importance of efficacy biomarkers that are intrinsically linked to the key mechanisms of action. A more logical design of studies should increase the likelihood that the encouraging preclinical results observed for many phytochemicals translate into tangible clinical benefit. PMID:19470784

  16. Plant Polyphenols as Chemopreventive Agents for Lung Cancer

    PubMed Central

    Amararathna, Madumani; Johnston, Michael R.; Rupasinghe, H. P. Vasantha

    2016-01-01

    Lung cancer may be prevented by a diet rich in fruits and vegetables as they are enriched with dietary antioxidant polyphenols, such as flavonoids, proanthocyanidins, lignans, stilbenes, and phenolic acids. Dietary polyphenols exert a wide range of beneficial biological functions beyond their antioxidative properties and are involved in regulation of cell survival pathways leading to anticarcinogenic and antimutagenic functions. There are sufficient evidence from in vitro, in vivo, and epidemiological studies to suggest that the dietary intervention of polyphenols in cancer prevention, including the chemopreventive ability of dietary polyphenols, act against lung carcinogens. Cohort and epidemiological studies in selected risk populations have evaluated clinical effects of polyphenols. Polyphenols have demonstrated three major actions: antioxidative activity, regulation of phase I and II enzymes, and regulation of cell survival pathways against lung carcinogenesis. They have also shown an inverse association of lung cancer occurrences among high risk populations who consumed considerable amounts of fruits and vegetables in their daily diet. In in vitro cell culture experimental models, polyphenols bind with electrophilic metabolites from carcinogens, inactivate cellular oxygen radicals, prevent membrane lipid peroxidation and DNA oxidative damage, and adduct formation. Further, polyphenols enhance the detoxifying enzymes such as the phase II enzymes, glutathione transferases and glucuronosyl transferases. PMID:27548149

  17. Chemopreventive Agents from Physalis minima Function as Michael Reaction Acceptors

    PubMed Central

    Men, Ruizhi; Li, Ning; Ding, Chihong; Tang, Yingzhan; Xing, Yachao; Ding, Wanjing; Ma, Zhongjun

    2016-01-01

    Background: The fruits of some varieties of genus Physalis have been used as delicious fruits and functional food in the Northeast of China. Materials and Methods: To reveal the functional material basis, we performed bioactivity-guided phytochemical research and chemopreventive effect assay of the constituents from Physalis minima. Results: It was demonstrated that the ethyl acetate extract of P. minima L. (EEPM) had potential quinone reductase (QR) inducing activity with induction ratio (IR, QR induction activity) value of 1.47 ± 0.24, and glutathione binding property as potential Michael reaction acceptors (with an α, β-unsaturated ketone moiety). Furthermore, bioactivity-guided phytochemical research led eight compounds (1–8), which were elucidated as 3-isopropyl-5-acetoxycyclohexene-2-one-1 (1), isophysalin B (2), physalin G (3), physalin D (4), physalin I (5), physordinose B (6), stigmasterol-3-O-β-D-glucopyranoside (7) and 5α-6β-dihydroxyphysalin R (8) on the basis of nuclear magnetic resonance spectroscopy analyses and HRESIMS. Then, isophysalin B (2) and physordinose B (6) showed significant QR inducing activity with IR value of 2.80 ± 0.19 and 2.38 ± 0.46, respectively. SUMMARY An ultra-performance liquid chromatographic method with glutathione as the substrate was used to detect the Michael reaction acceptors in extracts of Physalis minima (EPM)We investigated the chemical constituents of EPM guided by biological activity methodIsophysalin B (1) and physordinose B (6) showed strong quinone reductase inducing activity with induction ratio values of 2.80 ± 0.19 and 2.38 ± 0.46This study generated useful information for consumers and many encourage researchers to utilize edible fruits from Physalis as a source of phytochemicals Abbreviations used: EPM: Extracts of Physalis minima, EEPM: Ethyl acetate extract of Physalis minima L., GSH: Glutathione, MRAs: Michael reaction acceptors, QR: Quinone reductase. PMID:27279713

  18. Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents.

    PubMed

    Cassady, J M; Baird, W M; Chang, C J

    1990-01-01

    Recent advances in the chemistry of novel bioactive natural products are reported. This research is directed to the exploration of plants with confirmed activity in bioassays designed to detect potential cancer chemotherapeutic and chemopreventive agents. Structural work and chemical studies are reported for several cytotoxic agents from the plants Annona densicoma, Annona reticulata, Claopodium crispifolium, Polytrichum obioense, and Psorospermum febrifugum. Studies are also reported based on development of a mammalian cell culture benzo[a]pyrene metabolism assay for the detection of potential anticarcinogenic agents from natural products. In this study a number of isoflavonoids and flavonoids with antimutagenic activity have been discovered. PMID:2189947

  19. Total synthesis of plagiochin G and derivatives as potential cancer chemopreventive agents

    PubMed Central

    Li, Rui-Juan; Zhao, Yu; Tokuda, Harukuni; Yang, Xiao-Ming; Wang, Yue-Hu; Shi, Qian; Morris-Natschke, Susan L.; Lou, Hong-Xiang; Lee, Kuo-Hsiung

    2014-01-01

    A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein-Barr virus early antigen (EBVEA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents. PMID:25574060

  20. Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression.

    PubMed

    Wargovich, M J; Jimenez, A; McKee, K; Steele, V E; Velasco, M; Woods, J; Price, R; Gray, K; Kelloff, G J

    2000-06-01

    We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis. PMID:10837003

  1. Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

    PubMed Central

    Shan, T.; Ma, Q.; Guo, K.; Liu, J.; Li, W.; Wang, F.; Wu, E.

    2011-01-01

    Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent. PMID:21902651

  2. Tissue autofluorescence spectroscopy: an intermediate endpoint for chemopreventive agents

    NASA Astrophysics Data System (ADS)

    Schantz, Stimson P.; Savage, Howard E.; Sacks, Peter G.; Silverberg, Michael; Lipkin, Martin; Yang, Kan; Tang, Gui C.; Alfano, Robert R.

    1993-08-01

    We report on the fluorescence spectroscopy of a multicellular tumor spheroid treated and non- treated with (beta) -all-trans retinoic acid. Following ten days of treatment with RA (10-6M), reproducible fluorescent changes were measured using a Mediscience CD scanner. The most significant changes included an increase in emission at 520 nm in the RA treated spheroids when excited at 340 nm. When investigating fluorescence emission at 450 nm, a blue shift in the excitation profile was noted. Molecular alterations induced by RA and as measured by optical fluorescence spectroscopy may arise from qualitative and/or quantitative changes in a number of key molecules involved in cellular differentiation, proliferation and/or electron transfer, i.e. NADH at (450 nm emission), flavins (520 nm), or cytokeratins (520 nm). To further explore alterations of cytokeratins, immunohistochemical staining showed an increase in AE1 positive cells induced by RA which paralleled the increased 520 nm signal. Our results indicate that certain vitamin derivatives are capable of modulating the intrinsic fluorescence profile emitted by neoplastic mucosa. Tissue autofluorescence may represent a significant marker for the biologic effect of cancer preventing agents in clinical trials.

  3. Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract

    PubMed Central

    Atwell, Lauren L.; Hsu, Anna; Wong, Carmen P.; Stevens, Jan F.; Bella, Deborah; Yu, Tian-Wei; Pereira, Clifford B.; Löhr, Christiane V.; Christensen, John Mark; Dashwood, Roderick H.; Williams, David E.; Shannon, Jackilen; Ho, Emily

    2015-01-01

    Scope Sulforaphane (SFN), an isothiocyanate derived from crucifers, has numerous health benefits. SFN bioavailability from dietary sources is a critical determinant of its efficacy in humans. A key factor in SFN absorption is the release of SFN from its glucosinolate precursor, glucoraphanin, by myrosinase. Dietary supplements are used in clinical trials to deliver consistent SFN doses, but myrosinase is often inactivated in available supplements. We evaluated SFN absorption from a myrosinase-treated broccoli sprout extract (BSE) and are the first to report effects of twice daily, oral dosing on SFN exposure in healthy adults. Methods and results Subjects consumed fresh broccoli sprouts or the BSE, each providing 200 μmol SFN daily, as a single dose and as two 100-μmol doses taken 12 h apart. Using HPLC-MS/MS, we detected ~3 x higher SFN metabolite levels in plasma and urine of sprout consumers, indicating enhanced SFN absorption from sprouts. Twelve-hour dosing retained higher plasma SFN metabolite levels at later time points than 24-hour dosing. No dose responses were observed for molecular targets of SFN (i.e. heme oxygenase-1, histone deacetylase activity, p21). Conclusion We conclude that the dietary form and dosing schedule of SFN may impact SFN absorption and efficacy in human trials. PMID:25522265

  4. Curcumin as a therapeutic agent in the chemoprevention of inflammatory bowel disease.

    PubMed

    Sreedhar, Remya; Arumugam, Somasundaram; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Watanabe, Kenichi

    2016-05-01

    Inflammatory bowel diseases (IBD), mainly Crohn's disease (CD) and ulcerative colitis (UC) are chronic ailments of the gastrointestinal tract, characterized by recurrent inflammation. Current therapeutic strategies are based on the mitigation of symptoms, including inflammatory remission and healing of mucosal manifestations. Extensive studies have suggested that continuous oxidative damage can lead to the inflammatory signaling cascade in IBD. Curcumin, a potent modulator of cell signaling, is popular for its antioxidant and anti-inflammatory activities, and has already been shown remarkable therapeutic results in IBD. Here, we review and discuss the effects of curcumin as a therapeutic agent in the chemoprevention of IBD. PMID:26995272

  5. Targeting NRF2 signaling for cancer chemoprevention

    SciTech Connect

    Kwak, Mi-Kyoung; Kensler, Thomas W.

    2010-04-01

    Modulation of the metabolism and disposition of carcinogens through induction of cytoprotective enzymes is one of several promising strategies to prevent cancer. Chemopreventive efficacies of inducers such as dithiolethiones and sulforaphane have been extensively studied in animals as well as in humans. The KEAP1-NRF2 system is a key, but not unilateral, molecular target for these chemopreventive agents. The transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of the expression of a subset of genes, which produce proteins responsible for the detoxication of electrophiles and reactive oxygen species as well as the removal or repair of some of their damage products. It is believed that chemopreventive enzyme inducers affect the interaction between KEAP1 and NRF2 through either mediating conformational changes of the KEAP1 protein or activating phosphorylation cascades targeting the KEAP1-NRF2 complex. These events in turn affect NRF2 stability and trafficking. Recent advances elucidating the underlying structural biology of KEAP1-NRF2 signaling and identification of the gene clusters under the transcriptional control of NRF2 are facilitating understanding of the potential pleiotropic effects of NRF2 activators and discovery of novel classes of potent chemopreventive agents such as the triterpenoids. Although there is appropriately a concern regarding a deleterious role of the KEAP1-NRF2 system in cancer cell biology, especially as the pathway affects cell survival and drug resistance, the development and the use of NRF2 activators as chemopreventive agents still holds a great promise for protection of normal cells from a diversity of environmental stresses that contribute to the burden of cancer and other chronic, degenerative diseases.

  6. Dietary pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer

    PubMed Central

    Zhang, Liangfen; Rimando, Agnes M.; Lage, Janice M.; Lewin, Jack R.; Atfi, Azeddine; Zhang, Xu; Levenson, Anait S.

    2016-01-01

    Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1- targeted chemopreventive and therapeutic efficacy of pterostilbene, a natural potent analog of resveratrol, in pre-clinical models of prostate cancer. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. Loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis. This restrained prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice and reduced tumor development and progression in prostate-specific Pten-null mice. Our findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. More significantly, it offers pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer. PMID:26943043

  7. Chemopreventive Agents Attenuate Rapid Inhibition of Gap Junctional Intercellular Communication Induced by Environmental Toxicants.

    PubMed

    Babica, Pavel; Čtveráčková, Lucie; Lenčešová, Zuzana; Trosko, James E; Upham, Brad L

    2016-07-01

    Altered gap junctional intercellular communication (GJIC) has been associated with chemical carcinogenesis, where both chemical tumor promoters and chemopreventive agents (CPAs) are known to conversely modulate GJIC. The aim of this study was to investigate whether attenuation of chemically inhibited GJIC represents a common outcome induced by different CPAs, which could be effectively evaluated using in vitro methods. Rat liver epithelial cells WB-F344 were pretreated with a CPA for either 30 min or 24 h, and then exposed to GJIC-inhibiting concentration of a selected tumor promoter or environmental toxicant [12-O-tetradecanoylphorbol-13-acetate (TPA), lindane, fluoranthene, 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), perfluorooctanoic acid (PFOA), or pentachlorophenol]. Out of nine CPAs tested, quercetin and silibinin elicited the most pronounced effects, preventing the dysregulation of GJIC by all the GJIC inhibitors, but DDT. Metformin and curcumin attenuated the effects of three GJIC inhibitors, whereas the other CPAs prevented the effects of two (diallyl sulfide, emodin) or one (indole-3-carbinol, thymoquinone) GJIC inhibitor. Significant attenuation of chemically induced inhibition of GJIC was observed in 27 (50%) out of 54 possible combinations of nine CPAs and six GJIC inhibitors. Our data demonstrate that in vitro evaluation of GJIC can be used as an effective screening tool for identification of chemicals with potential chemopreventive activity. PMID:27266532

  8. Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets.

    PubMed

    Narayanan, Bhagavathi A

    2006-12-01

    Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B

  9. Stability of Sulforaphane for Topical Formulation

    PubMed Central

    Franklin, Stephen J.; Dickinson, Sally E.; Karlage, Kelly L.; Bowden, G Tim.; Myrdal, Paul B.

    2013-01-01

    Sulforaphane (SFN) is a natural compound that has been investigated as a chemopreventive agent. SFN has been shown to inhibit the activator-protein-1 (AP-1) transcription factor and may be effective for inhibition of ultraviolet (UV) induced skin carcinogenesis. This study was designed to investigate the stability of SFN as a function of pH, temperature and in various solvents and formulations. SFN was determined to undergo apparent first order degradation kinetics for the conditions explored. It was observed that SFN undergoes base catalyzed degradation. Buffer species and solvent type impacts stability as well. SFN was found to be very sensitive to temperature with degradation rate changing by a factor of nearly 3.1 for every 10°C change in temperature (at pH 4.0). SFN completely degraded after 30 days in a conventional pharmaceutical cream formulation. Improved stability was observed in organic formulation components. Stability studies were conducted on two non-aqueous topical formulations, a polyethylene glycol (PEG) ointment base and an organic oleaginous base. Topically applied SFN in the PEG base formulation significantly reduced AP-1 activation after UV stimulation in the skin of a transgenic mouse model, indicating that SFN in this formulation retains efficacy in vivo. PMID:23611476

  10. Sulforaphane as a promising molecule for fighting cancer.

    PubMed

    Lenzi, Monia; Fimognari, Carmela; Hrelia, Patrizia

    2014-01-01

    Cancer is a complex disease characterized by multiple genetic and molecular alterations involving transformation, deregulation of apoptosis, proliferation, invasion, angiogenesis, and metastasis. To grow, invade, and metastasize, tumors need host components and primary dysfunction in the tumor microenvironment, in addition to cell dysfunction, can be crucial for carcinogenesis. A great variety of phytochemicals have been shown to be potentially capable of inhibiting and modulating several relevant targets simultaneously and is therefore non-specific. Because of the enormous biological diversity of cancer, this pleiotropism might constitute an advantage. Phytochemicals, in particular diet-derived compounds, have therefore been proposed and applied in clinical trials as cancer chemopreventive/chemotherapeutic agents. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables. SFN has proved to be an effective chemoprotective agent in cell culture, in carcinogen-induced and genetic animal cancer models, as well as in xenograft models of cancer. It promoted potent cytostatic and cytotoxic effects orchestrated by the modulation of different molecular targets. Cell vulnerability to SFN-mediated apoptosis was subject to regulation by cell-cycle-dependent mechanisms but was independent of a mutated p53 status. Moreover, combination of SFN with cytotoxic therapy potentiated the cytotoxic effect mediated by chemotherapy in vitro, thus suggesting its potential therapeutic benefit in clinical settings. Overall, SFN appears to be an effective and safe chemopreventive molecule and a promising tool to fight cancer. PMID:24114482

  11. Sites of Alkylation of Human Keap1 by Natural Chemoprevention Agents

    PubMed Central

    Luo, Yan; Eggler, Aimee L.; Liu, Dongting; Liu, Guowen; Mesecar, Andrew D.; van Breemen, Richard B.

    2007-01-01

    Under basal conditions, the interaction of the cytosolic protein Keap1 with the transcription factor Nrf2 results in a low level of expression of cytoprotective genes whose promoter region contains the antioxidant response element (ARE). Alkylation of one or more of the 27 cysteine sulfhydryl groups of human Keap1 is proposed to lead to Nrf2 nuclear accumulation, to upregulation of cytoprotective gene expression via the ARE, and to prevention of degenerative diseases, such as cancer. Therefore, identification of the most reactive of these cysteine residues towards specific electrophiles should help clarify this mechanism of cancer prevention, also known as chemoprevention. To address this issue, preliminary analyses of tryptic digests of Keap1 alkylated by the model electrophile 1-biotinamido-4-(4′-[maleimidoethyl-cyclohexane]-carboxamido) butane were carried out using LC-MS/MS with a cylindrical ion trap mass spectrometer and also using LC-MS/MS with a hybrid linear ion trap FT ICR mass spectrometer. Since the FT ICR instrument provided more complete peptide sequencing coverage and enabled the identification of more alkylated cysteine residues, only this instrument was used in subsequent studies of Keap1 alkylation by three electrophilic natural products that can up-regulate the ARE, xanthohumol, isoliquiritigenin and 10-shogaol. Among the various cysteine residues of Keap1, C151 was most reactive towards these three electrophiles. These in vitro results agree with evidence from in vivo experiments, and indicate that C151 is the most important site of alkylation on Keap1 by chemoprevention agents that function by activating the ARE through Nrf2. PMID:17980616

  12. Phytochemical Modulators of Mitochondria: The Search for Chemopreventive Agents and Supportive Therapeutics

    PubMed Central

    Grabacka, Maja M.; Gawin, Malgorzata; Pierzchalska, Malgorzata

    2014-01-01

    Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders and chronic inflammation. Currently, in parallel to the classical drug design approaches, there is an increasing interest in the screening for natural bioactive substances, mainly phytochemicals, in order to develop new therapeutic solutions for the mentioned pathologies. Dietary phytochemicals such as resveratrol, curcumin and sulforaphane are very well tolerated and can effectively complement classical pharmacological therapeutic regimens. In this paper we disscuss the effect of the chosen phytochemicals (e.g., resveratrol, curcumin, sulforaphane) on various aspects of mitochondrial biology, namely mitochondrial biogenesis, membrane potential and reactive oxygen species production, signaling to and from the nucleus and unfolded protein response. PMID:25192192

  13. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer

    PubMed Central

    Bishayee, Anupam; Ahmed, Shamima; Brankov, Nikoleta; Perloff, Marjorie

    2010-01-01

    Breast cancer remains a major cause of death in the United States as well as the rest of the world. In view of the limited treatment options for patients with advanced breast cancer, preventive and novel therapeutic approaches play an important role in combating this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, posses various pharmacological properties. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells as well as anticancer efficacy in preclinical animal models. Numerous triterpenoids have been synthesized by structural modification of natural compounds. Some of these analogs are considered to be the most potent antiinflammatory and anticarcinogenic triterpenoids known. This review examines the potential role of natural triterpenoids and their derivatives in the chemoprevention and treatment of mammary tumors. Both in vitro and in vivo effects of these agents and related molecular mechanisms are presented. Potential challenges and future directions involved in the advancement of these promising compounds in the prevention and therapy of human breast cancer are also identified. PMID:21196213

  14. Topical Polyethylene Glycol as a Novel Chemopreventive Agent for Oral Cancer via Targeting of Epidermal Growth Factor Response

    PubMed Central

    Wali, Ramesh K.; Kunte, Dhananjay P.; De La Cruz, Mart; Tiwari, Ashish K.; Brasky, Jeffrey; Weber, Christopher R.; Gibson, Tina P.; Patel, Amir; Savkovic, Suzana D.; Brockstein, Bruce E.; Roy, Hemant K.

    2012-01-01

    Head and neck squamous cell carcinoma (HNSCC) is a major cause of morbidity and mortality underscoring the need for safe and effective chemopreventive strategies. Targeting epidermal growth factor receptor (EGFR) is attractive in that it is an early critical event in HNSCC pathogenesis. However, current agents lack efficacy or have unacceptable toxicity. Several groups have demonstrated that the over-the-counter medication, polyethylene glycol (PEG) has remarkable chemopreventive efficacy against colon carcinogenesis. Importantly, we reported that this effect is mediated through EGFR internalization/degradation. In the current study, we investigated the chemopreventive efficacy of this agent against HNSCC, using both the well validated animal model 4-NQO (4-nitroquinoline 1-oxide) rat model and cell culture with the human HNSCC cell line SCC-25. We demonstrated that daily topical application of 10% PEG-8000 in the oral cavity (tongue and cavity wall) post 4NQO initiation resulted in a significant reduction in tumor burden (both, tumor size and tumors/tumor bearing rat) without any evidence of toxicity. Immunohistochemical studies depicted decreased proliferation (number of Ki67-positive cells) and reduced expression of EGFR and its downstream effectors cyclin D1 in the tongue mucosa of 4NQO-rats treated with PEG. We showed that EGFR was also markedly downregulated in SCC-25 cells by PEG-8000 with a concomitant induction of G1-S phase cell-cycle arrest, which was potentially mediated through upregulated p21cip1/waf1. In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis. PMID:22675506

  15. Dietary Glucosinolates Sulforaphane, Phenethyl Isothiocyanate, Indole-3-Carbinol/3,3′-Diindolylmethane: Anti-Oxidative Stress/Inflammation, Nrf2, Epigenetics/Epigenomics and In Vivo Cancer Chemopreventive Efficacy

    PubMed Central

    Fuentes, Francisco; Paredes-Gonzalez, Ximena; Kong, Ah-Ng Tony

    2015-01-01

    Glucosinolates are a group of sulfur-containing glycosides found in many plant species, including cruciferous vegetables such as broccoli, cabbage, brussels sprouts, and cauliflower. Accumulating evidence increasingly supports the beneficial effects of dietary glucosinolates on overall health, including as potential anti-cancer agents, because of their role in the prevention of the initiation of carcinogenesis via the induction of cellular defense detoxifying/antioxidant enzymes and their epigenetic mechanisms, including modification of the CpG methylation of cancer-related genes, histone modification regulation and changes in the expression of miRNAs. In this context, the defense mechanism mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against oxidative stress and reactive metabolites of carcinogens. In this review, we summarize the cancer chemopreventive role of naturally occurring glucosinolate derivatives as inhibitors of carcinogenesis, with particular emphasis on specific molecular targets and epigenetic alterations in in vitro and in vivo human cancer animal models. PMID:26457242

  16. Characterization of chemopreventive agents from the dichloromethane extract of Eurycorymbus cavaleriei by liquid chromatography-ion trap mass spectrometry.

    PubMed

    Cheng, Lin; Zhang, Xiaoyu; Zhang, Min; Zhang, Peng; Song, Zhihang; Ma, Zhongjun; Cheng, Yiyu; Qu, Haibin

    2009-06-12

    In the present study, we examined the potential chemopreventive activity of dichloromethane extract of Eurycorymbus cavaleriei by investigating the change of constitutions after incubation with glutathione (GSH). The major constitutions in the dichloromethane extract of E. cavaleriei were cumarin compounds and their cleavage pattern was examined by LC-MS-MS and the characteristic product ions at m/z 206 and 207 were helpful to determine the substitutions of coumarinolignoid compounds. The mechanism of conjugations of 5'-demethylaquillochin and its isomer with GSH was discussed and validated through analysis of the conjugations of reference compound 6-hydroxy-7-methoxycoumarin with GSH by LC-MS-MS and NMR spectrum. The relative ability to induce the detoxification enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1) of nine coumarin compounds was tested which also showed 5'-demethylaquillochin exhibited the most potential chemopreventive ability. These observations suggest that 5'-demethylaquillochin and its isomer from the dichloromethane extract of E. cavaleriei have potential as chemopreventive agents through induction of detoxification enzymes. PMID:19439309

  17. Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism.

    PubMed

    Greaney, Allison J; Maier, Nolan K; Leppla, Stephen H; Moayeri, Mahtab

    2016-01-01

    The inflammasomes are intracellular complexes that have an important role in cytosolic innate immune sensing and pathogen defense. Inflammasome sensors detect a diversity of intracellular microbial ligands and endogenous danger signals and activate caspase-1, thus initiating maturation and release of the proinflammatory cytokines interleukin-1β and interleukin-18. These events, although crucial to the innate immune response, have also been linked to the pathology of several inflammatory and autoimmune disorders. The natural isothiocyanate sulforaphane, present in broccoli sprouts and available as a dietary supplement, has gained attention for its antioxidant, anti-inflammatory, and chemopreventive properties. We discovered that sulforaphane inhibits caspase-1 autoproteolytic activation and interleukin-1β maturation and secretion downstream of the nucleotide-binding oligomerization domain-like receptor leucine-rich repeat proteins NLRP1 and NLRP3, NLR family apoptosis inhibitory protein 5/NLR family caspase-1 recruitment domain-containing protein 4 (NAIP5/NLRC4), and absent in melanoma 2 (AIM2) inflammasome receptors. Sulforaphane does not inhibit the inflammasome by direct modification of active caspase-1 and its mechanism is not dependent on protein degradation by the proteasome or de novo protein synthesis. Furthermore, sulforaphane-mediated inhibition of the inflammasomes is independent of the transcription factor nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and the antioxidant response-element pathway, to which many of the antioxidant and anti-inflammatory effects of sulforaphane have been attributed. Sulforaphane was also found to inhibit cell recruitment to the peritoneum and interleukin-1β secretion in an in vivo peritonitis model of acute gout and to reverse NLRP1-mediated murine resistance to Bacillus anthracis spore infection. These findings demonstrate that sulforaphane inhibits the inflammasomes through a novel mechanism and contributes to

  18. Antibody Array as a Tool for Screening of Natural Agents in Cancer Chemoprevention.

    PubMed

    Pulito, Claudio; Sacconi, Andrea; Korita, Etleva; Maidecchi, Anna; Strano, Sabrina

    2016-01-01

    The efficacy of a given drug resides mainly on its ability to specifically target disease mechanisms. Natural products represent the leading source of bioactive molecules with a broad range of activities. It is becoming increasingly clear that natural compounds exert their chemopreventive or antitumoral activities targeting simultaneously diverse cellular pathways. Here we describe the use of antibody array to assess the effects of natural compounds on the expression of multiple proteins and of their posttranslational modifications in cellular systems. This might turn to be a very flexible application for cancer chemoprevention studies. PMID:26608301

  19. Perspectives in cancer chemoprevention.

    PubMed Central

    Stoner, G D; Morse, M A; Kelloff, G J

    1997-01-01

    Cancer chemoprevention can be defined as prevention of cancer by the administration of one or more chemical entities, either as individual drugs or as naturally occurring constituents of the diet. Based largely on the time period that chemopreventive agents exhibit activity in animal models of carcinogenesis, they can be classified as inhibitors of carcinogen formation, blocking agents, and suppressing agents. The majority of compounds that inhibit the formation of carcinogens prevent the formation of nitrosamines from secondary amines and nitrite in an acidic environment. Blocking agents are inhibitors of tumor initiation, while suppressing agents are inhibitors of tumor promotion/progression. Many well-characterized chemopreventive agents act at one or more steps in both tumor initiation and promotion/progression. The objective of this paper is to provide a general discussion of the mechanisms through which chemopreventive agents inhibit carcinogenesis. Examples of agents that act through these mechanisms are given; however, a complete listing of effective chemopreventive agents is not possible within the context of this paper. At the conclusion is a brief discussion of future prospects in cancer chemoprevention and obstacles to overcome. PMID:9255586

  20. Dietary Pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary nutrients with ability to reverse adverse epigenetic events have great potential for cancer chemoprevention. Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1-d...

  1. In vivo phase II-enzymes inducers, as potential chemopreventive agents, based on the chalcone and furoxan skeletons.

    PubMed

    Cabrera, Mauricio; Mastandrea, Ignacio; Otero, Gabriel; Cerecetto, Hugo; González, Mercedes

    2016-04-15

    Cancer chemoprevention involves prevention/delay/reverse of the carcinogenic process through administration of cancer chemopreventive agents (CCA). Compounds which are able to induce detoxification-enzymes, especially monofunctional phase II enzymes, have become in excellent approaches for new CCA. Herein, we report the synthesis of new furoxanyl chalcone-like hybrid compounds as CCA. In vitro studies showed that phenylfuroxanyl derivatives 6 and 9 displayed the best activities being 9 the greatest monofunctional-inducer. Additionally, compounds were non-mutagenic against TA98 Salmonella typhimurium strain (Ames test) and could be used in the prevention of the progression of pre-malignant lesions for their cytotoxic activity against tumoral cells. In vivo proof of concept showed increment on phase II-enzymes activities in liver, colon and mammary gland having derivative 9 the best induction profiles. We probed Nrf2 nuclear translocation is operative for both compounds allowing to exert protective effects via expression of downstream phase-II enzymes. PMID:26970663

  2. Inhibition of endothelial cell functions by novel potential cancer chemopreventive agents.

    PubMed

    Bertl, Elisabeth; Becker, Hans; Eicher, Theophil; Herhaus, Christian; Kapadia, Govind; Bartsch, Helmut; Gerhäuser, Clarissa

    2004-12-01

    Endothelial cells (EC) play a major role in tumor-induced neovascularization and bridge the gap between a microtumor and growth factors such as nutrients and oxygen supply required for expansion. Immortalized human microvascular endothelial cells (HMEC-1) were utilized to assess anti-endothelial effects of 10 novel potential cancer chemopreventive compounds from various sources that we have investigated previously in a human in vitro anti-angiogenic assay. These include the monoacylphloroglucinol isoaspidinol B, 1,2,5,7-tetrahydroxy-anthraquinone, peracetylated carnosic acid (PCA), isoxanthohumol, 2,2',4'-trimethoxychalcone, 3'-bromo-2,4-dimethoxychalcone as well as four synthetic derivatives of lunularic acid, a bibenzyl found in mosses [Int. J. Cancer Prev. 1 (2004) 47]. EC proliferation was inhibited with half-maximal inhibitory concentrations from 0.3 to 49.6muM, whereas EC migration was affected by most compounds at sub-micromolar concentrations. PCA and the bibenzyl derivative EC 1004 potently prevented differentiation of HMEC-1 into tubule-like structures. Overall, our data indicate that inhibition of endothelial cell function contributes to various extents to the chemopreventive or anti-angiogenic potential of these lead compounds. PMID:15522231

  3. Sugar-borate esters--potential chemical agents in prostate cancer chemoprevention.

    PubMed

    Scorei, Romulus Ion; Popa, Radu

    2013-07-01

    The potential value of sugar-borate esters (SBEs) in the chemo-preventive therapy of prostate cancer has been reviewed. We propose that SBEs act as boron (B) vehicles, increasing the concentration of borate inside cancer cells relative to normal cells. Increased intracellular concentration of borate activates borate transporters, but also leads to growth inhibition and apoptosis. The effects of SBEs on normal cells are less dramatic because SBEs are naturally-occurring biochemicals, common and abundant in some fruits and vegetables, and also because borate dissociated from SBEs in natural diet doses is easily exported from normal cells. Cancer cell lines that over-express sugar transporters or under-express borate export are potential targets for SBE-based therapy. With regard to efficiency against cancer cells and drug preparation requirements, trigonal cis-diol boric monoesters will be one of the most effective class of SBEs. Because negative correlation exists between borate intake and the incidence of prostate cancer, and because most cancer cells overexpress sugar transporters, SBEs are proposed as a potential chemopreventive avenue in the fight against primary and recurrent prostate cancer. PMID:23293883

  4. α-Santalol, a skin cancer chemopreventive agent with potential to target various pathways involved in photocarcinogenesis.

    PubMed

    Santha, Sreevidya; Dwivedi, Chandradhar

    2013-01-01

    This study is designed to investigate the chemopreventive effect and molecular mechanisms of α-santalol on UVB-induced skin tumor development in SKH-1 hairless mouse, a widely used model for human photocarcinogenesis. A dose of UVB radiation (30 mJ cm(-2) day(-1)) that is in the range of human sunlight exposure was used for the initiation and promotion of tumor. Topical treatment of mice with α-santalol (10%, wt/vol in acetone) caused reduction in tumor incidence, multiplicity and volume. In our study, the anticarcinogenic action of α-santalol against UVB-induced photocarcinogenesis was found to be associated with inhibition of inflammation and epidermal cell proliferation, cell cycle arrest and induction of apoptosis. α-Santalol pretreatment strongly inhibited UVB-induced epidermal hyperplasia and thickness of the epidermis, expression of proliferation and inflammation markers proliferating cell nuclear antigen (PCNA), Ki-67 and cyclooxygenase 2 (Cox-2). Significant decrease in the expression of cyclins A, B1, D1 and D2 and cyclin-dependent kinases (Cdk)s Cdk1 (Cdc2), Cdk2, Cdk4 and Cdk6 and an upregulated expression of cyclin-dependent kinase (CDK) inhibitor Cip1/p21 were found in α-santalol pretreated group. Furthermore, an elevated level of cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) were observed in α-santalol-treated group. Our data suggested that α-santalol is a safer and promising skin cancer chemopreventive agent with potential to target various pathways involved in photocarcinogenesis. PMID:23480292

  5. Endoscopic spectral domain optical coherence tomography of murine colonic morphology to determine effectiveness of chemopreventive and chemotherapeutic agents in colorectal cancer

    NASA Astrophysics Data System (ADS)

    LeGendre-McGhee, Susan; Rice, Photini F. S.; Wall, R. Andrew; Klein, Justin; Luttman, Amber; Sprute, Kyle; Gerner, Eugene; Barton, Jennifer K.

    2012-02-01

    Optical coherence tomography (OCT) is a minimally-invasive imaging modality capable of tracking the development of individual colonic adenomas. As such, OCT can be used to evaluate the mechanisms and effectiveness of chemopreventive and chemotherapeutic agents in colorectal cancer models. The data presented here represent part of a larger study evaluating α-difluoromethylornithine (DFMO) and Sulindac as chemopreventive and chemotherapeutic agents using mice treated with the carcinogen azoxymethane (AOM). 27 A/J mice were included in the chemoprevention study, subdivided into four treatment groups (No Drug, DFMO, Sulindac, DFMO/Sulindac). 30 mm lateral images of each colon at eight different rotations were obtained at five different time points using a 2 mm diameter spectral domain OCT endoscopy system centered at 890 nm with 3.5 μm axial resolution in air and 5 μm lateral resolution. Images were visually analyzed to determine number and size of adenomas. Gross photos of the excised colons and histology provided gold standard confirmation of the final imaging time point. Preliminary results show that 100% of mice in the No Drug group developed adenomas over the course of the chemoprevention study. Incidence was reduced to 71.43% in mice given DFMO, 85.71% for Sulindac and 0% for DFMO/Sulindac. Discrete adenoma size did not vary significantly between experimental groups. Additional experiments are currently under way to verify these results and evaluate DFMO and Sulindac for chemotherapeutic applications.

  6. Lung cancer chemoprevention.

    PubMed

    Keith, Robert L

    2012-05-01

    Lung cancer is the leading cause of cancer death in the United States, and the majority of diagnoses are made in former smokers. Although avoidance of tobacco abuse and smoking cessation clearly will have the greatest impact on lung cancer development, effective chemoprevention could prove to be more effective than treatment of established, advanced-stage disease. Chemoprevention is the use of dietary or pharmaceutical agents to reverse or block the carcinogenic process and has been successfully applied to common malignancies other than lung (including recent reports on the prevention of breast cancer in high-risk individuals). Despite previous studies in lung cancer chemoprevention failing to identify effective agents, our ability to define the highest-risk populations and the understanding of lung tumor and premalignant biology continue to make advances. Squamous cell carcinogenesis in the bronchial epithelium starts with normal epithelium and progresses through hyperplasia, metaplasia, dysplasia, and carcinoma in situ to invasive cancer. Precursor lesions also have been identified for adenocarcinoma, and these premalignant lesions are targeted by chemopreventive agents in current and future trials. Chemopreventive agents can currently only be recommended as part of well-designed clinical trials, and multiple trials have recently been completed or are enrolling subjects. PMID:22550242

  7. Sulforaphane: translational research from laboratory bench to clinic.

    PubMed

    Houghton, Christine A; Fassett, Robert G; Coombes, Jeff S

    2013-11-01

    Cruciferous vegetables are widely acknowledged to provide chemopreventive benefits in humans, but they are not generally consumed at levels that effect significant change in biomarkers of health. Because consumers have embraced the notion that dietary supplements may prevent disease, this review considers whether an appropriately validated sulforaphane-yielding broccoli sprout supplement may deliver clinical benefit. The crucifer-derived bioactive phytochemical sulforaphane is a significant inducer of nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor that activates the cell's endogenous defenses via a battery of cytoprotective genes. For a broccoli sprout supplement to demonstrate bioactivity in vivo, it must retain both the sulforaphane-yielding precursor compound, glucoraphanin, and the activity of glucoraphanin's intrinsic myrosinase enzyme. Many broccoli sprout supplements are myrosinase inactive, but current labeling does not reflect this. For the benefit of clinicians and consumers, this review summarizes the findings of in vitro studies and clinical trials, interpreting them in the context of clinical relevance. Standardization of sulforaphane nomenclature and assay protocols will be necessary to remove inconsistency and ambiguity in the labeling of currently available broccoli sprout products. PMID:24147970

  8. Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy

    PubMed Central

    PASTOREK, MICHAL; SIMKO, VERONIKA; TAKACOVA, MARTINA; BARATHOVA, MONIKA; BARTOSOVA, MARIA; HUNAKOVA, LUBA; SEDLAKOVA, OLGA; HUDECOVA, SONA; KRIZANOVA, OLGA; DEQUIEDT, FRANCK; PASTOREKOVA, SILVIA; SEDLAK, JAN

    2015-01-01

    One of the recently emerging anticancer strategies is the use of natural dietary compounds, such as sulforaphane, a cancer-chemopreventive isothiocyanate found in broccoli. Based on the growing evidence, sulforaphane acts through molecular mechanisms that interfere with multiple oncogenic pathways in diverse tumor cell types. Herein, we investigated the anticancer effects of bioavailable concentrations of sulforaphane in ovarian carcinoma cell line A2780 and its two derivatives, adriamycin-resistant A2780/ADR and cisplatin-resistant A2780/CP cell lines. Since tumor microenvironment is characterized by reduced oxygenation that induces aggressive tumor phenotype (such as increased invasiveness and resistance to chemotherapy), we evaluated the effects of sulforaphane in ovarian cancer cells exposed to hypoxia (2% O2). Using the cell-based reporter assay, we identified several oncogenic pathways modulated by sulforaphane in hypoxia by activating anticancer responses (p53, ARE, IRF-1, Pax-6 and XRE) and suppressing responses supporting tumor progression (AP-1 and HIF-1). We further showed that sulforaphane decreases the level of HIF-1α protein without affecting its transcription and stability. It can also diminish transcription and protein level of the HIF-1 target, CA IX, which protects tumor cells from hypoxia-induced pH imbalance and facilitates their migration/invasion. Accordingly, sulforaphane treatment leads to diminished pH regulation and reduced migration of ovarian carcinoma cells. These effects occur in all three ovarian cell lines suggesting that sulforaphane can overcome the chemoresistance of cancer cells. This offers a path potentially exploitable in sensitizing resistant cancer cells to therapy, and opens a window for the combined treatments of sulforaphane either with conventional chemotherapy, natural compounds, or with other small molecules. PMID:25955133

  9. Isolation and Characterization of Chemopreventive Agent from Sphaeranthus amaranthoides Burm F

    PubMed Central

    Gayatri, S.; Suresh, R.; Reddy, C. Uma Maheswara; Chitra, K.

    2016-01-01

    Objective: To investigate the in vitro cytotoxic effect and to isolate and characterize a chemopreventive secondary metabolite from Sphaeranthus amaranthoides Burm F (sivakaranthai). Materials and Methods: In vitro cytotoxic effect was carried out by 3 (4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay. Different concentrations of the extracts were tested on three different cell lines namely A549, HT29, and MCF7. The chloroform extract was subjected to column chromatography, and the isolated compound was characterized by various spectral methods and by single crystal X-ray crystallography. Results: The concentration that cause 50% growth inhibition value of chloroform extract was found to be 0.9 and 19 μg/mL against MCF7 and A549 cell lines, respectively. Chloroform extract was subjected to column chromatography for the isolation of phytoconstituent. The structure of the isolated compound was identified by spectroscopic techniques such as infrared, nuclear magnetic resonance, XRD, and mass spectroscopy. On comparison of complete spectral detail of the compound, the proposed structure was identified as chrysosplenol D (a flavonoid). Chrysosplenol D was isolated for the first time from this plant. Conclusion: The chloroform extract had higher cytotoxic effect, and the isolated chrysosplenol D may be responsible for the anti-proliferative effect of the plant. SUMMARY The plant Sphaeranthus amaranthoides Burm F was extracted with solvents of increasing polarity. The chloroform extract was found to have cell inhibition towards MCF 7 and HT 29 cell lines. This was subjected to fractionation. Chrysosplenol D was isolated from the chloroform extract PMID:26941538

  10. Identification of modulated genes by three classes of chemopreventive agents at preneoplastic stages in a p53-null mouse mammary tumor model

    PubMed Central

    ABBA, MARTÍN C.; HU, YUHUI; LEVY, CARLA C.; GADDIS, SALLY; KITTRELL, FRANCES S.; HILL, JAMAL; BISSONNETTE, REID P.; BROWN, POWEL H.; MEDINA, DANIEL; ALDAZ, C. MARCELO

    2011-01-01

    Genetically engineered mice cancer models are among the most useful tools for testing the in vivo effectiveness of the various chemopreventive approaches. The p53-null mouse model of mammary carcinogenesis was previously characterized by us at the cellular, molecular, and pathological levels. In a companion article, Medina et al. (2009) analyzed the efficacy of bexarotene, gefitinib, and celecoxib as chemopreventive agents in the same model. Here we report the global gene expression effects on mammary epithelium of such compounds, analyzing the data in light of their effectiveness as chemopreventive agents. SAGE was used to profile the transcriptome of p53 null mammary epithelium obtained from mice treated with each compound Vs controls. This information was also compared with SAGE data from p53-null mouse mammary tumors. Gene expression changes induced by the chemopreventive treatments revealed a common core of 87 affected genes across treatments (p<0.05). The effective compounds, bexarotene and gefitinib may at least in part exert their chemopreventive activity by affecting a set of 34 genes related to specific cellular pathways. The gene expression signature revealed various genes previously described to be associated with breast cancer, such as, the AP-1 complex member Fos like antigen 2, Early growth response1, Gelsolin and Tumor protein translationally-controlled 1, among others. The concerted modulation of many of these transcripts prior to malignant transformation appears conducive to predominantly decrease cell proliferation. This study has revealed candidate key pathways that can be experimentally tested in the same model system and may constitute novel targets for future translational research. PMID:19174580

  11. Chemoprevention of lung cancer.

    PubMed

    Keith, Robert L

    2009-04-15

    Lung cancer is the leading cause of cancer death in the United States, and the majority of diagnoses are made in former smokers. While avoidance of tobacco abuse and smoking cessation clearly will have the greatest impact on lung cancer development, effective chemoprevention could prove to be more effective than treatment of established disease. Chemoprevention is the use of dietary or pharmaceutical agents to reverse or inhibit the carcinogenic process and has been successfully applied to common malignancies other than lung. Despite previous studies in lung cancer chemoprevention failing to identify effective agents, our ability to determine higher risk populations and the understanding of lung tumor and pre-malignant biology continues to advance. Additional biomarkers of risk continue to be investigated and validated. The World Health Organization/International Association for the Study of Lung Cancer classification for lung cancer now recognizes distinct histologic lesions that can be reproducibly graded as precursors of non-small cell lung cancer. For example, carcinogenesis in the bronchial epithelium starts with normal epithelium and progresses through hyperplasia, metaplasia, dysplasia, and carcinoma in situ to invasive squamous cell cancer. Similar precursor lesions exist for adenocarcinoma, and these pre-malignant lesions are targeted by chemopreventive agents in current and future trials. At this time, chemopreventive agents can only be recommended as part of well-designed clinical trials, and multiple trials are currently in progress and additional trials are in the planning stages. This review will discuss the principles of chemoprevention, summarize the completed trials, and discuss ongoing and potential future trials with a focus on targeted pathways. PMID:19349487

  12. Stimulation of phagocytosis by sulforaphane

    SciTech Connect

    Suganuma, Hiroyuki; Fahey, Jed W.; Bryan, Kelley E.; Healy, Zachary R.; Talalay, Paul

    2011-02-04

    Research highlights: {yields} Sulforaphane stimulates the phagocytosis of RAW 264.7 macrophages under conditions of serum deprivation. {yields} This effect does not require Nrf2-dependent induction of phase 2 genes. {yields} Inactivation of macrophage migration inhibitory factor (MIF) by sulforaphane may be involved in stimulation of phagocytosis by sulforaphane. -- Abstract: Sulforaphane, a major isothiocyanate derived from cruciferous vegetables, protects living systems against electrophile toxicity, oxidative stress, inflammation, and radiation. A major protective mechanism is the induction of a network of endogenous cytoprotective (phase 2) genes that are regulated by transcription factor Nrf2. To obtain a more detailed understanding of the anti-inflammatory and immunomodulatory effects of sulforaphane, we evaluated its effect on the phagocytosis activity of RAW 264.7 murine macrophage-like cells by measuring the uptake of 2-{mu}m diameter polystyrene beads. Sulforaphane raised the phagocytosis activity of RAW 264.7 cells but only in the absence or presence of low concentrations (1%) of fetal bovine serum. Higher serum concentrations depressed phagocytosis and abolished its stimulation by sulforaphane. This stimulation did not depend on the induction of Nrf2-regulated genes since it occurred in peritoneal macrophages of nrf2{sup -/-} mice. Moreover, a potent triterpenoid inducer of Nrf2-dependent genes did not stimulate phagocytosis, whereas sulforaphane and another isothiocyanate (benzyl isothiocyanate) had comparable inducer potencies. It has been shown recently that sulforaphane is a potent and direct inactivator of macrophage migration inhibitory factor (MIF), an inflammatory cytokine. Moreover, the addition of recombinant MIF to RAW 264.7 cells attenuated phagocytosis, but sulforaphane-inactivated MIF did not affect phagocytosis. The inactivation of MIF may therefore be involved in the phagocytosis-enhancing activity of sulforaphane.

  13. Most effective colon cancer chemopreventive agents in rats: a systematic review of aberrant crypt foci and tumor data, ranked by potency

    PubMed Central

    Corpet, Denis E.; Taché, Sylviane

    2002-01-01

    Potential chemopreventive agents for colorectal cancer are assessed in rodents. We speculated that the magnitude of the effect is meaningful, and ranked all published agents according to their potency. Data were gathered systematically from 137 articles with the aberrant crypt foci (ACF) endpoint, and 146 articles with the tumor endpoint. A table was built containing potency of each agent to reduce the number of ACF. Another table was built with potency of each agent to reduce the tumor incidence. Both tables are shown in the present paper, and on a website with sorting abilities (http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html). Potency was estimated by the ratio of value in control rats divided by value in treated rats. From each article, only the most potent agent was kept, except from articles reporting the effect of more than 7 agents. Among the 186 agents in the ACF table, the median agent halved the number of ACF. The most potent agents to reduce azoxymethane-induced ACF were pluronic, polyethylene glycol, perilla oil with beta-carotene, and sulindac sulfide. Among the 160 agents in the tumor table, the median agent halved the tumor incidence in rats. The most potent agents to reduce the incidence of azoxymethane-induced tumors were celecoxib, a protease inhibitor from soy, difluoromethylornithine with piroxicam, polyethylene glycol, and a thiosulfonate. For the 57 agents present in both tables, a significant correlation was found between the potencies against ACF and tumors (r=0.45, p<0.001). Without celecoxib, a major outlying point in the correlation, it reached r=0.68 (p<0.001, N=56). In conclusion, this review gathers almost all known chemopreventive agents, ranks the most promising ones against colon carcinogenesis in rats or mice, and further supports the use of ACF as surrogate endpoint for tumors in rats. PMID:12467130

  14. Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents

    PubMed Central

    Sakai, Hiroyasu; Shirakami, Yohei; Shimizu, Masahito

    2016-01-01

    Obesity and its related metabolic disorders are serious health problems worldwide, and lead to various health-related complications, including cancer. Among human cancers, hepatocellular carcinoma (HCC) is one of the most common malignancies affected by obesity. Therefore, obesity and its related disorders might be a key target for the prevention of HCC. Recently, new research indicates that the molecular abnormalities associated with obesity, including insulin resistance/hyperinsulinemia, chronic inflammation, adipokine imbalance, and oxidative stress, are possible molecular mechanisms underlying the pathogenesis of obesity-related hepatocarcinogenesis. Green tea catechins and branched-chain amino acids, both of which are classified as nutraceutical agents, have been reported to prevent obesity-related HCC development by improving metabolic abnormalities. The administration of acyclic retinoid, a pharmaceutical agent, reduced the incidence of HCC in obese and diabetic mice, and was also associated with improvements in insulin resistance and chronic inflammation. In this article, we review the detailed molecular mechanisms that link obesity to the development of HCC in obese individuals. We also summarize recent evidence from experimental and clinical studies using either nutraceutical or pharmaceutical agents, and suggest that nutraceutical and pharmaceutical approaches targeting metabolic abnormalities might be a promising strategy to prevent the development of obesity-related HCC. PMID:26755885

  15. Microencapsulation of sulforaphane from broccoli seed extracts by gelatin/gum arabic and gelatin/pectin complexes.

    PubMed

    García-Saldaña, Jesús S; Campas-Baypoli, Olga N; López-Cervantes, Jaime; Sánchez-Machado, Dalia I; Cantú-Soto, Ernesto U; Rodríguez-Ramírez, Roberto

    2016-06-15

    Sulforaphane is a phytochemical that has received attention in recent years due to its chemopreventive properties. However, the uses and applications of this compound are very limited, because is an unstable molecule that is degraded mainly by changes in temperature and pH. In this research, the use of food grade polymers for microencapsulation of sulforaphane was studied by a complex coacervation method using the interaction of oppositely charged polymers as gelatin/gum arabic and gelatin/pectin. The polymers used were previously characterized in moisture content, ash and nitrogen. The encapsulation yield was over 80%. The gelatin/pectin complex had highest encapsulation efficiency with 17.91%. The presence of sulforaphane in the complexes was confirmed by FTIR and UV/visible spectroscopy. The materials used in this work could be a new and attractive option for the protection of sulforaphane. PMID:26868553

  16. Quantification of 4'-geranyloxyferulic acid, a new natural colon cancer chemopreventive agent, by HPLC-DAD in grapefruit skin extract.

    PubMed

    Genovese, S; Epifano, F; Carlucci, G; Marcotullio, M C; Curini, M; Locatelli, M

    2010-10-10

    Oxyprenylated natural products (isopentenyloxy-, geranyloxy- and the less spread farnesyloxy-compounds and their biosynthetic derivatives) represent a family of secondary metabolites that have been consider for years merely as biosynthetic intermediates of the most abundant C-prenylated derivatives. Many of the isolated oxyprenylated natural products were shown to exert in vitro and in vivo remarkable anti-cancer and anti-inflammatory effects. 4'-Geranyloxyferulic acid [3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic] has been discovered as a valuable chemopreventive agent of several types of cancer. After development of a high yield and "eco-friendly" synthetic scheme of this secondary metabolite, starting from cheap and non-toxic reagents and substrates, we developed a new HPLC-DAD method for its quantification in grapefruit skin extract. A preliminary study on C18 column showed the separation between GOFA and boropinic acid (having the same core but with an isopentenyloxy side chain), used as internal standard. The tested column were thermostated at 28+/-1 degrees C and the separation was achieved in gradient condition at a flow rate of 1 mL/min with a starting mobile phase of H(2)O:methanol (40:60, v/v, 1% formic acid). The limit of detection (LOD, S/N=3) was 0.5 microg/mL and the limit of quantification (LOQ, S/N=10) was 1 microg/mL. Matrix-matched standard curves showed linearity up to 75 microg/mL. In the analytical range the precision (RSD%) values were

  17. Zileuton, 5-Lipoxygenase Inhibitor, Acts as a Chemopreventive Agent in Intestinal Polyposis, by Modulating Polyp and Systemic Inflammation

    PubMed Central

    Heiferman, Jeffrey R.; Shrivastav, Manisha; Vitello, Dominic; Blatner, Nichole R.; Knab, Lawrence M.; Phillips, Joseph D.; Cheon, Eric C.; Grippo, Paul J.; Khazaie, Khashayarsha; Munshi, Hidayatullah G.; Bentrem, David J.

    2015-01-01

    Purpose Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice. Experimental Design In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation. Results Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. Conclusions This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer. PMID:25747113

  18. Resveratrol derivatives as promising chemopreventive agents with improved potency and selectivity

    PubMed Central

    Kondratyuk, Tamara P.; Park, Eun-Jung; Marler, Laura E.; Ahn, Soyoun; Yuan, Yang; Choi, Yongsoo; Yu, Rui; van Breemen, Richard B.; Sun, Bin; Hoshino, Juma; Cushman, Mark; Jermihov, Katherine C.; Mesecar, Andrew D.; Grubbs, Clinton J.; Pezzuto, John M.

    2014-01-01

    Despite scores of investigations, the actual impact of resveratrol (3,5,4′-trihydroxy-trans-stilbene) on human health, as a dietary component or supplement, remains moot. This is due to many factors, such as relatively low potency, pleiotropic mechanisms, and rapid metabolism. Nonetheless, as a promiscuous molecule that interacts with numerous targets, resveratrol can be viewed as a scaffold for designing structural relatives potentially capable of mediating more intense responses with greater mechanistic stringency. We currently report the synthesis and biological evaluation of 92 stilbene analogs. The compounds were tested with in vitro assays for activation of quinone reductase 1, inhibition of QR2, nitric oxide production, aromatase, NFκB, TPA-induced ornithine decarboxylase, or cyclooxygenase-1 and -2, quenching of 2,2-diphenyl-1-picrylhydrazyl free radical, interaction with estrogen receptors, and as antiproliferative agents. Several compounds were found to mediate responses with much greater potency than resveratrol; some mediated pleiotropic responses, as is the case with the parent molecule, but others were highly specific or totally inactive. When administered to rats, higher serum concentrations and greater stability was demonstrated with prototype lead molecules. Due to structural simplicity, facile syntheses are available for large-scale production. These data support the promise of more advanced development of novel resveratrol derivatives as drug entities. PMID:21714126

  19. N-acetil-l-cysteine and 2-amino-2-thiiazoline N-acetyl-l-cysteinate as a possible cancer chemopreventive agents in murine models.

    PubMed

    Simkeviciene, Vitalija; Straukas, J; Uleckiene, Saule

    2002-01-01

    The aim of this study was to investigate N-acetyl-cysteine (NAC) and its 2-amino-2-thiazoline salt (NACAT) as potential chemopreventive agents on experimentally induced lung tumours by urethane (U) in mice. Female BALB/c mice were used. U was given by intraperitoneal injections during 2 weeks (single dose - 10 mg/mouse, total - 50 mg/mouse). Mice were treated daily per os with NAC 1/10 LD50, NACAT 1/10 or 1/100 LD50 starting 2 weeks prior U administration, then during U treatment and thereafter for 2 months. The duration of experiment was 4 months. The results showed that NAC (1000 mg/kg) reduced the lung tumour incidence to 30% that of controls, P < or = 0.05. Most effective of NACAT was 100 mg/kg dose; it reduced an average of lung adenomas per mouse by 26%, P < or = 0.05, but lower dose (10 mg/kg) was less effective. In order to achieve similar chemopreventive effect (approximately 30%) on mice, it is necessary to use 0.38 mM/kg of NACAT or 6.13 mM/kg of NAC. It means that 16 times less of NACAT is required, if calculated by molar concentration. In general, NAC and NACAT have a moderate chemopreventive effect on lung tumorigenesis induced by urethane in mice. PMID:12371608

  20. Proceedings of the Indo-U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival

    PubMed Central

    B. Kumar, Nagi; Dhurandhar, Medha; Aggarwal, Bharat; Anant, Shrikant; Daniel, Kenyon; Deng, Gary; Djeu, Julie; Dou, Jinhui; Hawk, Ernest; Jayaram, B.; Jia, Libin; Joshi, Rajendra; Kararala, Madhuri; Karunagaran, Devarajan; Kucuk, Omer; Kumar, Lalit; Malafa, Mokenge; Samathanam, G. J.; Sarkar, Fazlul; Siddiqi, Maqsood; Singh, Rana P.; Srivastava, Anil; White, Jeffrey D.

    2013-01-01

    With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo-U.S. collaborative Workshop focusing on “Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment” was conducted at the Moffitt Cancer Center, 29–31 May 2012. Funded by the Indo-U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge (agents, molecular targets, biomarkers, approaches, target populations, regulatory standards, priorities, resources) of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo-U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop. PMID:24279005

  1. Nitric oxide-releasing sulindac is a novel skin cancer chemopreventive agent for UVB-induced photocarcinogenesis

    SciTech Connect

    Chaudhary, Sandeep C.; Singh, Tripti; Kapur, Puneet; Weng, Zhiping; Arumugam, Aadithya; Elmets, Craig A.; Kopelovich, Levy; Athar, Mohammad

    2013-05-01

    Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) which have been synthesized to reduce gastro-intestinal and cardiovascular toxicities of NSAIDs, possess anti-proliferative, pro-apoptotic and anti-cancer activities. Here, we show that NO-sulindac inhibited UVB-induced skin tumorigenesis in SKH-1 hairless mice. Topical application of NO-sulindac reduced tumor incidence, number (p < 0.05) and volume (p < 0.005) as compared to UVB (alone)-irradiated vehicle-treated mice. An increase in TUNEL-positive cells in skin lesions was accompanied by the enhanced Bax:Bcl-2 ratio. The expression of pro-apoptotic Bax was increased whereas anti-apoptotic Bcl-2 reduced. However, proliferation was identified as the major target of NO-sulindac in this study. A reduced expression of PCNA and cyclin D1 associated with the dampening of cell cycle progression was observed. The mechanism of this inhibition was related to the reduction in UVB-induced Notch signaling pathway. UVB-induced inflammatory responses were diminished by NO-sulindac as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases Erk1/2, p38 and JNK1/2. In this regard, NO-sulindac also inhibited NFκB by enhancing IκBα as evidenced by the reduced expression of iNOS and COX-2, the direct NFκB transcription target proteins. NO-sulindac significantly diminished the progression of benign lesions to invasive carcinomas by suppressing the tumor aggressiveness and retarding epithelial–mesenchymal transition. A marked decrease in the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist and an increase in epithelial cell polarity marker E-cadherin were noted in NO-sulindac-treated tumors. Our data suggest that NO-sulindac is a potent inhibitor of UVB-induced skin carcinogenesis and acts by targeting proliferation-regulatory pathways. - Highlights: ► NO-sulindac is a potent chemopreventive agent for UVB-induced skin cancer. ► NO

  2. Sulforaphane and Other Nutrigenomic Nrf2 Activators: Can the Clinician's Expectation Be Matched by the Reality?

    PubMed Central

    Houghton, Christine A.; Fassett, Robert G.; Coombes, Jeff S.

    2016-01-01

    The recognition that food-derived nonnutrient molecules can modulate gene expression to influence intracellular molecular mechanisms has seen the emergence of the fields of nutrigenomics and nutrigenetics. The aim of this review is to describe the properties of nutrigenomic activators of transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), comparing the potential for sulforaphane and other phytochemicals to demonstrate clinical efficacy as complementary medicines. Broccoli-derived sulforaphane emerges as a phytochemical with this capability, with oral doses capable of favourably modifying genes associated with chemoprevention. Compared with widely used phytochemical-based supplements like curcumin, silymarin, and resveratrol, sulforaphane more potently activates Nrf2 to induce the expression of a battery of cytoprotective genes. By virtue of its lipophilic nature and low molecular weight, sulforaphane displays significantly higher bioavailability than the polyphenol-based dietary supplements that also activate Nrf2. Nrf2 activation induces cytoprotective genes such as those playing key roles in cellular defense mechanisms including redox status and detoxification. Both its high bioavailability and significant Nrf2 inducer capacity contribute to the therapeutic potential of sulforaphane-yielding supplements. PMID:26881038

  3. Chemoprevention of prostate cancer.

    PubMed

    Stephenson, Andrew J; Abouassaly, Robert; Klein, Eric A

    2010-02-01

    Prostate cancer is an appropriate target for primary chemoprevention because of its ubiquity, disease-related mortality, treatment-related morbidity, and long latency period. The PCPT and REDUCE trials demonstrate that this cancer can be prevented by a relatively nontoxic oral pharmacologic agent (5alpha-reductase inhibitors). Evidence from the SELECT trial argues against the recommendation of the use of vitamins and micronutrients as chemoprevention of prostate cancer. Dietary modification may substantially alter a man's risk of prostate cancer, but the specific dietary manipulations that are necessary are poorly defined and these may need to be instituted in early adulthood to be successful. 5alpha-reductase inhibitors represent an effective primary prevention strategy, and these agents should be used more liberally for the prevention of prostate cancer, particularly in high-risk patients. PMID:20152515

  4. [6]-gingerol as a cancer chemopreventive agent: a review of its activity on different steps of the metastatic process.

    PubMed

    Poltronieri, Juliana; Becceneri, Amanda B; Fuzer, Angelina M; Filho, Julio Cesar C; Martin, Ana Carolina B M; Vieira, Paulo Cezar; Pouliot, Normand; Cominetti, Márcia R

    2014-04-01

    For many years, ginger or ginger root, the rhizome of the plant Zingiber officinale, has been consumed as a delicacy, medicine, or spice. Several studies have been conducted on the medicinal properties of ginger against various disorders, including cancer. Cancer is the second leading cause of death, and chemoprevention is defined as the use of natural or synthetic substances to prevent cancer initiation or progression. Evidence that ginger-derived compounds have inhibitory effects on various cancer cell types is increasingly being reported in the scientific literature. In this review we focused on the cancer chemopreventive effects of [6]-gingerol, the major pungent component of ginger, and its impact on different steps of the metastatic process. PMID:24552266

  5. The potential to intensify sulforaphane formation in cooked broccoli (Brassica oleracea var. italica) using mustard seeds (Sinapis alba).

    PubMed

    Ghawi, Sameer Khalil; Methven, Lisa; Niranjan, Keshavan

    2013-06-01

    Sulforaphane, a naturally occurring cancer chemopreventive, is the hydrolysis product of glucoraphanin, the main glucosinolate in broccoli. The hydrolysis requires myrosinase isoenzyme to be present in sufficient activity; however, processing leads to its denaturation and hence reduced hydrolysis. In this study, the effect of adding mustard seeds, which contain a more resilient isoform of myrosinase, to processed broccoli was investigated with a view to intensify the formation of sulforaphane. Thermal inactivation of myrosinase from both broccoli and mustard seeds was studied. Thermal degradation of broccoli glucoraphanin was investigated in addition to the effects of thermal processing on the formation of sulforaphane and sulforaphane nitrile. Limited thermal degradation of glucoraphanin (less than 12%) was observed when broccoli was placed in vacuum sealed bag (sous vide) and cooked in a water bath at 100°C for 8 and 12 min. Boiling broccoli in water prevented the formation of any significant levels of sulforaphane due to inactivated myrosinase. However, addition of powdered mustard seeds to the heat processed broccoli significantly increased the formation of sulforaphane. PMID:23411305

  6. Tissue distribution and metabolism of the putative cancer chemopreventive agent 3',4',5'-trimethoxyflavonol (TMFol) in mice.

    PubMed

    Saad, Shaban E A; Jones, Donald J L; Norris, Leonie M; Horner-Glister, Emma; Patel, Ketan R; Britton, Robert G; Steward, William P; Gescher, Andreas J; Brown, Karen; Sale, Stewart

    2012-12-01

    3',4',5'-Trimethoxyflavonol (TMFol) is a synthetic flavonol with preclinical cancer chemopreventive properties. The hypothesis was tested that, in mice, p.o. administration of TMFol results in measureable levels of the parent in target tissues. A single oral dose (240 mg/kg) was administered to mice (n = 4 per time point) with time points ranging from 5 to 1440 min. TMFol and its metabolites were identified and quantitated in all tissues by high-performance liquid chromatography (HPLC). Plasma levels of TMFol were at the limit of quantification or below, although metabolites were identified. Peak levels of TMFol in the gastrointestinal tract and the prostate averaged 1671 ± 265 µg/g (5.3 µmol/g) and 6.0 ± 1.6 µg/g (18.4 nmol/g), and occurred 20 and 360 min post-dose, respectively. The area under the tissue concentration-time curve (AUC) for TMFol was greater than those of the metabolites, indicating that TMFol is relatively metabolically stable. Micromolar TMFol levels are easily achieved in the prostate and gastrointestinal tract, suggesting that TMFol might exert chemopreventive efficacy at these tissue sites. Further investigations are warranted to elucidate the potential chemopreventive potency of TMFol. PMID:22454297

  7. Sulforaphane induces DNA double strand breaks predominantly repaired by homologous recombination pathway in human cancer cells

    SciTech Connect

    Sekine-Suzuki, Emiko; Yu, Dong; Kubota, Nobuo; Okayasu, Ryuichi; Anzai, Kazunori

    2008-12-12

    Cytotoxicity and DNA double strand breaks (DSBs) were studied in HeLa cells treated with sulforaphane (SFN), a well-known chemo-preventive agent. Cell survival was impaired by SFN in a concentration and treatment time-dependent manner. Both constant field gel electrophoresis (CFGE) and {gamma}-H2AX assay unambiguously indicated formation of DSBs by SFN, reflecting the cell survival data. These DSBs were predominantly processed by homologous recombination repair (HRR), judging from the SFN concentration-dependent manner of Rad51 foci formation. On the other hand, the phosphorylation of DNA-PKcs, a key non-homologous end joining (NHEJ) protein, was not observed by SFN treatment, suggesting that NHEJ may not be involved in DSBs induced by this chemical. G2/M arrest by SFN, a typical response for cells exposed to ionizing radiation was also observed. Our new data indicate the clear induction of DSBs by SFN and a useful anti-tumor aspect of SFN through the induction of DNA DSBs.

  8. Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog

    SciTech Connect

    Abel, E.L.; Boulware, S.; Fields, T.; McIvor, E.; Powell, K.L.; DiGiovanni, J.; Vasquez, K.M.; MacLeod, M.C.

    2013-02-01

    Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas. -- Highlights: ► Sulforaphane induces increased levels of glutathione in mouse skin. ► Sulforaphane induces increased levels of GSTA4 in mouse skin. ► Sulforaphane, applied after CEES-treatment, completely abolishes CEES-mutagenesis. ► The therapeutic effect may suggest a long biological half-life for CEES in vivo.

  9. Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: a review of in vitro studies.

    PubMed

    Casaburi, Ivan; Puoci, Francesco; Chimento, Adele; Sirianni, Rosa; Ruggiero, Carmen; Avena, Paola; Pezzi, Vincenzo

    2013-01-01

    Olive oil is a common component of Mediterranean dietary habits. Epidemiological studies have shown how the incidence of various diseases, including certain cancers, is relatively low in the Mediterranean basin compared to that of other European or North America countries. Current knowledge indicates that the phenolic fraction of olive oil has antitumor effects. In addition to the ability to be chemopreventive, with its high antioxidant activity, the antitumor effects of olive oil phenols (OO-phenols) has been studied because of their capacity to inhibit proliferation and promote apoptosis in several tumor cell lines, by diverse mechanisms. This review will summarize and discuss the most recent relevant results on the antitumor effect of OO-phenols on leukemia tumor cells, colorectal carcinoma cells, and breast cancer (BC) cells. In particular, very recent data will be reported and discussed showing the molecular signaling pathways activated by OO-phenols in different histopathological BC cell types, suggesting the potential use of OO-phenols as adjuvant treatment against several subsets of BC. Data summarized here represent a good starting point for more extensive studies for better insight into the molecular mechanisms induced by OO-phenols and to increase the availability of chemopreventive or therapeutic drugs to fight cancer. PMID:23193056

  10. Sulforaphane inhibits TGF-β-induced epithelial-mesenchymal transition of hepatocellular carcinoma cells via the reactive oxygen species-dependent pathway.

    PubMed

    Wu, Jinsheng; Han, Jingli; Hou, Benxin; Deng, Chengwei; Wu, Huanliang; Shen, Liangfang

    2016-05-01

    Sulforaphane is recognized as a safe antitumor agent derived from various cruciferous vegetables, including broccoli. It has been demonstrated that sulforaphase is a potent antitumor agent in diverse cancers. However, its effect on hepatocellular carcinoma remains largely unknown. Here, we show that sulforaphane inhibits TGF-β-induced epithelial-mesenchymal transition of hepatocellular carcinoma cell via the reactive oxygen species-dependent pathway. We found sulforaphane inhibited hepatocellular carcinoma cell proliferation in a dose- and time-dependent manner. Sulforaphane induced G0/G1 phase cell cycle arrest and promoted cell apoptosis. A set of experiments showed that sulforaphase inhibited hepatocellular carcinoma cell migration and invasion, inhibited the formation of fibroblast like mesenchymal cells and the expression of Vimentin, but increased the expression of E-cadherin, suggesting sulforaphane suppresses epithelial-mesenchymal transition (EMT) process. Cotreatment with N-acetyl-L-cysteine inhibited sulforaphane-inhibited invasion and upregulation of E-cadherin and almost completely abolished the sulforaphane-induced expression of Vimentin. The effect of sulforaphane on the growth of hepatocellular carcinoma cells was confirmed by a xenograft tumor growth model. All our finding indicated that sulforaphane is a promising and safe strategy for treating hepatocellular carcinoma. PMID:26935987

  11. Cancer chemoprevention: a rapidly evolving field

    PubMed Central

    Steward, W P; Brown, K

    2013-01-01

    Cancer chemoprevention involves the chronic administration of a synthetic, natural or biological agent to reduce or delay the occurrence of malignancy. The potential value of this approach has been demonstrated with trials in breast, prostate and colon cancer. The paradigm for developing new chemopreventive agents has changed markedly in the last decade and now involves extensive preclinical mechanistic evaluation of agents before clinical trials are instituted and a focus on defining biomarkers of activity that can be used as early predictors of efficacy. This review will summarise the current status of the field of chemoprevention and highlight potential new developments. PMID:23736035

  12. Chemoprevention for breast cancer.

    PubMed

    Bozovic-Spasojevic, I; Azambuja, E; McCaskill-Stevens, Worta; Dinh, P; Cardoso, F

    2012-08-01

    Despite the progress that has been made in breast cancer diagnosis and treatment, this disease is still a major health problem, being the most frequently diagnosed cancer and the first leading cause of cancer death among women both in developed and economically developing countries. In some developed countries incidence rate start to decrease from the end of last millennium and this can be explained, at least in part, by the decrease in hormone replacement therapy use by post-menopausal women. Chemoprevention has the potential to be an approach of utmost importance to reduce cancer burden at least among high-risk populations. Tamoxifen and raloxifene are both indicated for the prevention of breast cancer in women at high risk for the development of the disease, although raloxifene may have a more favorable adverse-effect profile, causing fewer uterine cancers and thromboembolic events. Aromatase inhibitors will most probably become an additional prevention treatment option in the near future, in view of the promising results observed in adjuvant trials and the interesting results of the very recently published first chemoprevention trial using an aromatase inhibitor.(2) Despite impressive results in most clinical trials performed to date, chemoprevention is still not widely used. Urgently needed are better molecular risk models to accurately identify high-risk subjects, new agents with a better risk/benefit ratio and validated biomarkers. PMID:21856081

  13. Cancer Chemoprevention: Current State of the Art

    PubMed Central

    Landis-Piwowar, Kristin R; Iyer, Neena R

    2014-01-01

    The aim of cancer chemoprevention is disruption or delay of the molecular pathways that lead to carcinogenesis. Chemopreventive blocking and/or suppressing agents disrupt the molecular mechanisms that drive carcinogenesis such as DNA damage by reactive oxygen species, increased signal transduction to NF-κB, epigenomic deregulation, and the epithelial mesenchymal transition that leads to metastatic progression. Numerous dietary phytochemicals have been observed to inhibit the initiation phase of carcinogenesis, and therefore are useful in primary chemoprevention. Moreover, phytochemicals are capable of interfering with the molecular mechanisms of metastasis. Likewise, numerous synthetic compounds are relevant and clinically viable as chemopreventive agents during the fundamental stages of carcinogenesis. While molecularly targeted anti-cancer therapies are in constant stages of development, superior patient outcomes are observed if carcinogenic processes are prevented altogether. This article reviews the role of chemopreventive compounds in inhibition of cancer initiation and their ability to reduce cancer progression. PMID:24987270

  14. Korean traditional natural herbs and plants as immune enhancing, antidiabetic, chemopreventive, and antioxidative agents: a narrative review and perspective.

    PubMed

    Park, Hyunjin; Kim, Hyun-Sook

    2014-01-01

    The world is becoming increasingly interested in Korean food and its ingredients. The attention goes beyond the typical examples, such as kimchi and fermented sauces; peculiar food ingredients that are widely consumed in Korea are now entering the world's functional food markets. This trend was supported by scientific research, and this review seeks to combine and summarize the findings of the past 10 years. The results are organized into four groups depending on whether the ingredient strengthens the immune system, has antidiabetic effects, has chemopreventive effects, or has an antioxidative effects. We would also like to point out that this review only covers the topic of Korean traditional plants and herbs. After the summary of research findings, we discuss challenges and opportunities, exploring the direction of future research and the potential of Korean traditional food ingredients in food industry and markets. PMID:24456351

  15. The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice

    PubMed Central

    To, Ciric; Kim, Eun-Hee; Royce, Darlene B.; Williams, Charlotte R.; Collins, Ryan M.; Risingsong, Renee; Sporn, Michael B.; Liby, Karen T.

    2014-01-01

    Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, are effective for delaying mammary gland tumor development in a BRCA1-deficient (BRCA1Co/Co; MMTV-Cre; p53+/−) mouse model. In dose de-escalation studies, mice were fed control, veliparib (100 mg/kg diet) or olaparib (200, 100, 50 or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 weeks and 6.5 weeks, respectively, compared to controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of Brca1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option. PMID:24817481

  16. Chemoprevention of breast cancer.

    PubMed

    Files, Julia A; Stan, Daniela L; Allen, Summer V; Pruthi, Sandhya

    2012-11-01

    The development of pharmacologic agents for the prevention of breast cancer is a significant milestone in medical and laboratory research. Despite these advances, the endorsement of preventive options has become challenging and complex, as physicians are expected to counsel and tailor their recommendations using a personalized approach taking into account medical comorbidities, degree of risk and patient preferences. This article provides a comprehensive overview of the major breast cancer prevention trials, review of the pharmacologic options available for breast cancer prevention, and strategies for integrating chemoprevention of breast cancer in high-risk women into clinical practice. PMID:23181529

  17. Chemoprevention of cancer: current evidence and future prospects

    PubMed Central

    Benetou, Vassiliki; Lagiou, Areti; Lagiou, Pagona

    2015-01-01

    Cancer chemoprevention refers to the use of agents for the inhibition, delay, or reversal of carcinogenesis before invasion. In the present review, agents examined in the context of cancer chemoprevention are classified in four major categories—hormonal, medications, diet-related agents, and vaccines—and the main representatives of each category are presented. Although there are serious constraints in the documentation of effectiveness of chemopreventive agents, mainly stemming from the long latency of the condition they are addressing and the frequent lack of intermediate biomarkers, there is little disagreement about the role of aspirin, whereas a diet rich in vegetables and fruits appears to convey more protection than individual micronutrients. Among categories of cancer chemopreventive agents, hormonal ones and vaccines might hold more promise for the future. Also, the identification of individuals who would benefit most from chemopreventive interventions on the basis of their genetic profiles could open new prospects for cancer chemoprevention. PMID:27006756

  18. The chemopreventive agent myoinositol inhibits Akt and extracellular signal-regulated kinase in bronchial lesions from heavy smokers.

    PubMed

    Han, Wei; Gills, Joell J; Memmott, Regan M; Lam, Stephen; Dennis, Phillip A

    2009-04-01

    Myoinositol is an isomer of glucose that has chemopreventive activity in animal models of cancer. In a recent phase I clinical trial, myoinositol administration correlated with a statistically significant regression of preexisting bronchial dysplastic lesions in heavy smokers. To shed light on the potential mechanisms involved, activation of Akt and extracellular signal-regulated kinase (ERK), two kinases that control cellular proliferation and survival, was assessed in 206 paired bronchial biopsies from 21 patients who participated in this clinical trial. Before myoinositol treatment, strongly positive staining for activation of Akt was detected in 27% of hyperplastic/metaplastic lesions and 58% of dysplastic lesions (P = 0.05, chi(2) test). There was also a trend toward increased activation of ERK (28% in regions of hyperplasia/metaplasia to 42% of dysplastic lesions). Following myoinositol treatment, significant decreases in Akt and ERK phosphorylation were observed in dysplastic (P < 0.01 and 0.05, respectively) but not hyperplastic/metaplastic lesions (P > 0.05). In vitro, myoinositol decreased endogenous and tobacco carcinogen-induced activation of Akt and ERK in immortalized human bronchial epithelial cells, which decreased cell proliferation and induced a G(1)-S cell cycle arrest. These results show that the phenotypic progression of premalignant bronchial lesions from smokers correlates with increased activation of Akt and ERK and that these kinases are targets of myoinositol. Moreover, they suggest that myoinositol might cause regression of bronchial dysplastic lesions through inhibition of active Akt and ERK. PMID:19336734

  19. The antioxidant properties of organosulfur compounds (sulforaphane).

    PubMed

    de Figueiredo, Sonia M; Binda, Nancy S; Nogueira-Machado, Jose A; Vieira-Filho, Sidney A; Caligiorne, Rachel B

    2015-01-01

    Sulforaphane (SFN) is a molecule within the isothiocyanate (ITC) group of organosulfur compounds. SFN is a phytochemical commonly found in cruciferous vegetables such as broccoli, brussels sprouts and cabbages. It has been widely studied in order to evaluate its chemopreventive properties and some of those have already been established by means of animal and human models. The SFN induces Phase I and II enzymes involved in detoxification processes of chemical carcinogens in order to prevent the start of carcinogenesis. It also presents anti-tumor action at post-initiation Phase, suggesting supplementary roles in cancer prevention. In a dose dependent manner, ITC inhibits the viability of human cancer cells, modifies epigenetic events that occur in cancer cells and present antiinflammatory effect acting during the initial of uncontrolled cell proliferation. This protective effect may be due to its antioxidant status, its recognized capacity to induce the expression and/or activity of of different cytoprotective proteins involved in the activating "Nuclear factor erythroid-derived 2-like 2" (Nrf2). Nevertheless, the effects on health and the possible connections among different diet constituents in humans must be carefully studied as there are limitations in the current data in order to better understand the molecular mechanisms responsible for those effects. This survey also includes relevant patents on the use of SFN, like its use in skin cancer treatment (US2015038580); and as an adjuvant in anti-cancer treatment (US2014228419). The use of SFN as an antioxidant dietary supplement, methods for compositions that promote glutathione production (WO2015002279) and methods for extracting and purifying SFN from broccoli seeds (CN104086469) are also included in this review. PMID:25944116

  20. Sulforaphane exerts neuroprotective effects via suppression of the inflammatory response in a rat model of focal cerebral ischemia

    PubMed Central

    Ma, Li-Li; Xing, Guo-Ping; Yu, Yin; Liang, Hui; Yu, Tian-Xia; Zheng, Wei-Hong; Lai, Tian-Bao

    2015-01-01

    Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a promising target for treatment. Sulforaphane exerts protective effects in a rat model of focal cerebral ischemia/reperfusion injury by alleviating brain edema. However, the possible mechanisms of sulforaphane after cerebral ischemia/reperfusion injury have not been fully elucidated. Therefore, in the present study, we investigated the effect of sulforaphane on inflammatory reaction and the potential molecular mechanisms in cerebral ischemia rats. We found that sulforaphane significantly attenuated the blood-brain barrier (BBB) disruption; decreased the levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β; reduced the nitric oxide (NO) levels and inducible nitric oxide synthase (iNOS) activity; inhibited the expression of iNOS and cyclooxygenase-2 (COX-2). In addition, sulforaphane inhibits the expression of p-NF-κB p65 after focal cerebral ischemia-reperfusion injury. Taken together, our results suggest that sulforaphane suppresses the inflammatory response via inhibiting the NF-κB signaling pathway in a rat model of focal cerebral ischemia, and sulforaphane may be a potential therapeutic agent for the treatment of cerebral ischemia injury. PMID:26770373

  1. Chemoprevention by WR-2721

    SciTech Connect

    Grdina, D.J. |; Carnes, B.A.

    1993-05-01

    WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] is an effective chemopreventive agent. C57BL {times} BALB/c F{sub 1} female mice, were exposed to a single whole-body dose of 206 cGy from a {sup 60}Co photon source. Those groups treated with VATR-2721 (400 mg/kg) were administered the agent i.p. 30 min prior to irradiation. Over 90% of deaths were determined to be due to tumor involvement. WR-2721 afforded significant protection against life shortening due to radiation-induced tumors of connective tissue and epithelial tissue origins. Subsequent survival time in WR-2721-treated and irradiated animals as compared to matched irradiated-only controls was extended up to 59 days. A single exposure of animals to VVR-2721 did not affect the cumulative survival curves for unirradiated mice. WR-2721 possesses chemopreventive properties which can be clinically exploited to reduce the risk to therapy-induced secondary cancers in patients who otherwise would have an excellent prognosis for cure and long-term survival.

  2. Chemoprevention by WR-2721

    SciTech Connect

    Grdina, D.J. Chicago Univ., IL . Dept. of Radiation and Cellular Oncology); Carnes, B.A. )

    1993-01-01

    WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] is an effective chemopreventive agent. C57BL [times] BALB/c F[sub 1] female mice, were exposed to a single whole-body dose of 206 cGy from a [sup 60]Co photon source. Those groups treated with VATR-2721 (400 mg/kg) were administered the agent i.p. 30 min prior to irradiation. Over 90% of deaths were determined to be due to tumor involvement. WR-2721 afforded significant protection against life shortening due to radiation-induced tumors of connective tissue and epithelial tissue origins. Subsequent survival time in WR-2721-treated and irradiated animals as compared to matched irradiated-only controls was extended up to 59 days. A single exposure of animals to VVR-2721 did not affect the cumulative survival curves for unirradiated mice. WR-2721 possesses chemopreventive properties which can be clinically exploited to reduce the risk to therapy-induced secondary cancers in patients who otherwise would have an excellent prognosis for cure and long-term survival.

  3. Sulforaphane is anticonvulsant and improves mitochondrial function.

    PubMed

    Carrasco-Pozo, Catalina; Tan, Kah Ni; Borges, Karin

    2015-12-01

    The nuclear factor erythroid 2-related factor 2 pathway (Nrf2) has been previously identified to protect the brain against various impacts. Here, we investigated the effect of the Nrf2 activator sulforaphane in various seizure models and hippocampal mitochondrial bioenergetics. We found that daily injections of sulforaphane for 5 days elevated the seizure thresholds to 6 Hz stimulation and fluorothyl-, but not pentylenetetrazole-induced tonic seizures and protected mice against pilocarpine-induced status epilepticus (SE). Also, sulforaphane increased the antioxidant defences within hippocampal formations and blood plasma. In addition, sulforaphane treatment reduced the extent of hippocampal lipid peroxidation 24 h post-SE and protected hippocampal mitochondria against SE-induced reduction in state 2 and uncoupler-stimulated state 3 respiration. SE-mediated partial loss of rotenone-sensitive and complex II-driven respiration was reduced, consistent with the enhanced activities of complexes I and II in sulforaphane-treated SE mice. In mitochondria isolated from both no SE and SE mice, sulforaphane increased state 3 respiration and respiration linked to ATP synthesis, which may contribute to its anticonvulsant and antioxidant effects by providing more ATP for cellular vital and protective functions. However, sulforaphane did not prevent SE-induced hippocampal cell death. In conclusion, sulforaphane and/or Nrf2 activation are viable anticonvulsant strategies, which are antioxidant and enhance mitochondrial function, especially the ability to produce ATP. Sulforaphane was anticonvulsant in two acute mouse models of epilepsy and protected mice against pilocarpine-induced status epilepticus (SE). We also found antioxidant effects of sulforaphane in mouse plasma and hippocampal formations, exhibited by increased catalase and superoxide dismutase (SOD) activity, as well as increased abilities of hippocampal mitochondria to produce ATP. These effects likely underlie

  4. Antineoplastic effect of a novel chemopreventive agent, neokestose, on the Caco-2 cell line via inhibition of expression of nuclear factor-κB and cyclooxygenase-2.

    PubMed

    Lee, Shun-Mei; Chang, Jan-Yi; Wu, Jiann-Shing; Sheu, Dey-Chyi

    2015-07-01

    Neokestose is a 6G-fructooligosaccharide (FOS) and an important prebiotic. When FOS are ingested by patients with colorectal cancer, they may come into contact with cancer cells prior to being fermented by bifidobacteria in the colon. In the present study, the effects of neokestose on cell proliferation, cell cycle and apoptosis of the colorectal cancer cell line Caco-2 were investigated to evaluate its anti-cancer effect. An MTT assay showed that neokestose-treated Caco-2 cells exhibited a significant and dose-dependent loss of viability. Flow cytometric analysis indicated that the sub-G1 population of Caco-2 cells was significantly increased following treatment with neokestose, and the percentage of Caco-2 cells in the stage of late apoptosis was also significantly increased in a dose-dependent manner. Western blot analysis showed that the overexpression of nuclear factor-κB, a central molecule responsible for the transition from inflammation to cancer, and cyclooxygenase-2, an important enzyme in colorectal tumorigenesis, in colorectal carcinoma cells was inhibited by neokestose. Accordingly, the present study provided in vitro evidence that neokestose may be used as a dietary chemopreventive agent, whose application is more rational than that of COX-2 inhibitors or aspirin for preventing colorectal cancer. PMID:25815878

  5. Localized sequence-specific release of a chemopreventive agent and an anticancer drug in a time-controllable manner to enhance therapeutic efficacy.

    PubMed

    Pan, Wen-Yu; Lin, Kun-Ju; Huang, Chieh-Cheng; Chiang, Wei-Lun; Lin, Yu-Jung; Lin, Wei-Chih; Chuang, Er-Yuan; Chang, Yen; Sung, Hsing-Wen

    2016-09-01

    Combination chemotherapy with multiple drugs commonly requires several injections on various schedules, and the probability that the drug molecules reach the diseased tissues at the proper time and effective therapeutic concentrations is very low. This work elucidates an injectable co-delivery system that is based on cationic liposomes that are adsorbed on anionic hollow microspheres (Lipos-HMs) via electrostatic interaction, from which the localized sequence-specific release of a chemopreventive agent (1,25(OH)2D3) and an anticancer drug (doxorubicin; DOX) can be thermally driven in a time-controllable manner by an externally applied high-frequency magnetic field (HFMF). Lipos-HMs can greatly promote the accumulation of reactive oxygen species (ROS) in tumor cells by reducing their cytoplasmic expression of an antioxidant enzyme (superoxide dismutase) by 1,25(OH)2D3, increasing the susceptibility of cancer cells to the cytotoxic action of DOX. In nude mice that bear xenograft tumors, treatment with Lipos-HMs under exposure to HFMF effectively inhibits tumor growth and is the most effective therapeutic intervention among all the investigated. These empirical results demonstrate that the synergistic anticancer effects of sequential release of 1,25(OH)2D3 and DOX from the Lipos-HMs may have potential for maximizing DOX cytotoxicity, supporting more effective cancer treatment. PMID:27294541

  6. Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China

    PubMed Central

    Kensler, Thomas W.; Ng, Derek; Carmella, Steven G.; Chen, Menglan; Jacobson, Lisa P.; Muñoz, Alvaro; Egner, Patricia A.; Chen, Jian Guo; Qian, Geng Sun; Chen, Tao Yang; Fahey, Jed W.; Talalay, Paul; Groopman, John D.; Yuan, Jian-Min; Hecht, Stephen S.

    2012-01-01

    Epidemiological evidence has suggested that consumption of a diet rich in cruciferous vegetables reduces the risk of several types of cancers and chronic degenerative diseases. In particular, broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can release the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases. Two broccoli sprout-derived beverages, one sulforaphane-rich (SFR) and the other glucoraphanin-rich (GRR), were evaluated for pharmacodynamic action in a crossover clinical trial design. Study participants were recruited from the farming community of He Zuo Township, Qidong, China, previously documented to have a high incidence of hepatocellular carcinoma with concomitant exposures to aflatoxin and more recently characterized with exposures to substantive levels of airborne pollutants. Fifty healthy participants were randomized into two treatment arms. The study protocol was as follows: a 5 days run-in period, a 7 days administration of beverage, a 5 days washout period and a 7 days administration of the opposite beverage. Urinary excretion of the mercapturic acids of acrolein, crotonaldehyde, ethylene oxide and benzene were measured both pre- and postinterventions using liquid chromatography tandem mass spectrometry. Statistically significant increases of 20–50% in the levels of excretion of glutathione-derived conjugates of acrolein, crotonaldehyde and benzene were seen in individuals receiving SFR, GRR or both compared with their preintervention baseline values. No significant differences were seen between the effects of SFR versus GRR. Intervention with broccoli sprouts may enhance detoxication of airborne pollutants and attenuate their associated health risks. PMID:22045030

  7. Chemoprevention of bladder cancer.

    PubMed

    Kamat, Ashish M; Lamm, Donald L

    2002-02-01

    The data presented herein, although highly supportive for a protective role of various nutrients against bladder cancer, are far from definitive. Many authorities question the validity of current recommendations for nutritional chemoprevention against bladder cancer. The reason for the wide variations reported in epidemiologic studies lies in the nature of observational studies. Dietary studies are limited in their conclusions because the protection afforded by the consumption of a particular nutrient may be multifactorial, with different components of the food exerting potential chemopreventive effects. Furthermore, measuring levels of nutrients in the food intake of populations is confounded by factors that might affect these levels and also the incidence of cancer. For example, vitamin A can come from animal or vegetarian sources. Because animal fat has been identified as a potential carcinogen in man, depending on the source of the vitamin, varying levels of protection might be deduced. In addition, chemoprevention studies using dietary supplements are expected to have mild effects, and large studies would be required to confirm statistical significance. Even with agents such as intravesical chemotherapy, only half the studies achieve statistical significance [29]. Prospective randomized trials with a large sample size, longer follow-up, and an extended duration of treatment are needed to clarify the association between micronutrients and cancer protection. With these caveats in mind, several recommendations can be made. Simple measures, such as drinking more fluids (especially water), can have a profound impact on the incidence of bladder cancer. Vitamins are being extensively studied in chemopreventive trials for different cancers. There is strong evidence for a chemoprotective effect of vitamin A in bladder cancer. The authors recommend 32,000 IU/day of vitamin A initially, with lower doses (24,000 IU) for persons less than 50 kg. Because liver toxicity is a

  8. Combination chemoprevention with grape antioxidants.

    PubMed

    Singh, Chandra K; Siddiqui, Imtiaz A; El-Abd, Sabah; Mukhtar, Hasan; Ahmad, Nihal

    2016-06-01

    Antioxidant ingredients present in grape have been extensively investigated for their cancer chemopreventive effects. However, much of the work has been done on individual ingredients, especially focusing on resveratrol and quercetin. Phytochemically, whole grape represents a combination of numerous phytonutrients. Limited research has been done on the possible synergistic/additive/antagonistic interactions among the grape constituents. Among these phytochemical constituents of grapes, resveratrol, quercetin, kaempferol, catechin, epicatechin, and anthocyanins (cyanidin and malvidin) constitute more than 70% of the grape polyphenols. Therefore, these have been relatively well studied for their chemopreventive effects against a variety of cancers. While a wealth of information is available individually on cancer chemopreventive/anti-proliferative effects of resveratrol and quercetin, limited information is available regarding the other major constituents of grape. Studies have also suggested that multiple grape antioxidants, when used in combination, alone or with other agents/drugs show synergistic or additive anti-proliferative response. Based on strong rationale emanating from published studies, it seems probable that a combination of multiple grape ingredients alone or together with other agents could impart 'additive synergism' against cancer. PMID:26829056

  9. Neuroprotective effect of sulforaphane against methylglyoxal cytotoxicity.

    PubMed

    Angeloni, Cristina; Malaguti, Marco; Rizzo, Benedetta; Barbalace, Maria Cristina; Fabbri, Daniele; Hrelia, Silvana

    2015-06-15

    Glycation, an endogenous process that leads to the production of advanced glycation end products (AGEs), plays a role in the etiopathogenesis of different neurodegenerative diseases, such as Alzheimer's disease (AD). Methylglyoxal is the most potent precursor of AGEs, and high levels of methylglyoxal have been found in the cerebrospinal fluid of AD patients. Methylglyoxal may contribute to AD both inducing extensive protein cross-linking and mediating oxidative stress. The aim of this study was to investigate the role of sulforaphane, an isothiocyanate found in cruciferous vegetables, in counteracting methylglyoxal-induced damage in SH-SY5Y neuroblastoma cells. The data demonstrated that sulforaphane protects cells against glycative damage by inhibiting activation of the caspase-3 enzyme, reducing the phosphorylation of MAPK signaling pathways (ERK1/2, JNK, and p38), reducing oxidative stress, and increasing intracellular glutathione levels. For the first time, we demonstrate that sulforaphane enhances the methylglyoxal detoxifying system, increasing the expression and activity of glyoxalase 1. Sulforaphane modulated brain-derived neurotrophic factor and its pathway, whose dysregulation is related to AD development. Moreover, sulforaphane was able to revert the reduction of glucose uptake caused by methylglyoxal. In conclusion, sulforaphane demonstrates pleiotropic behavior thanks to its ability to act on different cellular targets, suggesting a potential role in preventing/counteracting multifactorial neurodegenerative diseases such as Alzheimer's. PMID:25933243

  10. Chemoprevention of skin melanoma: facts and myths.

    PubMed

    Uzarska, Małgorzata; Czajkowski, Rafał; Schwartz, Robert A; Bajek, Anna; Zegarska, Barbara; Drewa, Tomasz

    2013-12-01

    Melanoma is the most dangerous type of skin cancer. Despite the rise of public awareness, the incidence rate among the white population has been rising constantly for several decades. Systematic improvement in knowledge about the biology of pigment cells and molecular mechanisms of their neoplastic transformation has enhanced the possibility of melanoma chemoprevention. Hence, chemopreventive agents that prevent, inhibit, or reverse melanoma development are being investigated intensively. Among synthetic compounds, especially well studied are lipid-lowering drugs and cyclooxygenase inhibitors. Substances found in everyday diet, such as genistein, apigenin, quercetin, resveratrol, and curcumin may also have potential chemopreventive qualities. However, studies examining the chemopreventive activity of these compounds have shown widely varying results. Early reports on the possible chemopreventive activity of statins and fibrates were not proved by the results of randomized clinical trials. Similarly, case-control studies examining the influence of NSAIDs on the risk of melanoma do not confirm the antitumor activity of cyclooxygenase inhibitors. Further clinical trials involving carefully selected target populations as well as the identification of specific biomarkers of prognostic and predictive value seem to be essential for the evaluation of the chemopreventive activity of the studied substances. PMID:24077511

  11. Chemoprevention of familial adenomatous polyposis.

    PubMed

    Lynch, Patrick M

    2016-07-01

    Familial adenomatous polyposis (FAP) has always been first and foremost a surgical disease, whose treatment with colectomy has long been known to reduce risk of premature cancer death. The notion of reducing polyp burden and potentially delaying surgical intervention has spawned a host of "chemoprevention" trials. In this paper I selectively review the findings from these studies, highlighting trial design issues and in particular some of the limitations of historical and existing trial endpoint measures. Nonsteroidal anti-inflammatory agents have been the most commonly employed chemopreventive agents. Sulindac, largely by historical accident, has been the most extensively studied, and is widely considered the standard of care when a clinical decision to intervene medically is made. Newer trials are evaluating combinations of agents in order to take advantage of differing mechanisms of action, in the hope of achieving synergy, as no single agent predictably or completely suppresses adenoma growth. Some of these studies and other single-agent interventions are discussed, though an exploration of the various mechanisms of action is beyond the scope of this paper. It is essential that future trials focus on the issue of "clinical benefit", not simply because the US Food and Drug Administration has insisted on it, but because only real evidence-based advances can improve the standard of medical care for FAP patients. Hence my focus on issues of trial design and clinically relevant endpoints. PMID:27083160

  12. A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer

    PubMed Central

    Alumkal, Joshi J.; Slottke, Rachel; Schwartzman, Jacob; Cherala, Ganesh; Munar, Myrna; Graff, Julie N.; Beer, Tomasz M.; Ryan, Christopher W.; Koop, Dennis R.; Gibbs, Angela; Gao, Lina; Flamiatos, Jason F.; Tucker, Erin; Kleinschmidt, Richard; Mori, Motomi

    2014-01-01

    Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. We treated 20 patients who had recurrent prostate cancer with 200μmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50% PSA declines, the primary endpoint. Only one subject experienced a ≥50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p=0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. Treatment with 200μmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent. PMID:25431127

  13. Sulforaphane Induces Cell Cycle Arrest and Apoptosis in Acute Lymphoblastic Leukemia Cells

    PubMed Central

    Suppipat, Koramit; Park, Chun Shik; Shen, Ye; Zhu, Xiao; Lacorazza, H. Daniel

    2012-01-01

    Acute lymphoblastic leukemia (ALL) is the most common hematological cancer in children. Although risk-adaptive therapy, CNS-directed chemotherapy, and supportive care have improved the survival of ALL patients, disease relapse is still the leading cause of cancer-related death in children. Therefore, new drugs are needed as frontline treatments in high-risk disease and as salvage agents in relapsed ALL. In this study, we report that purified sulforaphane, a natural isothiocyanate found in cruciferous vegetables, has anti-leukemic properties in a broad range of ALL cell lines and primary lymphoblasts from pediatric T-ALL and pre-B ALL patients. The treatment of ALL leukemic cells with sulforaphane resulted in dose-dependent apoptosis and G2/M cell cycle arrest, which was associated with the activation of caspases (3, 8, and 9), inactivation of PARP, p53-independent upregulation of p21CIP1/WAF1, and inhibition of the Cdc2/Cyclin B1 complex. Interestingly, sulforaphane also inhibited the AKT and mTOR survival pathways in most of the tested cell lines by lowering the levels of both total and phosphorylated proteins. Finally, the administration of sulforaphane to the ALL xenograft models resulted in a reduction of tumor burden, particularly following oral administration, suggesting a potential role as an adjunctive agent to improve the therapeutic response in high-risk ALL patients with activated AKT signaling. PMID:23251470

  14. Sulforaphane treatment of autism spectrum disorder (ASD).

    PubMed

    Singh, Kanwaljit; Connors, Susan L; Macklin, Eric A; Smith, Kirby D; Fahey, Jed W; Talalay, Paul; Zimmerman, Andrew W

    2014-10-28

    Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)--derived from broccoli sprout extracts--or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation. PMID:25313065

  15. Sulforaphane treatment of autism spectrum disorder (ASD)

    PubMed Central

    Singh, Kanwaljit; Connors, Susan L.; Macklin, Eric A.; Smith, Kirby D.; Fahey, Jed W.; Talalay, Paul; Zimmerman, Andrew W.

    2014-01-01

    Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13–27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)—derived from broccoli sprout extracts—or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50–150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015–0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation. PMID:25313065

  16. Lung cancer chemoprevention: current status and future prospects

    PubMed Central

    Keith, Robert L.; Miller, York E.

    2015-01-01

    Lung cancer is the leading cause of cancer death worldwide, making it an attractive disease for chemoprevention. Although avoidance of tobacco use and smoking cessation will have the greatest impact on lung cancer development, chemoprevention could prove to be very effective, particularly in former smokers. Chemoprevention is the use of agents to reverse or inhibit carcinogenesis and has been successfully applied to other common malignancies. Despite prior studies in lung cancer chemoprevention failing to identify effective agents, we now have the ability to identify high-risk populations, and our understanding of lung tumour and premalignant biology continues to advance. There are distinct histological lesions that can be reproducibly graded as precursors of non-small-cell lung cancer and similar precursor lesions exist for adenocarcinoma. These premalignant lesions are being targeted by chemopreventive agents in current trials and will continue to be studied in the future. In addition, biomarkers that predict risk and response to targeted agents are being investigated and validated. In this Review, we discuss the principles of chemoprevention, data from preclinical models, completed clinical trials and observational studies, and describe new treatments for novel targeted pathways and future chemopreventive efforts. PMID:23689750

  17. Impact of thermal processing on sulforaphane yield from broccoli (Brassica oleracea L. var. italica)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In broccoli, sulforaphane forms when the glucosinolate glucoraphanin is hydrolyzed by the endogenous plant thiohydrolase myrosinase. A myrosinase cofactor directs hydrolysis away from formation of bioactive sulforaphane and toward an inactive product, sulforaphane nitrile. The cofactor is more hea...

  18. Natural Products for Chemoprevention of Breast Cancer

    PubMed Central

    Ko, Eun-Yi; Moon, Aree

    2015-01-01

    Breast cancer is the primary cause of cancer death in women. Although current therapies have shown some promise against breast cancer, there is still no effective cure for the majority of patients in the advanced stages of breast cancer. Development of effective agents to slow, reduce, or reverse the incidence of breast cancer in high-risk women is necessary. Chemoprevention of breast cancer by natural products is advantageous, as these compounds have few side effects and low toxicity compared to synthetic compounds. In the present review, we summarize natural products which exert chemopreventive activities against breast cancer, such as curcumin, sauchinone, lycopene, denbinobin, genipin, capsaicin, and ursolic acid. This review examines the current knowledge about natural compounds and their mechanisms that underlie breast cancer chemopreventive activity both in vitro and in vivo. The present review may provide information on the use of these compounds for the prevention of breast cancer. PMID:26734584

  19. Effects of co-treatment with sulforaphane and autophagy modulators on uridine 5′-diphospho-glucuronosyltransferase 1A isoforms and cytochrome P450 3A4 expression in Caco-2 human colon cancer cells

    PubMed Central

    WANG, MIN; ZHU, JING-YU; CHEN, SHUO; QING, YING; WU, DONG; LIN, YING-MIN; LUO, JI-ZHUANG; HAN, WEI; LI, YAN-QING

    2014-01-01

    Sulforaphane (SFN), which is highly enriched in cruciferous vegetables, has been investigated for its cancer chemopreventive properties and ability to induce autophagy. Uridine 5′-diphospho (UDP)-glucuronosyltransferase (UGT)1A induction is one of the mechanisms that is responsible for the cancer chemopreventive activity of SFN. The current study demonstrates that rapamycin may enhance the chemopreventive effects of SFN on Caco-2 cells; this may be partially attributed to nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2)- and human pregnane X receptor (hPXR)-mediated UGT1A1, UGT1A8 and UGT1A10 induction. These results indicate that targeting autophagy modulation may be a promising strategy for increasing the chemopreventive effects of SFN in cases of colon cancer. PMID:25364403

  20. SUV39H1/H3K9me3 attenuates sulforaphane-induced apoptotic signaling in PC3 prostate cancer cells.

    PubMed

    Watson, G W; Wickramasekara, S; Palomera-Sanchez, Z; Black, C; Maier, C S; Williams, D E; Dashwood, R H; Ho, E

    2014-01-01

    The isothiocyanate sulforaphane is a promising molecule for development as a therapeutic agent for patients with metastatic prostate cancer. Sulforaphane induces apoptosis in advanced prostate cancer cells, slows disease progression in vivo and is well tolerated at pharmacological doses. However, the underlying mechanism(s) responsible for cancer suppression remain to be fully elucidated. In this investigation we demonstrate that sulforaphane induces posttranslational modification of histone methyltransferase SUV39H1 in metastatic, androgen receptor-negative PC3 prostate cancer cells. Sulforaphane stimulates ubiquitination and acetylation of SUV39H1 within a C-terminal nuclear localization signal peptide motif and coincides with its dissociation from chromatin and a decrease in global trimethyl-histone H3 lysine 9 (H3K9me3) levels. Exogenous SUV39H1 expression leads to an increase in H3K9me3 and decreases sulforaphane-induced apoptotic signaling. SUV39H1 is thus identified as a novel mediator of sulforaphane cytotoxicity in PC3 cells. Our results also suggest SUV39H1 dynamics as a new therapeutic target in advanced prostate cancers. PMID:25486523

  1. Sarcophine-diol, a skin cancer chemopreventive agent, inhibits proliferation and stimulates apoptosis in mouse melanoma B₁₆F₁₀ cell line.

    PubMed

    Szymanski, Pawel T; Kuppast, Bhimanna; Ahmed, Safwat A; Khalifa, Sherief; Fahmy, Hesham

    2012-01-01

    Sarcodiol (SD) is a semi-synthetic derivative of sarcophine, a marine natural product. In our previous work, we reported the significant chemopreventive effects of SD against non-melanoma skin cancer both in vitro and in vivo mouse models. In this investigation, we extended this work to study the effect of sarcodiol on melanoma development, the more deadly form of skin cancer, using the mouse melanoma B₁₆F₁₀ cell line. In this study we report that SD inhibits the de novo DNA synthesis and enhances fragmentation of DNA. We also evaluated the antitumor effect of SD on melanoma cell viability using several biomarkers for cell proliferation and apoptosis. SD inhibits the expression levels of signal transducers and activators of transcription protein (STAT-3) and cyclin D1, an activator of cyclin-dependent kinase 4 (Cdk4). SD treatment also enhances cellular level of tumor suppressor protein 53 (p53) and stimulates cleavage of the nuclear poly (ADP-ribose) polymerase (cleaved-PARP). SD also enhances cellular levels of cleaved Caspase-3, -8, -9 and stimulates enzymatic activities of Caspase-3, -8 and -9. These results, in addition to inhibition of cell viability, suggest that SD inhibits melanoma cell proliferation by arresting the cell-division cycle in a Go quiescent phase and activates programmed cell death (apoptosis) via extrinsic and intrinsic pathways. Finally, these studies demonstrate that SD shows a very promising chemopreventive effect in melanoma B₁₆F₁₀ tumor cells. PMID:22363217

  2. Pancreatic Cancer Chemoprevention Translational Workshop: Meeting Report.

    PubMed

    Miller, Mark Steven; Allen, Peter; Brentnall, Teresa A; Goggins, Michael; Hruban, Ralph H; Petersen, Gloria M; Rao, Chinthalapally V; Whitcomb, David C; Brand, Randall E; Chari, Suresh T; Klein, Alison P; Lubman, David M; Rhim, Andrew D; Simeone, Diane M; Wolpin, Brian M; Umar, Asad; Srivastava, Sudhir; Steele, Vernon E; Rinaudo, Jo Ann S

    2016-09-01

    Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States with a 5-year survival rate of less than 10%. The Division of Cancer Prevention of the National Cancer Institute sponsored the Pancreatic Cancer Chemoprevention Translational Workshop on September 10 to 11, 2015. The goal of the workshop was to obtain information regarding the current state of the science and future scientific areas that should be prioritized for pancreatic cancer prevention research, including early detection and intervention for high-risk precancerous lesions. The workshop addressed the molecular/genetic landscape of pancreatic cancer and precursor lesions, high-risk populations and criteria to identify a high-risk population for potential chemoprevention trials, identification of chemopreventative/immunopreventative agents, and use of potential biomarkers and imaging for assessing short-term efficacy of a preventative agent. The field of chemoprevention for pancreatic cancer is emerging, and this workshop was organized to begin to address these important issues and promote multi-institutional efforts in this area. The meeting participants recommended the development of an National Cancer Institute working group to coordinate efforts, provide a framework, and identify opportunities for chemoprevention of pancreatic cancer. PMID:27518363

  3. Chemoprevention of hereditary colon cancers: time for new strategies.

    PubMed

    Ricciardiello, Luigi; Ahnen, Dennis J; Lynch, Patrick M

    2016-06-01

    Colorectal cancer (CRC) is potentially preventable. Chemoprevention, a focus of research for the past three decades, aims to prevent or delay the onset of cancer through the regression or prevention of colonic adenomas. Ideal pharmacological agents for chemoprevention should be cheap and nontoxic. Although data indicate that aspirin can reduce the risk of CRC in the general population, the highest return from chemopreventive strategies would be expected in patients with the highest risk of developing the disease, particularly those with a defined hereditary predisposition. Despite compelling data showing that a large number of chemopreventive agents show promise in preclinical CRC models, clinical studies have yielded conflicting results. This Review provides a historical and methodological perspective of chemoprevention in familial adenomatous polyposis and Lynch syndrome, and summarizes the current status of CRC chemoprevention in humans. Our goal is to critically focus on important issues of trial design, with particular attention on the choice of appropriate trial end points, how such end points should be measured, and which patients are the ideal candidates to be included in a chemopreventive trial. PMID:27095653

  4. Endocrine Disruption throughout the Hypothalamus-Pituitary-Gonadal-Liver (HPGL) Axis in Marine Medaka (Oryzias melastigma) Chronically Exposed to the Antifouling and Chemopreventive Agent, 3,3'-Diindolylmethane (DIM).

    PubMed

    Chen, Lianguo; Ye, Rui; Zhang, Weipeng; Hu, Chenyan; Zhou, Bingsheng; Peterson, Drew R; Au, Doris W T; Lam, Paul K S; Qian, Pei-Yuan

    2016-06-20

    Despite being proposed as a promising antifouling and chemopreventive agent, the environmental risks of 3,3'-diindolylmethane (DIM) are scarcely investigated. Therefore, this study used adult marine medaka (Oryzias melastigma) as a model organism to examine the toxicological effects and underlying mechanism of DIM throughout the hypothalamus-pituitary-gonadal-liver (HPGL) axis following 28 days of exposure to low DIM concentrations (0 and 8.46 μg/L). The results showed that altered gene transcription in the hypothalamus, pituitary, and gonads contributed to the great imbalance in hormone homeostasis. The lowered estradiol (E2)/testosterone (T) and E2/11-keto-testosterone (11-KT) ratios in female plasma resulted in decreased synthesis and levels of vitellogenin (VTG) and choriogenin in the liver and plasma, and vice versa in males. Subsequently, VTG and choriogenin deficiency blocked the reproductive function of the ovary as indicated by decreased fecundity and offspring viability, whereas in male medaka, DIM mainly targeted the liver and induced severe vacuolization. Proteomic profiling of plasma revealed that the sex-specific susceptibility to DIM could be attributed to the increased detoxification and oxidative defense in males. Overall, this study identified the endocrine disruption and reproductive impairment potency of DIM and first elucidated its mechanisms of action in medaka. The differential responses to DIM (estrogenic activities in the male but antiestrogenic activities in the female) provided sensitive biomarkers characteristic of each sex. Considering the chemical stability and potent endocrine disturbance at low concentration, the application of DIM either as an antifouling or chemopreventive agent should be approached with caution in marine environments. PMID:27092574

  5. Exploring the Potential Role of Chemopreventive Agent, Hesperetin Conjugated Pegylated Gold Nanoparticles in Diethylnitrosamine-Induced Hepatocellular Carcinoma in Male Wistar Albino Rats.

    PubMed

    Gokuladhas, Krishnan; Jayakumar, Subramaniyan; Rajan, Balan; Elamaran, Ramasamy; Pramila, Chengalvarayan Subramani; Gopikrishnan, Mani; Tamilarasi, Sasivarman; Devaki, Thiruvengadam

    2016-04-01

    Liver cancer is the fifth most common cancer and is still one of the leading causes of death world wide, due to food additives, alcohol, fungal toxins, air, toxic industrial chemicals, and water pollutants. Chemopreventive drugs play a potential role in liver cancer treatment. Obviously in the production of anticancer drugs, the factors like poor solubility, bioavailability, biocompatibility, limited chemical stability, large amount of dose etc., plays a major role. Against this backdrop, the idea of designing the chemopreventive nature of bio flavanoid hesperetin (HP) drug conjugated with pegylated gold nanoparticles to increasing the solubility, improve bioavailability and enhance the targeting capabilities of the drug during diethylnitrosamine (DEN) induced liver cancer in male wistar albino rats. The dose fixation studies and the toxicity of pure HP and HP conjugated gold nanoparticles (Au-mPEG(5000)-S-HP) were analysed. After concluded the dose fixation and toxicity studies the experimental design were segregated in six groups for the anticancer analysis of DEN induced HCC for 16 weeks. After the experimental period the body weight, relative liver weight, number of nodules and size of nodules, the levels of tumor markers like CEA, AFP and the level of lipid peroxidation, lipid hydroperoxides and the activities of antioxidant enzymes were assessed. The administration of DEN to rats resulted in increased relative liver weight and serum marker enzymes aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma glutamyl transpeptidase. The levels of lipid peroxides elevated (in both serum and tissue) with subsequent decrease in the final body weight and tissue antioxidants like superoxide dismutase, catalase, reduced glutathione, glutathione peroxidise, and glutathione reductase. HP supplementation (20 mg/kg b.wt) significantly attenuated these alterations, thereby showing potent anticancer effect in liver cancer and the

  6. Chemotherapy and Chemoprevention by Thiazolidinediones

    PubMed Central

    2015-01-01

    Thiazolidinediones (TZDs) are synthetic ligands of Peroxisome-Proliferator-Activated Receptor gamma (PPARγ). Troglitazone, rosiglitazone, and pioglitazone have been approved for treatment of diabetes mellitus type II. All three compounds, together with the first TZD ciglitazone, also showed an antitumor effect in preclinical studies and a beneficial effect in some clinical trials. This review summarizes hypotheses on the role of PPARγ in tumors, on cellular targets of TZDs, antitumor effects of monotherapy and of TZDs in combination with other compounds, with a focus on their role in the treatment of differentiated thyroid carcinoma. The results of chemopreventive effects of TZDs are also considered. Existing data suggest that the action of TZDs is highly complex and that actions do not correlate with cellular PPARγ expression status. Effects are cell-, species-, and compound-specific and concentration-dependent. Data from human trials suggest the efficacy of TZDs as monotherapy in prostate cancer and glioma and as chemopreventive agent in colon, lung, and breast cancer. TZDs in combination with other therapies might increase antitumor effects in thyroid cancer, soft tissue sarcoma, and melanoma. PMID:25866814

  7. Sulforaphane inhibits CYP1A1 activity and promotes genotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vitro

    SciTech Connect

    Yang, Fangxing; Zhuang, Shulin; Zhang, Chao; Dai, Heping; Liu, Weiping

    2013-06-15

    Increasing environmental pollution by carcinogens such as some of persistent organic pollutants (POPs) has prompted growing interest in searching for chemopreventive compounds which are readily obtainable. Sulforaphane (SFN) is isolated from cruciferous vegetables and has the potentials to reduce carcinogenesis through various pathways. In this study, we studied the effects of SFN on CYP1A1 activity and genotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The results showed that SFN inhibited TCDD-induced CYP1A1 activity in H4IIE cells by directly inhibiting CYP1A1 activity, probably through binding to aryl hydrocarbon receptor and/or CYP1A1 revealed by molecular docking. However, SFN promoted TCDD-induced DNA damage in yeast cells and reduced the viability of initiated yeast cells. Besides, it is surprising that SFN also failed to reduce genotoxicity induced by other genotoxic reagents which possess different mechanisms to lead to DNA damage. Currently, it is difficult to predict whether SFN has the potentials to reduce the risk of TCDD based on the conflicting observations in the study. Therefore, further studies should be urgent to reveal the function and mechanism of SFN in the stress of such POPs on human health. - Highlights: • Sulforaphane inhibited TCDD-induced CYP1A1 activity in H4IIE cells. • Sulforaphane may bind to aryl hydrocarbon receptor and/or CYP1A1. • Sulforaphane promoted TCDD-induced DNA damage in yeast cells. • Sulforaphane may promote DNA damage by DNA strand breaks or DNA alkylation.

  8. Comet Assay in Cancer Chemoprevention.

    PubMed

    Santoro, Raffaela; Ferraiuolo, Maria; Morgano, Gian Paolo; Muti, Paola; Strano, Sabrina

    2016-01-01

    The comet assay can be useful in monitoring DNA damage in single cells caused by exposure to genotoxic agents, such as those causing air, water, and soil pollution (e.g., pesticides, dioxins, electromagnetic fields) and chemo- and radiotherapy in cancer patients, or in the assessment of genoprotective effects of chemopreventive molecules. Therefore, it has particular importance in the fields of pharmacology and toxicology, and in both environmental and human biomonitoring. It allows the detection of single strand breaks as well as double-strand breaks and can be used in both normal and cancer cells. Here we describe the alkali method for comet assay, which allows to detect both single- and double-strand DNA breaks. PMID:26608293

  9. Chemoprevention of Gastrointestinal Cancer: The Reality and the Dream

    PubMed Central

    Chun, Kyung-Soo; Kim, Eun-Hee; Lee, Sooyeon

    2013-01-01

    Despite substantial progress in screening, early diagnosis, and the development of noninvasive technology, gastrointestinal (GI) cancer remains a major cause of cancer-associated mortality. Chemoprevention is thought to be a realistic approach for reducing the global burden of GI cancer, and efforts have been made to search for chemopreventive agents that suppress acid reflux, GI inflammation and the eradication of Helicobacter pylori. Thus, proton pump inhibitors, statins, monoclonal antibodies targeting tumor necrosis factor-alpha, and nonsteroidal anti-inflammatory agents have been investigated for their potential to prevent GI cancer. Besides the development of these synthetic agents, a wide variety of the natural products present in a plant-based diet, which are commonly called phytoceuticals, have also sparked hope for the chemoprevention of GI cancer. To perform successful searches of chemopreventive agents for GI cancer, it is of the utmost importance to understand the factors contributing to GI carcinogenesis. Emerging evidence has highlighted the role of chronic inflammation in inducing genomic instability and telomere shortening and affecting polyamine metabolism and DNA repair, which may help in the search for new chemopreventive agents for GI cancer. PMID:23560148

  10. Lung cancer: chemoprevention and intermediate effect markers.

    PubMed

    Tockman, M S

    2001-01-01

    Even after smoking cessation, genetic damage in the airways epithelium may lead to focal progression of lung carcinogenesis. Some centres now report as many new lung cancer cases among former smokers as among current smokers. Chemoprevention is a potential approach to diminish the progression of pre-clinical genetic damage. The most intensively studied lung cancer chemoprevention agents are the retinoids, including vitamin A and its synthetic analogues and precursors. While effective in suppressing lung carcinogenesis in animal models, retinoids have failed to inhibit carcinogenesis in human chemoprevention trials with premalignant end-points (sputum atypia, bronchial metaplasia). In trials with lung cancer end-points, administration of retinoids either was ineffective or, in the case of beta-carotene, led to greater lung cancer incidence and mortality. In view of these findings, markers of specific retinoid effect (i.e., levels of RAR-beta) become less relevant. Other markers of genetic instability and proliferation may be useful for both early detection and potentially as intermediate-effect markers for new chemoprevention trials. Cytological atypia, bronchial metaplasia, protein (hnRNP A2/B1) overexpression, ras oncogene activation and tumour-suppressor gene deletion, genomic instability (loss of heterozygosity, microsatellite alterations), abnormal methylation, helical CT detection of atypical adenomatous hyperplasia and fluorescent bronchoscopic detection of angiogenic squamous dysplasia offer great promise for molecular diagnosis of lung cancer far in advance of clinical presentation. These end-points can now be evaluated as monitors of response to chemoprevention as potential intermediate-effect markers. PMID:11220665

  11. The Role of Sulforaphane in Epigenetic Mechanisms, Including Interdependence between Histone Modification and DNA Methylation.

    PubMed

    Kaufman-Szymczyk, Agnieszka; Majewski, Grzegorz; Lubecka-Pietruszewska, Katarzyna; Fabianowska-Majewska, Krystyna

    2015-01-01

    Carcinogenesis as well as cancer progression result from genetic and epigenetic changes of the genome that leads to dysregulation of transcriptional activity of genes. Epigenetic mechanisms in cancer cells comprise (i) post-translation histone modification (i.e., deacetylation and methylation); (ii) DNA global hypomethylation; (iii) promoter hypermethylation of tumour suppressor genes and genes important for cell cycle regulation, cell differentiation and apoptosis; and (iv) posttranscriptional regulation of gene expression by noncoding microRNA. These epigenetic aberrations can be readily reversible and responsive to both synthetic agents and natural components of diet. A source of one of such diet components are cruciferous vegetables, which contain high levels of a number of glucosinolates and deliver, after enzymatic hydrolysis, sulforaphane and other bioactive isothiocyanates, that are involved in effective up-regulation of transcriptional activity of certain genes and also in restoration of active chromatin structure. Thus a consumption of cruciferous vegetables, treated as a source of isothiocyanates, seems to be potentially useful as an effective cancer preventive factor or as a source of nutrients improving efficacy of standard chemotherapies. In this review an attempt is made to elucidate the role of sulforaphane in regulation of gene promoter activity through a direct down-regulation of histone deacetylase activity and alteration of gene promoter methylation in indirect ways, but the sulforaphane influence on non-coding micro-RNA will not be a subject of this review. PMID:26703571

  12. The Role of Sulforaphane in Epigenetic Mechanisms, Including Interdependence between Histone Modification and DNA Methylation

    PubMed Central

    Kaufman-Szymczyk, Agnieszka; Majewski, Grzegorz; Lubecka-Pietruszewska, Katarzyna; Fabianowska-Majewska, Krystyna

    2015-01-01

    Carcinogenesis as well as cancer progression result from genetic and epigenetic changes of the genome that leads to dysregulation of transcriptional activity of genes. Epigenetic mechanisms in cancer cells comprise (i) post-translation histone modification (i.e., deacetylation and methylation); (ii) DNA global hypomethylation; (iii) promoter hypermethylation of tumour suppressor genes and genes important for cell cycle regulation, cell differentiation and apoptosis; and (iv) posttranscriptional regulation of gene expression by noncoding microRNA. These epigenetic aberrations can be readily reversible and responsive to both synthetic agents and natural components of diet. A source of one of such diet components are cruciferous vegetables, which contain high levels of a number of glucosinolates and deliver, after enzymatic hydrolysis, sulforaphane and other bioactive isothiocyanates, that are involved in effective up-regulation of transcriptional activity of certain genes and also in restoration of active chromatin structure. Thus a consumption of cruciferous vegetables, treated as a source of isothiocyanates, seems to be potentially useful as an effective cancer preventive factor or as a source of nutrients improving efficacy of standard chemotherapies. In this review an attempt is made to elucidate the role of sulforaphane in regulation of gene promoter activity through a direct down-regulation of histone deacetylase activity and alteration of gene promoter methylation in indirect ways, but the sulforaphane influence on non-coding micro-RNA will not be a subject of this review. PMID:26703571

  13. Chemoprevention of colorectal cancer.

    PubMed

    Lang, Michaela; Gasche, Christoph

    2015-01-01

    Colorectal cancer has become one of the most prevalent malignant diseases for both men and women. Patients with inflammatory bowel diseases or certain inherited cancer syndromes are at high risk of developing colorectal cancer and have naturally the highest need for cancer prevention. In familial adenomatous polyposis (FAP) and Lynch syndrome, most of the underlying germline mutations can be detected by DNA sequencing, and medical counselling of affected individuals involves both surveillance tests and chemopreventive measures. However, as the mechanisms leading to colorectal cancer differ in these high-risk groups, the molecular action of chemopreventive drugs needs to be adjusted to the certain pathway of carcinogenesis. In the last decades, a number of drugs have been tested, including sulindac, aspirin, celecoxib, and mesalazine, but some of them are still controversially discussed. This review summarizes the advances and current standards of colorectal cancer prevention in patients with inflammatory bowel disease, FAP and Lynch syndrome. PMID:25531498

  14. Intermediate endpoint biomarkers for lung cancer chemoprevention

    NASA Astrophysics Data System (ADS)

    MacAulay, Calum E.; Lam, Stephen; Klein-Parker, Helga; Gazdar, Adi; Guillaud, Martial; Payne, Peter W.; Le Riche, Jean C.; Dawe, Chris; Band, Pierre; Palcic, Branko

    1998-04-01

    Given the demographics of current and ex-smoking populations in North America, lung cancer will be a major problem in the foreseeable future. Early detection and treatment of lung cancer holds great promise for the management of this disease. Unlike cervical cancer, the physical, complete removal/destruction of all dysplastic lesions in the bronchial tree is not possible; however, treatment of the lesions using a chemopreventive agent is. Intermediate biomarkers have been used to screen promising chemopreventive agents for larger population studies. We have examined the natural history of lung cancer development by following a group of subjects at high risk of developing lung cancer using fluorescence endoscopy to identify the areas of abnormality for biopsy. Approximately 900 biopsies have been collected in this fashion and graded by at least two experienced, expert pathologists. Using an interactive version of the Cyto-Savant (Oncometrics Imaging Corp.), cytometric and tissue architectural data were collected from these biopsies. Using only the data from the normal and invasive cancer biopsies, quantitative morphometric and architectural indices were generated and calculated for all the collected biopsies. These indices were compared with Loss of Heterozygosity (LOH) of ten sites commonly associated with cancer. These results and the application of these quantitative measures to two small chemoprevention studies will be reported.

  15. Dietary chalcones with chemopreventive and chemotherapeutic potential.

    PubMed

    Orlikova, Barbora; Tasdemir, Deniz; Golais, Frantisek; Dicato, Mario; Diederich, Marc

    2011-05-01

    Chalcones are absorbed in the daily diet and appear to be promising cancer chemopreventive agents. Chalcones represent an important group of the polyphenolic family, which includes a large number of naturally occurring molecules. This family possesses an interesting spectrum of biological activities, including antioxidative, antibacterial, anti-inflammatory, anticancer, cytotoxic, and immunosuppressive potential. Compounds of this family have been shown to interfere with each step of carcinogenesis, including initiation, promotion and progression. Moreover, numerous compounds from the family of dietary chalcones appear to show activity against cancer cells, suggesting that these molecules or their derivatives may be considered as potential anticancer drugs. This review will focus primarily on prominent members of the chalcone family with an 1,3-diphenyl-2-propenon core structure. Specifically, the inhibitory effects of these compounds on the different steps of carcinogenesis that reveal interesting chemopreventive and chemotherapeutic potential will be discussed. PMID:21484163

  16. Chemoprevention in gastrointestinal physiology and disease. Anti-inflammatory approaches for colorectal cancer chemoprevention.

    PubMed

    Fajardo, Alexandra M; Piazza, Gary A

    2015-07-15

    Colorectal cancer (CRC) is one of the most common human malignancies and a leading cause of cancer-related deaths in developed countries. Identifying effective preventive strategies aimed at inhibiting the development and progression of CRC is critical for reducing the incidence and mortality of this malignancy. The prevention of carcinogenesis by anti-inflammatory agents including nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and natural products is an area of considerable interest and research. Numerous anti-inflammatory agents have been identified as potential CRC chemopreventive agents but vary in their mechanism of action. This review will discuss the molecular mechanisms being studied for the CRC chemopreventive activity of NSAIDs (i.e., aspirin, sulindac, and ibuprofen), COX-2 inhibitors (i.e., celecoxib), natural products (i.e., curcumin, resveratrol, EGCG, genistein, and baicalein), and metformin. A deeper understanding of how these anti-inflammatory agents inhibit CRC will provide insight into the development of potentially safer and more effective chemopreventive drugs. PMID:26021807

  17. Chemoprevention in gastrointestinal physiology and disease. Anti-inflammatory approaches for colorectal cancer chemoprevention

    PubMed Central

    Piazza, Gary A.

    2015-01-01

    Colorectal cancer (CRC) is one of the most common human malignancies and a leading cause of cancer-related deaths in developed countries. Identifying effective preventive strategies aimed at inhibiting the development and progression of CRC is critical for reducing the incidence and mortality of this malignancy. The prevention of carcinogenesis by anti-inflammatory agents including nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and natural products is an area of considerable interest and research. Numerous anti-inflammatory agents have been identified as potential CRC chemopreventive agents but vary in their mechanism of action. This review will discuss the molecular mechanisms being studied for the CRC chemopreventive activity of NSAIDs (i.e., aspirin, sulindac, and ibuprofen), COX-2 inhibitors (i.e., celecoxib), natural products (i.e., curcumin, resveratrol, EGCG, genistein, and baicalein), and metformin. A deeper understanding of how these anti-inflammatory agents inhibit CRC will provide insight into the development of potentially safer and more effective chemopreventive drugs. PMID:26021807

  18. D, L-Sulforaphane Loaded Fe3O4@ Gold Core Shell Nanoparticles: A Potential Sulforaphane Delivery System

    PubMed Central

    Kheiri Manjili, Hamidreza; Ma’mani, Leila; Tavaddod, Sharareh; Mashhadikhan, Maedeh; Shafiee, Abbas; Naderi-Manesh, Hossein

    2016-01-01

    A novel design of gold-coated iron oxide nanoparticles was fabricated as a potential delivery system to improve the efficiency and stability of d, l-sulforaphane as an anticancer drug. To this purpose, the surface of gold-coated iron oxide nanoparticles was modified for sulforaphane delivery via furnishing its surface with thiolated polyethylene glycol-folic acid and thiolated polyethylene glycol-FITC. The synthesized nanoparticles were characterized by different techniques such as FTIR, energy dispersive X-ray spectroscopy, UV-visible spectroscopy, scanning and transmission electron microscopy. The average diameters of the synthesized nanoparticles before and after sulforaphane loading were obtained ∼ 33 nm and ∼ 38 nm, respectively, when ∼ 2.8 mmol/g of sulforaphane was loaded. The result of cell viability assay which was confirmed by apoptosis assay on the human breast cancer cells (MCF-7 line) as a model of in vitro-cancerous cells, proved that the bare nanoparticles showed little inherent cytotoxicity, whereas the sulforaphane-loaded nanoparticles were cytotoxic. The expression rate of the anti-apoptotic genes (bcl-2 and bcl-xL), and the pro-apoptotic genes (bax and bak) were quantified, and it was found that the expression rate of bcl-2 and bcl-xL genes significantly were decreased when MCF-7 cells were incubated by sulforaphane-loaded nanoparticles. The sulforaphane-loaded into the designed gold-coated iron oxide nanoparticles, acceptably induced apoptosis in MCF-7 cells. PMID:26982588

  19. D, L-Sulforaphane Loaded Fe3O4@ Gold Core Shell Nanoparticles: A Potential Sulforaphane Delivery System.

    PubMed

    Kheiri Manjili, Hamidreza; Ma'mani, Leila; Tavaddod, Sharareh; Mashhadikhan, Maedeh; Shafiee, Abbas; Naderi-Manesh, Hossein

    2016-01-01

    A novel design of gold-coated iron oxide nanoparticles was fabricated as a potential delivery system to improve the efficiency and stability of d, l-sulforaphane as an anticancer drug. To this purpose, the surface of gold-coated iron oxide nanoparticles was modified for sulforaphane delivery via furnishing its surface with thiolated polyethylene glycol-folic acid and thiolated polyethylene glycol-FITC. The synthesized nanoparticles were characterized by different techniques such as FTIR, energy dispersive X-ray spectroscopy, UV-visible spectroscopy, scanning and transmission electron microscopy. The average diameters of the synthesized nanoparticles before and after sulforaphane loading were obtained ∼ 33 nm and ∼ 38 nm, respectively, when ∼ 2.8 mmol/g of sulforaphane was loaded. The result of cell viability assay which was confirmed by apoptosis assay on the human breast cancer cells (MCF-7 line) as a model of in vitro-cancerous cells, proved that the bare nanoparticles showed little inherent cytotoxicity, whereas the sulforaphane-loaded nanoparticles were cytotoxic. The expression rate of the anti-apoptotic genes (bcl-2 and bcl-xL), and the pro-apoptotic genes (bax and bak) were quantified, and it was found that the expression rate of bcl-2 and bcl-xL genes significantly were decreased when MCF-7 cells were incubated by sulforaphane-loaded nanoparticles. The sulforaphane-loaded into the designed gold-coated iron oxide nanoparticles, acceptably induced apoptosis in MCF-7 cells. PMID:26982588

  20. Prostate cancer chemoprevention: Current status and future prospects

    SciTech Connect

    Gupta, Sanjay

    2007-11-01

    Chemoprevention is a strategy that aims to reduce the incidence and burden of cancer through the development of agents to prevent, reverse or delay the carcinogenic process. Prostate cancer is a suitable target for prevention because it has a high incidence and prevalence, as well as a long latency and disease-related mortality, and furthermore it is a disease in which lifestyle and environmental factors may play critical roles. The development of chemoprevention strategies against prostate cancer will have a huge impact, both medically and economically. Large-scale clinical trials suggest that some agents such as selenium, lycopene, soy, green tea, vitamins D and E, anti-inflammatory and inhibitors of 5{alpha}-reductase are effective in preventing prostate cancer. Although each agent has the potential to affect the natural history of the disease, it is important to develop strategies to strategically proceed for the design and selection of test agents in order to demonstrate clinical benefit with the minimum of adverse effects. Appropriate selection of agent(s), disease stage, trial design and endpoints is critical in selecting the most promising regimens to accomplish these goals. This review highlights the present status of prostate cancer chemoprevention and discusses future prospects for chemopreventive strategies that are safe and clinically beneficial.

  1. Chemoprevention of esophageal squamous cell carcinoma

    SciTech Connect

    Stoner, Gary D. Wang Lishu; Chen Tong

    2007-11-01

    Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, and to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.

  2. Interaction of Sulforaphane with DNA and RNA

    PubMed Central

    Abassi Joozdani, Farzaneh; Yari, Faramarz; Abassi Joozdani, Parvaneh; Nafisi, Shohreh

    2015-01-01

    Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables with anti-inflammatory, anti-oxidant and anti-cancer activities. However, the antioxidant and anticancer mechanism of sulforaphane is not well understood. In the present research, we reported binding modes, binding constants and stability of SFN–DNA and -RNA complexes by Fourier transform infrared (FTIR) and UV–Visible spectroscopic methods. Spectroscopic evidence showed DNA intercalation with some degree of groove binding. SFN binds minor and major grooves of DNA and backbone phosphate (PO2), while RNA binding is through G, U, A bases with some degree of SFN–phosphate (PO2) interaction. Overall binding constants were estimated to be K(SFN–DNA)=3.01 (± 0.035)×104 M-1 and K(SFN–RNA)= 6.63 (±0.042)×103 M-1. At high SFN concentration (SFN/RNA = 1/1), DNA conformation changed from B to A occurred, while RNA remained in A-family structure. PMID:26030290

  3. Sulforaphane Treatment of Young Men with Autism Spectrum Disorder.

    PubMed

    Singh, Kanwaljit; Zimmerman, Andrew W

    2016-01-01

    Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders that begin in early childhood. They are characterized by differences in behavior and delays in communication and affect at least 1% of children. Observational studies have now confirmed that behaviors of a substantial percentage of children with autism tend to improve with the onset of febrile illness, which might be the downstream effects of altered metabolic pathways involving increased expression of heat shock proteins (HSP) and cellular stress responses. Sulforaphane, a phytochemical derived from a number of cruciferous vegetables, most notably broccoli sprouts, has metabolic effects that in some ways resemble that of fever. This review paper discusses this "fever effect" and the intracellular effects of sulforaphane as well as the results of our recent clinical trial of sulforaphane in young adults with autism. The accompanying review by Liu et al. describes the cellular actions of sulforaphane and potential biomarkers in the study of ASD. PMID:27071786

  4. Natural chemopreventive alternatives in oral cancer chemoprevention.

    PubMed

    Scrobota, I; Bolfa, P; Filip, A G; Catoi, C; Alb, C; Pop, O; Tatomir, C; Baciut, G

    2016-02-01

    We studied the effect of grape seed extract Burgund Mare (BM) on oral carcinogenesis and compared it with that of curcumin (CU). Wistar rats were divided into six groups (n = 10): 4-nitro-quinoline-1-oxide (4NQO) oral carcinogenesis was induced to groups 1 - 5; groups 2 and 3 received BM and CU respectively during initiation and groups 4 and 5 BM and CU during post-initiation of carcinogenesis; group 6 represented the negative control group. Total malondialdehyde (MDA) and reduced glutathione (GSH) were assayed fluorometrically in oral tissue (gingival, jugal, palatal, lingual mucosa) and serum. Histopathological exam was performed and a dysplasia score given to each oral mucosal lesion. Ki67, cyclin D1, p63, Bcl2 and p53 were immunohistochemically evaluated. BM and CU reduced tissue MDA values elevated by 4NQO (P = 0.000). The difference between CU and BM effect was significant in the initiation (P = 0.02) but not in the post-initiation phase of carcinogenesis (P = 0.58). Tissue GSH levels decreased by 4NQO (P < 0.001) were not significantly modified by BM or CU. Serum MDA levels increased by 4NQO (P = 0.000) were significantly lowered by CU (P = 0.04) and BM (P = 0.04) during initiation and by CU during post-initiation of carcinogenesis (P = 0.01). CU was more potent than BM during post-initiation of carcinogenesis (P = 0.01). Serum GSH lowered by 4NQO (P = 0.55) was significantly decreased by BM and CU (P < 0.012), with no significant difference between groups receiving BM or CU. Moderate dysplasia was the most advanced dysplasia induced and gingival localization the most frequent. Both BM and CU lowered dysplasia scores, with BM being the most efficient during post-initiation of carcinogenesis (P = 0.001). Ki67, cyclin D1, p63, Bcl2 and p53 expression increased with dysplasia scores. BM showed chemopreventive properties during initiation and post-initiation of oral carcinogenesis, reducing local and general oxidative stress and the intensity of dysplasia

  5. Advanced Drug-Delivery Systems of Curcumin for Cancer Chemoprevention

    PubMed Central

    Bansal, Shyam S.; Goel, Mehak; Aqil, Farrukh; Vadhanam, Manicka V.; Gupta, Ramesh C.

    2011-01-01

    From ancient times, chemopreventive agents have been used to treat/prevent several diseases, including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, anti-oxidant, anti-proliferative, anti-carcinogenic, and anti-angiogenic activity in various cell culture and some animal studies. Research over the past four decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell-culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been demonstrated to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician’s armamentarium. PMID:21546540

  6. Advanced drug delivery systems of curcumin for cancer chemoprevention.

    PubMed

    Bansal, Shyam S; Goel, Mehak; Aqil, Farrukh; Vadhanam, Manicka V; Gupta, Ramesh C

    2011-08-01

    Since ancient times, chemopreventive agents have been used to treat/prevent several diseases including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, antioxidant, antiproliferative, anticarcinogenic, and antiangiogenic activity in various cell cultures and some animal studies. Research over the past 4 decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician's armamentarium. PMID:21546540

  7. [Chemoprevention of lung cancer].

    PubMed

    Tsuchida, Takaaki; Saito, Makoto; Honda, Hidetoshi; Hirata, Takeshi; Kato, Harubumi

    2003-02-01

    Since a high concentration of beta-carotene in blood reduces the risk of lung cancer, a large-scale intervention examination containing beta-carotene was conducted, mainly by the National Cancer Institute. The results showed that the risk of lung cancer increased with administration of beta-carotene. This result demonstrates that continuation of smoking is an important factor in the increased risk, and not smoking is confirmed to be the most important prevention method. The authors examined the treatment effect of raising the concentration of folic acid and vitamin B12 in blood on bronchial dysplasia as a pre-cancerous lesion. A significant medical treatment effect was see in the folic acid and vitamin B12 medication groups, which seems promising for the chemoprevention of lung cancer. PMID:12610863

  8. Biomarkers and surrogacy: relevance to chemoprevention.

    PubMed

    Kensler, T W; Davidson, N E; Groopman, J D; Muñoz, A

    2001-01-01

    Clinical cancer prevention trials that use disease as the end-point are of necessity large, lengthy and costly. While such trials will always remain the 'gold standard' for establishing efficacy, they are unwieldy and inefficient for the rapid translation of our accelerating understanding of the molecular basis of cancer into preventive strategies. The inclusion of biomarkers in the process of chemopreventive agent development is crucial for the advancement of the field. This overview highlights the types of approach that are being used in the development and application of biomarkers in chemoprevention studies. Biomarkers, which measure exposure, susceptibility or risk factors, can be used in selecting study cohorts, assessing participant compliance and/or determining agent efficacy. Key features of biomarkers include reliability, precision, accuracy and validity. Not all biomarkers are suitable for all purposes and are likely to be imperfect in any single setting. Judicious selection and matching of biomarkers with agents and study cohorts is required for their effective utilization. A critical but non-dichotomous element of risk biomarkers is their degree of surrogacy. A classification scheme is provided that relates the degree of surrogacy of risk biomarkers to their utility in preventive interventions. PMID:11220666

  9. Aspirin and colorectal cancer: the promise of precision chemoprevention.

    PubMed

    Drew, David A; Cao, Yin; Chan, Andrew T

    2016-03-01

    Aspirin (acetylsalicylic acid) has become one of the most commonly used drugs, given its role as an analgesic, antipyretic and agent for cardiovascular prophylaxis. Several decades of research have provided considerable evidence demonstrating its potential for the prevention of cancer, particularly colorectal cancer. Broader clinical recommendations for aspirin-based chemoprevention strategies have recently been established; however, given the known hazards of long-term aspirin use, larger-scale adoption of an aspirin chemoprevention strategy is likely to require improved identification of individuals for whom the protective benefits outweigh the harms. Such a precision medicine approach may emerge through further clarification of aspirin's mechanism of action. PMID:26868177

  10. Sulforaphane modulates telomerase activity via epigenetic regulation in prostate cancer cell lines.

    PubMed

    Abbas, Ata; Hall, J Adam; Patterson, William L; Ho, Emily; Hsu, Anna; Al-Mulla, Fahd; Georgel, Philippe T

    2016-02-01

    Epidemiologic studies have revealed that diets rich in sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables, are associated with a marked decrease in prostate cancer incidence. The chemo-preventive role of SFN is associated with its histone de-acetylase inhibitor activity. However, the effect of SFN on chromatin composition and dynamic folding, especially in relation to HDAC inhibitor activity, remains poorly understood. In this study, we found that SFN can inhibit the expression and activity of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, in 2 prostate cancer cell lines. This decrease in gene expression is correlated with SFN-induced changes in chromatin structure and composition. The SFN-mediated changes in levels of histone post-translational modifications, more specifically acetylation of histone H3 lysine 18 and di-methylation of histone H3 lysine 4, 2 modifications linked with high risk of prostate cancer recurrence, were associated with regulatory elements within the hTERT promoter region. Chromatin condensation may also play a role in SFN-mediated hTERT repression, since expression and recruitment of MeCP2, a known chromatin compactor, were altered in SFN treated prostate cancer cells. Chromatin immuno-precipitation (ChIP) of MeCP2 showed enrichment over regions of the hTERT promoter with increased nucleosome density. These combined results strongly support a role for SFN in the mediation of epigenetic events leading to the repression of hTERT in prostate cancer cells. This ability of SFN to modify chromatin composition and structure associated with target gene expression provides a new model by which dietary phytochemicals may exert their chemoprevention activity. PMID:26458818

  11. Continuous exposure of pancreatic cancer cells to dietary bioactive agents does not induce drug resistance unlike chemotherapy.

    PubMed

    Fan, P; Zhang, Y; Liu, L; Zhao, Z; Yin, Y; Xiao, X; Bauer, N; Gladkich, J; Mattern, J; Gao, C; Schemmer, P; Gross, W; Herr, I

    2016-01-01

    The repeated treatment of cancer cells with chemo- or radiotherapy induces therapy resistance, but it was previously unknown whether the same effect occurs upon continuous exposure of cancer cells to diet-derived chemopreventive agents. We elucidated this interesting question in pancreatic ductal adenocarcinoma, which is a highly aggressive cancer entity with a marked resistance toward gemcitabine and other cytotoxic drugs. The isothiocyanate sulforaphane, present in cruciferous vegetables, and the polyphenol quercetin, present in many fruits and vegetables induced apoptosis and reduced viability in gemcitabine-sensitive BxPC-3 cells but not in non-malignant ductal pancreas cells and mesenchymal stromal cells. In turn, BxPC-3 cells were treated with increasing concentrations of gemcitabine, sulforaphane or quercetin for more than 1 year and the surviving subclones Bx-GEM, Bx-SF and Bx-Q were selected, respectively. While Bx-GEM cells acquired a total resistance, Bx-SF or Bx-Q cells largely kept their sensitivity as proved by MTT assay, annexin staining and FACS analysis. The evaluation of the self-renewal-, differentiation- and migration-potential by colony formation, differentiation or migration assays demonstrated that cancer stem cell features were enriched in gemcitabine-resistant cells, but decreased in sulforaphane- and quercetin-long time-treated cells. These results were confirmed by orthotopic xenotransplantation of cancer cells to the mouse pancreas, where Bx-GEM formed large, Bx-Q small and Bx-SF cells almost undetectable tumors. An mRNA expression profiling array and subsequent gene set enrichment analysis and qRT-PCR confirmed that tumor progression markers were enriched in Bx-GEM, but reduced in Bx-SF and Bx-Q cells. This study demonstrates that the continuous exposure of pancreatic cancer cells to sulforaphane or quercetin does not induce resistance in surviving cells but reduces tumorigenicity by inhibition of tumor progression markers. These

  12. Is There a Future for Chemoprevention of Prostate Cancer?

    PubMed

    Bosland, Maarten C

    2016-08-01

    The outcome of the Selenium and Vitamin E Cancer Prevention Trial, demonstrating harm and no preventive activity of selenomethionine and α-tocopherol for prostate cancer, and the lack of approval by the FDA for the use of 5α-reductase inhibitors to prevent prostate cancer have cast doubt about the future of chemoprevention of prostate cancer. This article attempts to critically assess whether the notion that chemoprevention of prostate cancer has no future is warranted. Risk of prostate cancer is modifiable and chemoprevention of prostate cancer, particularly fatal/lethal cancer, is both needed and possible. However, the approach to prostate cancer-chemopreventive agent development has not followed a rational and systematic process. To make progress, the following steps are necessary: (i) identification of intermediate biomarkers predictive of fatal/lethal disease; (ii) development of a rational approach to identification of candidate agents, including high-throughput screening and generation of information on mechanism and biology of candidate agents and potential molecular targets; and (iii) systematic evaluation of the predictive value of preclinical models, phase II trials, and intermediate biomarkers for the outcome of phase III trials. New phase III trials should be based on adequate preclinical and phase II studies. Cancer Prev Res; 9(8); 642-7. ©2016 AACR. PMID:27099271

  13. Chemoprevention of prostate cancer with nutrients and supplements.

    PubMed

    Van Poppel, Hendrik; Tombal, Bertrand

    2011-01-01

    As the adult population is increasing, prostate cancer (PCa) will become a considerable health problem in the next millennium. This has raised public interest in potential chemoprevention of this disease. As PCa is extremely common and generally slow to progress it is regarded as an ideal candidate for chemoprevention. At present, the 5 alpha-reductase inhibitors finasteride and dutasteride have been identified as preventive agents. This review describes whether selenium, alpha-tocopherol, isoflavones, lycopene green tea polyphenols, calcium, and resveratrol may be useful for decreasing the risk of PCa in men. Although encouraging results are present, some studies show negative results. Differences in study design, sample size, dose administered, and/or concentrations achieved in the body may be the reason for these inconsistencies. Today, chemopreventive agents may be appropriate for high-risk patients like those with high-grade prostatic intraepithelial neoplasia and other high-risk groups such as patients with elevated prostate specific antigen (PSA) and negative biopsy, rapid PSA velocity, and with a family history of PCa. Although larger randomized controlled studies are needed and epidemiologic evidence should be placed in a clinical context, physicians must be aware of these preventive opportunities in PCa care. Combinations of chemopreventive agents should be carefully investigated because mechanisms of action may be additive or synergistic. PMID:21629831

  14. Chemoprevention targets for tobacco-related head and neck cancer: past lessons and future directions.

    PubMed

    Sheth, Siddharth H; Johnson, Daniel E; Kensler, Thomas W; Bauman, Julie E

    2015-06-01

    Progress toward identifying an effective chemopreventive agent to reduce the incidence of head and neck squamous cell carcinoma (HNSCC) has been limited by poor efficacy and intolerable toxicity profiles. In this review, we summarize the biological basis of HNSCC chemoprevention, and outline challenges associated with identifying appropriate high-risk HNSCC populations for chemoprevention studies. We discuss findings and lessons learned from clinical trials that have investigated micronutrient and molecular targeting interventions. Finally, we introduce the concept of green chemoprevention, interventions based upon whole plant foods or simple extracts that may represent a safe and cost-conscious option for the next generation of studies. As our scientific understanding of HNSCC reaches new levels, the field is poised to develop chemoprevention studies based on rigorous biological validation with accessibility to all affected individuals regardless of socioeconomic barriers. PMID:25868717

  15. A Perspective on Prostate Carcinogenesis and Chemoprevention

    PubMed Central

    Bosland, Maarten C.; Ozten, Nur; Eskra, Jillian N.; Mahmoud, Abeer M.

    2015-01-01

    In this perspective, modifiable carcinogenic factors for the prostate are summarized. This is followed by a discussion of how current knowledge about causation of prostate cancer and chemoprevention of prostate cancer can be used to develop preventive strategies. Prostate cancer is a slowly developing cancer which offers opportunities for preventive interventions. Only a few randomized clinical trials of prostate cancer prevention have been completed. The SELECT study with selenium and vitamin E did not find protective effects, but in two trials with 5α-reductase inhibitors risk was reduced about 25%, showing that chemoprevention is possible and indicating that the androgen receptor is a suitable target. Besides smoking cessation and reduction of obesity, there are no known dietary or life style interventions that will have a major impact on prostate cancer risk. Inflammation of the prostate is an attractive target and aspirin may be a promising candidate agent, but has not been addressed yet in preclinical and clinical studies. Antioxidants other than selenium and vitamin E are unlikely to be very effective and data on several dietary supplements are not encouraging. More candidate agents need to be identified and tested in relevant and adequate preclinical models and Phase II trials that have predictive value for outcome of Phase III randomized studies. Doing this will require a systematic approach comparing preclinical and clinical study outcomes to determine their predictive value of preventive efficacy. PMID:26442200

  16. Chemoprevention in Barrett's Esophagus: Current Status.

    PubMed

    Zeb, Muhammad H; Baruah, Anushka; Kossak, Sarah K; Buttar, Navtej S

    2015-06-01

    Chemoprevention in Barrett's esophagus is currently applied only in research settings. Identifying pathways that can be targeted by safe, pharmaceutical or natural compounds is key to expanding the scope of chemoprevention. Defining meaningful surrogate markers of cancer progression is critical to test the efficacy of chemopreventive approaches. Combinatorial chemoprevention that targets multiple components of the same pathway or parallel pathways could reduce the risk and improve the efficacy of chemoprevention. Here we discuss the role of chemoprevention as an independent or an adjuvant management option in BE-associated esophageal adenocarcinoma. PMID:26021201

  17. SPBP Is a Sulforaphane Induced Transcriptional Coactivator of NRF2 Regulating Expression of the Autophagy Receptor p62/SQSTM1

    PubMed Central

    Darvekar, Sagar Ramesh; Elvenes, Julianne; Brenne, Hanne Britt; Johansen, Terje; Sjøttem, Eva

    2014-01-01

    Organisms exposed to oxidative stress respond by orchestrating a stress response to prevent further damage. Intracellular levels of antioxidant agents increase, and damaged components are removed by autophagy induction. The KEAP1-NRF2 signaling pathway is the main pathway responsible for cell defense against oxidative stress and for maintaining the cellular redox balance at physiological levels. Sulforaphane, an isothiocyanate derived from cruciferous vegetables, is a potent inducer of KEAP1-NRF2 signaling and antioxidant response element driven gene expression. In this study, we show that sulforaphane enhances the expression of the transcriptional coregulator SPBP. The expression curve peaks 6–8 hours post stimulation, and parallels the sulforaphane-induced expression of NRF2 and the autophagy receptor protein p62/SQSTM1. Reporter gene assays show that SPBP stimulates the expression of p62/SQSTM1 via ARE elements in the promoter region, and siRNA mediated knock down of SPBP significantly decreases the expression of p62/SQSTM1 and the formation of p62/SQSTM1 bodies in HeLa cells. Furthermore, SPBP siRNA reduces the sulforaphane induced expression of NRF2, and the expression of the autophagy marker protein LC3B. Both these proteins contain ARE-like elements in their promoter regions. Over-expressed SPBP and NRF2 acts synergistically on the p62/SQSTM1 promoter and colocalize in nuclear speckles in HeLa cells. Collectively, these results suggest that SPBP is a coactivator of NRF2, and hence may be important for securing enhanced and sustained expression of NRF2 induced genes such as proteins involved in selective autophagy. PMID:24416372

  18. SPBP is a sulforaphane induced transcriptional coactivator of NRF2 regulating expression of the autophagy receptor p62/SQSTM1.

    PubMed

    Darvekar, Sagar Ramesh; Elvenes, Julianne; Brenne, Hanne Britt; Johansen, Terje; Sjøttem, Eva

    2014-01-01

    Organisms exposed to oxidative stress respond by orchestrating a stress response to prevent further damage. Intracellular levels of antioxidant agents increase, and damaged components are removed by autophagy induction. The KEAP1-NRF2 signaling pathway is the main pathway responsible for cell defense against oxidative stress and for maintaining the cellular redox balance at physiological levels. Sulforaphane, an isothiocyanate derived from cruciferous vegetables, is a potent inducer of KEAP1-NRF2 signaling and antioxidant response element driven gene expression. In this study, we show that sulforaphane enhances the expression of the transcriptional coregulator SPBP. The expression curve peaks 6-8 hours post stimulation, and parallels the sulforaphane-induced expression of NRF2 and the autophagy receptor protein p62/SQSTM1. Reporter gene assays show that SPBP stimulates the expression of p62/SQSTM1 via ARE elements in the promoter region, and siRNA mediated knock down of SPBP significantly decreases the expression of p62/SQSTM1 and the formation of p62/SQSTM1 bodies in HeLa cells. Furthermore, SPBP siRNA reduces the sulforaphane induced expression of NRF2, and the expression of the autophagy marker protein LC3B. Both these proteins contain ARE-like elements in their promoter regions. Over-expressed SPBP and NRF2 acts synergistically on the p62/SQSTM1 promoter and colocalize in nuclear speckles in HeLa cells. Collectively, these results suggest that SPBP is a coactivator of NRF2, and hence may be important for securing enhanced and sustained expression of NRF2 induced genes such as proteins involved in selective autophagy. PMID:24416372

  19. Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition

    PubMed Central

    APPARI, MAHESH; BABU, KAMESH R.; KACZOROWSKI, ADAM; GROSS, WOLFGANG; HERR, INGRID

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all malignancies, and current therapeutic options do not target cancer stem cells (CSCs), which may be the reason for the extreme aggressiveness. The dietary agents sulforaphane and quercetin enriched e.g., in broccoli, and the main and best studied green tea catechin EGCG hold promise as anti-CSC agents in PDA. We examined the efficacy of additional catechins and the combination of these bioactive agents to stem cell features and miRNA signaling. Two established and one primary PDA cell line and non-malignant pancreatic ductal cells were used. Whereas each agent strongly inhibited colony formation, the catechins ECG and CG were more effective than EGCG. A mixture of green tea catechins (GTCs) significantly inhibited viability, migration, expression of MMP-2 and -9, ALDH1 activity, colony and spheroid formation and induced apoptosis, but the combination of GTCs with sulforaphane or quercetin was superior. Following treatment with bioactive agents, the expression of miR-let7-a was specifically induced in cancer cells but not in normal cells and it was associated with K-ras inhibition. These data demonstrate that sulforaphane, quercetin and GTC complement each other in inhibition of PDA progression by induction of miR-let7-a and inhibition of K-ras. PMID:25017900

  20. Cancer chemopreventive and therapeutic effects of diosgenin, a food saponin.

    PubMed

    Raju, Jayadev; Mehta, Rekha

    2009-01-01

    Cancer chemoprevention is a strategy taken to retard, regress, or resist the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal-preneoplasia-neoplasia-metastasis. For several reasons, including safety, minimal (or no) toxicity and side-effects, and better availability, alternatives such as naturally occurring phytochemicals that are found in foods are becoming increasingly popular over synthetic drugs. Food saponins have been used in complimentary and traditional medicine against a variety of diseases including several cancers. Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a well-known precursor of various synthetic steroidal drugs that are extensively used in the pharmaceutical industry. Over the past decade, a series of preclinical and mechanistic studies have been conducted to understand the role of diosgenin as a chemopreventive/therapeutic agent against several cancers. This review highlights the biological activity of diosgenin that contributes to cancer chemoprevention and control. The anticancer mode of action of diosgenin has been demonstrated via modulation of multiple cell signaling events involving critical molecular candidates associated with growth, differentiation, apoptosis, and oncogenesis. Altogether, these preclinical and mechanistic findings strongly implicate the use of diosgenin as a novel, multitarget-based chemopreventive or therapeutic agent against several cancer types. Future research in this field will help to establish not only whether diosgenin is safe and efficacious as a chemopreventive agent against several human cancers, but also to develop and evaluate standards of evidence for health claims for diosgenin-containing foods as they become increasingly popular and enter the marketplace labeled as functional foods and nutraceuticals. PMID:19116873

  1. Sulforaphane protects the heart from doxorubicin-induced toxicity.

    PubMed

    Singh, Preeti; Sharma, Rajendra; McElhanon, Kevin; Allen, Charles D; Megyesi, Judit K; Beneš, Helen; Singh, Sharda P

    2015-09-01

    Cardiotoxicity is one of the major side effects encountered during cancer chemotherapy with doxorubicin (DOX) and other anthracyclines. Previous studies have shown that oxidative stress caused by DOX is one of the primary mechanisms for its toxic effects on the heart. Since the redox-sensitive transcription factor, Nrf2, plays a major role in protecting cells from the toxic metabolites generated during oxidative stress, we examined the effects of the phytochemical sulforaphane (SFN), a potent Nrf2-activating agent, on DOX-induced cardiotoxicity. These studies were carried out both in vitro and in vivo using rat H9c2 cardiomyoblast cells and wild type 129/sv mice, and involved SFN pretreatment followed by SFN administration during DOX exposure. SFN treatment protected H9c2 cells from DOX cytotoxicity and also resulted in restored cardiac function and a significant reduction in DOX-induced cardiomyopathy and mortality in mice. Specificity of SFN induction of Nrf2 and protection of H9c2 cells was demonstrated in Nrf2 knockdown experiments. Cardiac accumulation of 4-hydroxynonenal (4-HNE) protein adducts, due to lipid peroxidation following DOX-induced oxidative stress, was significantly attenuated by SFN treatment. The respiratory function of cardiac mitochondria isolated from mice exposed to DOX alone was repressed, while SFN treatment with DOX significantly elevated mitochondrial respiratory complex activities. Co-administration of SFN reversed the DOX-associated reduction in nuclear Nrf2 binding activity and restored cardiac expression of Nrf2-regulated genes at both the RNA and protein levels. Together, our results demonstrate for the first time that the Nrf2 inducer, SFN, has the potential to provide protection against DOX-mediated cardiotoxicity. PMID:26025579

  2. Nigerian foodstuffs with prostate cancer chemopreventive polyphenols.

    PubMed

    Atawodi, Sunday Eneojo

    2011-09-23

    Dietary polyphenols are antioxidants that can scavenge biological free radicals, and chemoprevent diseases with biological oxidation as their main etiological factor. In this paper, we review our laboratory data vis-ὰ-vis available literature on prostate cancer chemopreventive substances in Nigerian foodstuffs. Dacryodes edulis fruit, Moringa oleifera and Syzygium aromaticum contained prostate active polyphenols like ellagic acid, gallate, methylgallate, catechol, kaempferol quercetin and their derivatives. Also Canarium schweinfurthii Engl oil contained ten phenolic compounds and lignans, namely; catechol, p-hydroxybenzaldehyde, dihydroxyphenylacetic acid, tyrosol, p-hydroxybenzoic acid, dihydroxybenzoic acid, vanillic acid, phloretic acid, pinoresinol, secoisolariciresinol. In addition, tomatoes (Lycopersicon esculentum Mill) which contains the powerful antioxidant and anti-prostate cancer agent, lycopene; cabbage (Brassica oleracea) containing indole-3-carbinol; citrus fruits containing pectin; Soursop (Annona muricata) containing annonaceous acetogenins; soya beans (Glycine max) containing isoflavones; chilli pepper (Capsicum annuum) containing capsaicin, and green tea (Camellia sinensis) containing (-) epigallocatechin gallate (EGCG), (-) epicatechin, (-) epicatechin-3-gallate and (-) epigallocatechin -3-gallate which are widely reported to posses prostate cancer chemopreventive compounds are also grown in Nigeria and other African countries. Thus, the high incidence of prostate cancer among males of African extraction can be dramatically reduced, and the age of onset drastically increased, if the population at risk consumes the right kinds of foods in the right proportion, beginning early in life, especially as prostate cancer has a latency period of about 50 years. PMID:21992488

  3. Chemoprevention studies within lung cancer screening programmes.

    PubMed

    Veronesi, G; Guerrieri-Gonzaga, A; Infante, M; Bonanni, B

    2015-01-01

    While aggressive tobacco control and help to stop smoking are essential weapons in the fight against lung cancer, screening with low-dose computed tomography (LDCT) in high-risk populations and chemoprevention may also contribute to reducing lung cancer deaths. Persons undergoing LDCT screening are an ideal population to be tested for agents potentially able to prevent the development of lung cancer by the regression of precancerous lesions, which are routinely monitored as part of the screening process. Peripheral subsolid nodules appear as particularly suitable targets, since many are adenocarcinoma precursors. A study on inhaled budesonide (a potential chemopreventive drug) for 1 year found that the mean size of non-solid lung nodules was significantly reduced over 5 years of follow-up, compared to inhaled placebo, in a population of high-risk individuals with indeterminate lung nodules not requiring immediate specific investigation for lung cancer and detected as part of a lung cancer screening program with LDCT. A new randomised placebo-controlled phase-II trial to test the ability of aspirin to induce the regression of non-solid and partially solid nodules detected by LDCT screening has been started. The effect of aspirin on a miRNA signature able to predict the presence of both cancer and precancerous lesions in high-risk asymptomatic individuals is also being monitored in the trial. This signature was previously shown to predict the presence of both lung cancer and non-solid lung nodules in asymptomatic individuals. PMID:26635901

  4. Nigerian foodstuffs with prostate cancer chemopreventive polyphenols

    PubMed Central

    2011-01-01

    Dietary polyphenols are antioxidants that can scavenge biological free radicals, and chemoprevent diseases with biological oxidation as their main etiological factor. In this paper, we review our laboratory data vis-ὰ-vis available literature on prostate cancer chemopreventive substances in Nigerian foodstuffs. Dacryodes edulis fruit, Moringa oleifera and Syzygium aromaticum contained prostate active polyphenols like ellagic acid, gallate, methylgallate, catechol, kaempferol quercetin and their derivatives. Also Canarium schweinfurthii Engl oil contained ten phenolic compounds and lignans, namely; catechol, p-hydroxybenzaldehyde, dihydroxyphenylacetic acid, tyrosol, p-hydroxybenzoic acid, dihydroxybenzoic acid, vanillic acid, phloretic acid, pinoresinol, secoisolariciresinol. In addition, tomatoes (Lycopersicon esculentum Mill) which contains the powerful antioxidant and anti-prostate cancer agent, lycopene; cabbage (Brassica oleracea) containing indole-3-carbinol; citrus fruits containing pectin; Soursop (Annona muricata) containing annonaceous acetogenins; soya beans (Glycine max) containing isoflavones; chilli pepper (Capsicum annuum) containing capsaicin, and green tea (Camellia sinensis) containing (-) epigallocatechin gallate (EGCG), (-) epicatechin, (-) epicatechin-3-gallate and (-) epigallocatechin -3-gallate which are widely reported to posses prostate cancer chemopreventive compounds are also grown in Nigeria and other African countries. Thus, the high incidence of prostate cancer among males of African extraction can be dramatically reduced, and the age of onset drastically increased, if the population at risk consumes the right kinds of foods in the right proportion, beginning early in life, especially as prostate cancer has a latency period of about 50 years. PMID:21992488

  5. Strategy and planning for chemopreventive drug development: clinical development plans II.

    PubMed

    Kelloff, G J; Crowell, J A; Hawk, E T; Steele, V E; Lubet, R A; Boone, C W; Covey, J M; Doody, L A; Omenn, G S; Greenwald, P; Hong, W K; Parkinson, D R; Bagheri, D; Baxter, G T; Blunden, M; Doeltz, M K; Eisenhauer, K M; Johnson, K; Knapp, G G; Longfellow, D G; Malone, W F; Nayfield, S G; Seifried, H E; Swall, L M; Sigman, C C

    1996-01-01

    This is the second publication of Clinical Development Plans from the National Cancer Institute, Division of Cancer Prevention and Control, Chemoprevention Branch and Agent Development Committee. The Clinical Development Plans summarize the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. They also contain the strategy for further development of these drugs, addressing pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen new Clinical Development Plans are presented here: curcumin, dehydroepiandrosterone, folic acid, genistein, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, 13-cis-retinoic acid, l-selenomethionine and 1, 4-phenylenebis(methylene)selenocyanate, sulindac sulfone, tea, ursodiol, vitamin A, and (+)-vorozole. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing these and future generations of chemopreventive drugs. PMID:9154168

  6. Repeated Nrf2 stimulation using sulforaphane protects fibroblasts from ionizing radiation

    SciTech Connect

    Mathew, Sherin T.; Bergström, Petra; Hammarsten, Ola

    2014-05-01

    Most of the cytotoxicity induced by ionizing radiation is mediated by radical-induced DNA double-strand breaks. Cellular protection from free radicals can be stimulated several fold by sulforaphane-mediated activation of the transcription factor Nrf2 that regulates more than 50 genes involved in the detoxification of reactive substances and radicals. Here, we report that repeated sulforaphane treatment increases radioresistance in primary human skin fibroblasts. Cells were either treated with sulforaphane for four hours once or with four-hour treatments repeatedly for three consecutive days prior to radiation exposure. Fibroblasts exposed to repeated-sulforaphane treatment showed a more pronounced dose-dependent induction of Nrf2-regulated mRNA and reduced amount of radiation-induced free radicals compared with cells treated once with sulforaphane. In addition, radiation- induced DNA double-strand breaks measured by gamma-H2AX foci were attenuated following repeated sulforaphane treatment. As a result, cellular protection from ionizing radiation measured by the 5-ethynyl-2′-deoxyuridine (EdU) assay was increased, specifically in cells exposed to repeated sulforaphane treatment. Sulforaphane treatment was unable to protect Nrf2 knockout mouse embryonic fibroblasts, indicating that the sulforaphane-induced radioprotection was Nrf2-dependent. Moreover, radioprotection by repeated sulforaphane treatment was dose-dependent with an optimal effect at 10 uM, whereas both lower and higher concentrations resulted in lower levels of radioprotection. Our data indicate that the Nrf2 system can be trained to provide further protection from radical damage. - Highlights: • Repeated treatment with sulforaphane protects fibroblasts from ionizing radiation • Repeated sulforaphane treatment attenuates radiation induced ROS and DNA damage • Sulforaphane mediated protection is Nrf2 dependent.

  7. Omics underpins novel clues on VDR chemoprevention target in breast cancer.

    PubMed

    Muti, Paola; Benassi, Barbara; Falvo, Elisabetta; Santoro, Raffaela; Galanti, Sergio; Citro, Gennaro; Carrubba, Giuseppe; Blandino, Giovanni; Strano, Sabrina

    2011-06-01

    Breast cancer is the commonest form of female malignancy among women in Western countries. The advent of genomic technologies has enhanced the diagnosis and the biological classification of such pathology. It has been demonstrated that cancer takes many years to be fully established. This long dormancy could represent a potential window for intervening with chemoprevention studies. Cancer chemoprevention is by definition the use of natural, synthetic, or biological chemical agents to reverse, suppress, or delay the genetic or other alterations that culminate in the appearance of the tumor phenotype. An important step for the success of chemoprevention is the identification of molecularly targeted agents to prevent cancer development. Currently, only two chemoprevention agents, raloxifene and tamoxifen, are used in clinical practice to prevent breast cancer. In this review, we will mainly focus on: (1) the application of genomic technologies for the identification and validation of molecular targets for chemoprevention; (2) the role of vitamin D and its cognate receptor VDR (vitamin D receptor) as a model for the molecularly targeted chemoprevention of breast cancer. PMID:21348760

  8. Chemoprevention of colon cancer: current status and future prospects.

    PubMed

    Gustin, David M; Brenner, Dean E

    2002-01-01

    Colorectal cancer is an important public health problem in the western world. Although some progress has been made in the prevention and management of this disease, colon cancer still remains one of the most common types of epithelial malignancies in both genders and is essentially incurable when it reaches the most advanced stages. Given the substantial morbidity and mortality associated with colorectal malignancies and their treatment, cancer prevention in its many forms emerges as a very attractive approach. Colorectal cancer chemoprevention refers to the administration of natural or synthetic compounds to block, reverse, delay or prevent the development of invasive large bowel neoplasms. The ultimate goal of implementing a chemopreventive intervention in the general, or alternatively, in an at-risk population is to decrease the incidence rate of the specific cancer being targeted. This article reviews the present status of colorectal cancer chemoprevention. Current insights into the molecular and genetic models of human colorectal carcinogenesis, preclinical models for efficacy testing as well as into promising biomarkers for colorectal chemoprevention are provided. The developmental status of many promising agents is also discussed emphasizing the epidemiological evidence, preclinical information substantiating an anticarcinogenic effect, their postulated mechanism of action and the status of human clinical development. Our perspective of the future prospects in this scientific area is also provided and has been predicated primarily on the firm belief that the proper integration of advances in the biology of colon carcinogenesis, experimental therapeutics and clinical trial methodology will be critical for the success of this promising field. PMID:12549770

  9. The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention.

    PubMed

    Vahora, Huzefa; Khan, Munawwar Ali; Alalami, Usama; Hussain, Arif

    2016-03-01

    Nitric oxide (NO) in general plays a beneficial physiological role as a vasorelaxant and the role of NO is decided by its concentration present in physiological environments. NO either facilitates cancer-promoting characters or act as an anti-cancer agent. The dilemma in this regard still remains unanswered. This review summarizes the recent information on NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents which have NO-modulating properties with safe cytotoxic profile. Understanding the molecular mechanisms and cross-talk modulating NO effect by these chemopreventive agents can allow us to develop better therapeutic strategies for cancer treatment. PMID:27051643

  10. The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention

    PubMed Central

    Vahora, Huzefa; Khan, Munawwar Ali; Alalami, Usama; Hussain, Arif

    2016-01-01

    Nitric oxide (NO) in general plays a beneficial physiological role as a vasorelaxant and the role of NO is decided by its concentration present in physiological environments. NO either facilitates cancer-promoting characters or act as an anti-cancer agent. The dilemma in this regard still remains unanswered. This review summarizes the recent information on NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents which have NO-modulating properties with safe cytotoxic profile. Understanding the molecular mechanisms and cross-talk modulating NO effect by these chemopreventive agents can allow us to develop better therapeutic strategies for cancer treatment. PMID:27051643

  11. Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions.

    PubMed

    Zhang, Rui; Zhang, Jingzhu; Fang, Lingduo; Li, Xi; Zhao, Yue; Shi, Wanying; An, Li

    2014-01-01

    Alzheimer's disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and D-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics. PMID:25196440

  12. Suppression of microtubule dynamic instability and turnover in MCF7 breast cancer cells by sulforaphane

    PubMed Central

    Azarenko, Olga; Okouneva, Tatiana; Singletary, Keith W.; Jordan, Mary Ann; Wilson, Leslie

    2008-01-01

    Sulforaphane (SFN), a prominent isothiocyanate present in cruciferous vegetables, is believed to be responsible along with other isothiocyanates for the cancer preventive activity of such vegetables. SFN arrests mitosis, possibly by affecting spindle microtubule function. A critical property of microtubules is their rapid and time-sensitive growth and shortening dynamics (dynamic instability), and suppression of dynamics by antimitotic anticancer drugs (e.g. taxanes and the vinca alkaloids) is central to the anticancer mechanisms of such drugs. We found that at concentrations that inhibited proliferation and mitosis of MCF7-green fluorescent protein-α-tubulin breast tumor cells by ∼50% (∼15 μM), SFN significantly modified microtubule organization in arrested spindles without modulating the spindle microtubule mass, in a manner similar to that of much more powerful antimitotic drugs. By using quantitative fluorescence video microscopy, we determined that at its mitotic concentration required to inhibit mitosis by 50%, SFN suppressed the dynamic instability of the interphase microtubules in these cells, strongly reducing the rate and extent of growth and shortening and decreasing microtubule turnover, without affecting the polymer mass. SFN suppressed the dynamics of purified microtubules in a similar fashion at concentrations well below those required to depolymerize microtubules, indicating that the suppression of dynamic instability by SFN in cells is due to a direct effect on the microtubules. The results indicate that SFN arrests proliferation and mitosis by stabilizing microtubules in a manner weaker than but similar to more powerful clinically used antimitotic anticancer drugs and strongly support the hypothesis that inhibition of mitosis by microtubule stabilization is important for SFN's chemopreventive activity. PMID:18952594

  13. Evidence supporting the conceptual framework of cancer chemoprevention in canines

    PubMed Central

    Kondratyuk, Tamara P.; Adrian, Julie Ann Luiz; Wright, Brian; Park, Eun-Jung; van Breemen, Richard B.; Morris, Kenneth R.; Pezzuto, John M.

    2016-01-01

    As with human beings, dogs suffer from the consequences of cancer. We investigated the potential of a formulation comprised of resveratrol, ellagic acid, genistein, curcumin and quercetin to modulate biomarkers indicative of disease prevention. Dog biscuits were evaluated for palatability and ability to deliver the chemopreventive agents. The extent of endogenous DNA damage in peripheral blood lymphocytes from dogs given the dietary supplement or placebo showed no change. However, H2O2-inducible DNA damage was significantly decreased after consumption of the supplement. The expression of 11 of 84 genes related to oxidative stress was altered. Hematological parameters remained in the reference range. The concept of chemoprevention for the explicit benefit of the canine is compelling since dogs are an important part of our culture. Our results establish a proof-of-principle and provide a framework for improving the health and well-being of “man’s best friend”. PMID:27216246

  14. Evidence supporting the conceptual framework of cancer chemoprevention in canines.

    PubMed

    Kondratyuk, Tamara P; Adrian, Julie Ann Luiz; Wright, Brian; Park, Eun-Jung; van Breemen, Richard B; Morris, Kenneth R; Pezzuto, John M

    2016-01-01

    As with human beings, dogs suffer from the consequences of cancer. We investigated the potential of a formulation comprised of resveratrol, ellagic acid, genistein, curcumin and quercetin to modulate biomarkers indicative of disease prevention. Dog biscuits were evaluated for palatability and ability to deliver the chemopreventive agents. The extent of endogenous DNA damage in peripheral blood lymphocytes from dogs given the dietary supplement or placebo showed no change. However, H2O2-inducible DNA damage was significantly decreased after consumption of the supplement. The expression of 11 of 84 genes related to oxidative stress was altered. Hematological parameters remained in the reference range. The concept of chemoprevention for the explicit benefit of the canine is compelling since dogs are an important part of our culture. Our results establish a proof-of-principle and provide a framework for improving the health and well-being of "man's best friend". PMID:27216246

  15. Chemoprevention of lung squamous cell carcinoma by ginseng.

    PubMed

    Pan, Jing; Zhang, Qi; Li, Kezhen; Liu, Qian; Wang, Yian; You, Ming

    2013-06-01

    Ginseng has been used as a medicinal herb to maintain physical vitality for thousands of years, and it has also been shown to be a nonorgan-specific cancer preventive agent by several epidemiologic studies. However, the chemopreventive effects of Korea white ginseng (KWG) in lung squamous cell carcinoma (SCC) have not been tested. In this study, we investigated the chemopreventive activity of KWG in a mouse lung SCC model. N-nitroso-trischloroethylurea (NTCU) was used to induce lung tumors in female Swiss mice, and KWG was given orally. KWG significantly reduced the percentage of lung SCCs from 26.5% in the control group to 9.1% in the KWG group and in the meantime, increased the percentage of normal bronchial and hyperplasia. KWG was also found to greatly reduce squamous cell lung tumor area from an average of 9.4% in control group to 1.5% in the KWG group. Treatment with KWG decreased Ki-67 staining, suggesting that the lung tumor inhibitory effects of KWG were partly through inhibition of proliferation. High-performance liquid chromatography/mass spectrometry identified 10 ginsenosides from KWG extracts, Rb1 and Rd being the most abundant as detected in mouse blood and lung tissue. The tumor inhibitory effects of KWG are mediated by inhibition of activator protein (AP-1), as showed by in vitro study conducted on AP-1/NF-κB-dependent mouse non-small cell lung carcinoma cell lines. Western blotting of lung tissues also indicated that NTCU upregulated AP-1 through phosphorylation of c-jun-NH2-kinase, which was downregulated by KWG in concurrence with its chemoprevention function. These results suggest that KWG could be a potential chemopreventive agent for lung SCC. PMID:23550152

  16. Chemoprevention of colorectal cancer

    PubMed Central

    LANGMAN, M; BOYLE, P

    1998-01-01

    Department of Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH, UK P BOYLE Colorectal cancer is the fourth commonest form of cancer in men with 678 000 estimated new cases per year worldwide, representing 8.9% of all new cancers. The disease is most frequent in Occidental countries and particularly so in North America, Australia, New Zealand, and parts of Europe. Prospects for colorectal cancer control are bright and a number of possible approaches could prove fruitful. Among these, pharmaceutical measures seem to be valid and logical approaches to the prevention of colorectal cancer and diminishing its impact. Such approaches could concentrate in primary prevention in at-risk subjects or be applied in altering the course of precursor or established disease. Treatments used must fulfil basic requirements of biological plausibility and safety in continued use in large numbers of subjects. Those available include vitamins and minerals, and other drugs with potential as antioxidants, immune modulators or promoters of cell differentiation or apoptosis. Of the various regimens suggested, vitamin A supplementation may even predispose to adverse outcomes, and antioxidant vitamins in general have no coherent body of evidence to support their use. N-acetylcysteine and ursodeoxycholic acid have promising characteristics but there are as yet no clinical data to support the use of the former in gut epithelial cancer, and formal dose ranging studies must be carried out before the latter is submitted to large scale trial. Folate shows promising characteristics but non-steroidal anti-inflammatory drugs and vitamin D seem the most promising agents. Both seem to reduce the incidence of disease, and to reduce growth rates and/or induce differentiation or apoptosis in gut epithelial cancer cells. Both are also well understood pharmacologically. They may be preferred to newer selective compounds in the same class until these newer compounds are confirmed as safe for widespread

  17. Chemoprevention--history and general principles.

    PubMed

    Wu, Xiangwei; Patterson, Sherri; Hawk, Ernest

    2011-08-01

    Our current understanding of tumourigenesis suggests that cancer develops as a series of cumulative genetic and epigenetic derangements across time culminating in a clone of cells differing from its population of origin in terms of cellular identity, growth control, and its contextual relationship to its environment. Our increasing knowledge of the timing, sequence, frequency, and specific implications of these changes provides unique opportunities for earlier identification of aberrations and preventive interventions. Here we discuss the fundamentals of cancer prevention including the targets, cohorts, agents, endpoints, mechanistic biomarkers, designs, and strategies employed in preventive drug development. There have been many notable successes in this field such as the identification and development of tamoxifen and raloxifene for breast cancer risk reduction, instillational BCG and valrubicin for treatment of preinvasive bladder cancer, and a variety of topical and systemic agents that effectively treat preinvasive neoplastic lesions of the skin. A variety of null or negative developmental endeavours have occurred as well, including trials of beta-carotene for lung cancer prevention, nutritional modifications for colorectal adenoma prevention, and most recently, selenium and alpha-tocopherol for prostate cancer prevention. A third category of prevention trials can be summarized as investigationally successful, but not achieving regulatory success. The development of finasteride and dutasteride for prostate cancer prevention, and celecoxib for colorectal neoplasia prevention fall into this category. In less than four decades, cancer chemoprevention has transformed from a concept to an achievable reality. PMID:22122762

  18. Cytotoxic and Antitumor Activity of Sulforaphane: The Role of Reactive Oxygen Species

    PubMed Central

    Sestili, Piero; Fimognari, Carmela

    2015-01-01

    According to recent estimates, cancer continues to remain the second leading cause of death and is becoming the leading one in old age. Failure and high systemic toxicity of conventional cancer therapies have accelerated the identification and development of innovative preventive as well as therapeutic strategies to contrast cancer-associated morbidity and mortality. In recent years, increasing body of in vitro and in vivo studies has underscored the cancer preventive and therapeutic efficacy of the isothiocyanate sulforaphane. In this review article, we highlight that sulforaphane cytotoxicity derives from complex, concurring, and multiple mechanisms, among which the generation of reactive oxygen species has been identified as playing a central role in promoting apoptosis and autophagy of target cells. We also discuss the site and the mechanism of reactive oxygen species' formation by sulforaphane, the toxicological relevance of sulforaphane-formed reactive oxygen species, and the death pathways triggered by sulforaphane-derived reactive oxygen species. PMID:26185755

  19. Modulation of Histone Deacetylase Activity by Dietary Isothiocyanates and Allyl Sulfides: Studies with Sulforaphane and Garlic Organosulfur Compounds

    PubMed Central

    Nian, Hui; Delage, Barbara; Ho, Emily; Dashwood, Roderick H.

    2009-01-01

    Histone deacetylase (HDAC) inhibitors reactivate epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic. Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention. PMID:19197985

  20. A novel target for oral cancer chemoprevention? Notch quite, yet….

    PubMed

    William, William N; El-Naggar, Adel K

    2015-04-01

    The two major goals of oral cancer chemoprevention efforts are the ability to segregate the high-risk patients and the identification of an effective pharmacologic agent that halts progression to invasive cancer. Considerable progress has recently been achieved in profiling invasive head and neck squamous cell carcinomas, particularly with the use of high-throughput technologies. A similar molecular characterization of potentially malignant oral epithelial lesions (OPML; leukoplakia and erythroplakia) is yet to be accomplished. It is postulated, though, that molecular profiling could lead to the discovery of novel markers of cancer risk that could also serve as potential targets for chemoprevention. In this perspective, we comment on the work by Izumchenko and colleagues that reports a high prevalence of NOTCH1 gain-of-function mutations in Chinese patients with OPMLs. Although additional studies are needed to validate the findings, the study is the first to link alterations in this gene in oral premalignancy. These findings could serve as a first prototype of a single gene mutation as a potential target in clinical chemoprevention setting. PMID:25712052

  1. Biomarkers and chemopreventives in oral carcinogenesis and its prevention

    PubMed Central

    Shah, Sonalee; Kaur, Manpreet

    2014-01-01

    Squamous cell carcinoma is the predominant type of oral malignancy and is a result of oral carcinogenesis. Oral carcinogenesis is a mutifactorial and complex process related to the sequential occurrence of alterations in genetic structures, promoting inhibitory or excitatory effects of the tumor oncogenes and gene suppressors, compromising the histophysiology of the division, differentiation and cell death; and therefore, methods to prevent, detect, or treat it in the best way is constantly being searched for. Biomarkers reveal the genetic and molecular changes related to early, intermediate and late endpoints in the process of oral carcinogenesis. Thereby, they are likely to not only refine our ability to predict the biologic course of oral cancer and distinguish individuals at high and/or low risk of oral cancer development; but, also they will also reveal the genetic and molecular changes related to various endpoints of oral carcinogenesis. Chemopreventives are chemicals of natural or synthetic origin, which reduce the incidence of fatal diseases such as cancer before clinical symptoms occur. Chemopreventives are agents whose curative capacity is defined with help of biomarkers, as the later determine the effectiveness and safety of chemopreventives. PMID:24959040

  2. Chemoprevention of head and neck squamous cell carcinoma through inhibition of NF-κB signaling.

    PubMed

    Vander Broek, Robert; Snow, Grace E; Chen, Zhong; Van Waes, Carter

    2014-10-01

    Nuclear factor-kappa B (NF-κB) transcription factors regulate cellular processes such as inflammation and cell survival. The NF-κB pathway is often activated with development and progression of head and neck squamous cell carcinoma (HNSCC). As such, NF-κB represents an attractive target for chemoprevention. HNSCC involves progression of lesions from premalignant to malignant, providing a window of opportunity for intervention with chemopreventive agents. Appropriate chemopreventive agents should be inexpensive, nontoxic, and target important pathways involved in the development of HNSCC. Several such agents that inhibit the NF-κB pathway have been investigated in HNSCC. Retinoids have been studied most extensively but have shown limited potential in human trials. Epidermal growth factor receptor inhibitors and PI3K-mTOR inhibitors may benefit a subset of patients. Other agents such as green tea extract and curcumin are appealing because they are generally regarded as safe. In contrast, there is evidence that Vitamin E supplementation may actually increase mortality of cancer patients. Repurposed drugs such as cyclooxygenase (COX) inhibitors and antidiabetic drugs are an emerging area of interest. Future research to develop agents with lower toxicity and higher specificity for the NF-κB pathway, and to target these therapies to individual patient genetic signatures should help to increase the utility of chemoprevention in HSNCC. PMID:24177052

  3. Aspirin chemoprevention of gastrointestinal cancer in the next decade. A review of the evidence.

    PubMed

    Jankowska, Helena; Hooper, Patricia; Jankowski, Janusz A

    2010-10-01

    Together, gastrointestinal (GI) cancers now account for 25% of neoplastic deaths in the West. In Poland, GI cancer rates are likely to increase further as westernization progresses. Given that conventional cancer therapies have made only modest reductions in cancer mortality, there is a great interest in chemoprevention to prevent or slow malignant transformation from premalignant lesions. The financial pressures in the immediate future require even more stringent criteria for chemopreventive agents - they must be cheap but also safe and efficacious. In this regard, several reviews have indicated that aspirin possesses many favorable qualities for chemoprevention. Furthermore, meta-analyses indicate that aspirin may decrease cancer by approximately 30%. Several large clinical trials are underway, including AspECT (Aspirin and Esomeprazole Chemoprevention Trial) that aims not only to prevent cancer but also decrease the gastric side effects by combining aspirin with potent acid-suppressing drugs. In conclusion, whether aspirin will be the world's first proven chemopreventive agent is currently unknown but the evidence looks hopeful. PMID:20980946

  4. The Role of Nutraceuticals in Chemoprevention and Chemotherapy and Their Clinical Outcomes

    PubMed Central

    Saldanha, Sabita N.; Tollefsbol, Trygve O.

    2012-01-01

    The genesis of cancer is often a slow process and the risk of developing cancer increases with age. Altering a diet that includes consumption of beneficial phytochemicals can influence the balance and availability of dietary chemopreventive agents. In chemopreventive approaches, foods containing chemicals that have anticancer properties can be supplemented in diets to prevent precancerous lesions from occurring. This necessitates further understanding of how phytochemicals can potently maintain healthy cells. Fortunately there is a plethora of plant-based phytochemicals although few of them are well studied in terms of their application as cancer chemopreventive and therapeutic agents. In this analysis we will examine phytochemicals that have strong chemopreventive and therapeutic properties in vitro as well as the design and modification of these bioactive compounds for preclinical and clinical applications. The increasing potential of combinational approaches using more than one bioactive dietary compound in chemoprevention or cancer therapy will also be evaluated. Many novel approaches to cancer prevention are on the horizon, several of which are showing great promise in saving lives in a cost-effective manner. PMID:22187555

  5. Natural compounds as anticancer agents: Experimental evidence

    PubMed Central

    Wang, Jiao; Jiang, Yang-Fu

    2012-01-01

    Cancer prevention research has drawn much attention worldwide. It is believed that some types of cancer can be prevented by following a healthy life style. Cancer chemoprevention by either natural or synthetic agents is a promising route towards lowering cancer incidence. In recent years, the concept of cancer chemoprevention has evolved greatly. Experimental studies in animal models demonstrate that the reversal or suppression of premalignant lesions by chemopreventive agents is achievable. Natural occurring agents such as dietary phytochemicals, tea polyphenols and resveratrol show chemopreventive activity in animal models. Moreover, clinical trials for testing the safety and efficacy of a variety of natural agents in preventing or treating human malignancy have been ongoing. Here, we summarize experimental data on the chemopreventive or tumor suppressive effects of several natural compounds including curcumin, (-)-epigallocatechin-3-gallate, resveratrol, indole-3-carbinol, and vitamin D. PMID:24520533

  6. Sulforaphane Bioavailability from Glucoraphanin-Rich Broccoli: Control by Active Endogenous Myrosinase

    PubMed Central

    Fahey, Jed W.; Holtzclaw, W. David; Wehage, Scott L.; Wade, Kristina L.; Stephenson, Katherine K.; Talalay, Paul

    2015-01-01

    Glucoraphanin from broccoli and its sprouts and seeds is a water soluble and relatively inert precursor of sulforaphane, the reactive isothiocyanate that potently inhibits neoplastic cellular processes and prevents a number of disease states. Sulforaphane is difficult to deliver in an enriched and stable form for purposes of direct human consumption. We have focused upon evaluating the bioavailability of sulforaphane, either by direct administration of glucoraphanin (a glucosinolate, or β-thioglucoside-N-hydroxysulfate), or by co-administering glucoraphanin and the enzyme myrosinase to catalyze its conversion to sulforaphane at economic, reproducible and sustainable yields. We show that following administration of glucoraphanin in a commercially prepared dietary supplement to a small number of human volunteers, the volunteers had equivalent output of sulforaphane metabolites in their urine to that which they produced when given an equimolar dose of glucoraphanin in a simple boiled and lyophilized extract of broccoli sprouts. Furthermore, when either broccoli sprouts or seeds are administered directly to subjects without prior extraction and consequent inactivation of endogenous myrosinase, regardless of the delivery matrix or dose, the sulforaphane in those preparations is 3- to 4-fold more bioavailable than sulforaphane from glucoraphanin delivered without active plant myrosinase. These data expand upon earlier reports of inter- and intra-individual variability, when glucoraphanin was delivered in either teas, juices, or gelatin capsules, and they confirm that a variety of delivery matrices may be equally suitable for glucoraphanin supplementation (e.g. fruit juices, water, or various types of capsules and tablets). PMID:26524341

  7. [Sulforaphane (1-isothiocyanato-4-(methylsulfinyl)-butane) content in cruciferous vegetables].

    PubMed

    Campas-Baypoli, Olga N; Bueno-Solano, Carolina; Martínez-Ibarra, Diana M; Camacho-Gil, Francisco; Villa-Lerma, Alma G; Rodríguez-Núñez, Jesús R; Lóez-Cervantes, Jaime; Sánchez-Machado, Dalia I

    2009-03-01

    Sulforaphane (1-isothiocyanato-4-(methylsulfinyl)-butane) content in cruciferous vegetables. Sulforaphane is an isothiocyanate which has antimicrobial and anticarcinogenic properties, this compound is found in a wide variety of plants from genus Brassica oleracea, being the most important broccoli and cabbage. The objective of this research was to quantify sulforaphane in the edible parts of broccoli and cabbage leaves by high-performance liquid chromatography (HPLC). Sample preparation for the quantification of sulforaphane include the conversion of glucoraphanin to sulforaphane (45 +/- 2 degrees C for 2.5 h), extracted with dichloromethane, purification of the extract in columns of solid phase extraction and detection by HPLC- UV. Sulforaphane concentration in broccoli is in the range of 214 microg/g DW (stems) to 499 microg/g DW (inflorescences). The purple cabbage (101.99 microg/g DW) has values greater than the green cabbage (7.58 microg/g DW). The inflorescences of broccoli and red cabbage leaves are rich in sulforaphane. PMID:19480351

  8. Chemoprevention of prostate cancer: current status and future directions.

    PubMed

    Lieberman, Ronald

    2002-01-01

    Prostate cancer chemoprevention can be described as the administration of natural products and pharmaceutical agents that inhibit one or more steps in the natural history of prostatic carcinogenesis. The principle components of the chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and metastatic disease. Another important target for chemoprevention is to modulate progression to clinically aggressive disease and to maintain an androgen-sensitive clinical state and delay the emergence of androgen resistance. There is a rationale for use of antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for chemoprevention of prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of drug (androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic pharmaceutical and natural products already in clinical development create many opportunities for rational combination therapy. Several agent classes have a pharmacodynamic basis for combination with antiandrogens including antiproliferatives, selective estrogen receptor modulators (SERMs), proapoptotic antioxidant micronutrients and selective cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without antiandrogens are feasible. It is anticipated that in the

  9. Primary prevention: phytoprevention and chemoprevention of colorectal cancer.

    PubMed

    Turini, Marco E; DuBois, Raymond N

    2002-08-01

    Considering the various stages of carcinogenesis and the numerous tumor types and available chemoprevention agents, knowledge of the etiology and the type of cancer to be treated, or possibly prevented, and understanding of the mechanisms by which agents exert their chemoprevention benefits may provide for improved strategy in designing therapeutic regimens. Because cancer usually develops over a 10- to 20-year period, it may be necessary for some agents to be provided before or early in the initiation steps of carcinogenesis to have beneficial effects. On the other hand, some agents may be more suitable for CRC prevention if provided at a later stage of carcinogenesis. Gene array, genomics, and proteomics are useful tools in advancing our understanding of the molecular events involved in carcinogenesis and in identifying markers of risk and surrogate end-points for colorectal cancer progression. These techniques may also serve for screening, identifying, and providing treatment targets for high-risk patients populations. Treatment could be developed depending on a patient's individual needs and genomic tumor profile. Clinical markers and surrogate end-points should be considered, together with molecular measurements, to more accurately assess risk. NSAIDs and COXIBs are clinically recognized as chemoprevention agents, and clinical trials evaluating their efficacy are ongoing. Treatment protocols, including dose and timing, remain to be determined, however. DFMO may best be used in combination with other chemoprevention agents. Dietary fiber and calcium supplements, as part of an overall low-fat diet, may decrease CRC risk. Long-term compliance with this regimen may be necessary to effect a beneficial outcome. Folate holds promise but needs further investigation, especially because its beneficial effects may depend on cancer type. Phytochemicals have been identified as strong candidates for use as agents to prevent colorectal cancer in cell culture and in rodent

  10. Cost-Effectiveness of Chemoprevention with Proton Pump Inhibitors in Barrett’s Esophagus

    PubMed Central

    Freedberg, Daniel E.; Abrams, Julian A.; Wang, Y. Claire

    2015-01-01

    Background Proton pump inhibitors (PPIs) may reduce the risk of esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus. PPIs are prescribed for virtually all patients with Barrett’s esophagus, irrespective of the presence of reflux symptoms, and represent a de facto chemopreventive agent in this population. However, long-term PPI use has been associated with several adverse effects, and the cost-effectiveness of chemoprevention with PPIs has not been evaluated. Aim The purpose of this study was to assess the cost-effectiveness of PPIs for the prevention of EAC in Barrett’s esophagus without reflux. Methods We designed a state-transition Markov micro-simulation model of a hypothetical cohort of 50-year-old white men with Barrett’s esophagus. We modeled chemoprevention with PPIs or no chemoprevention, with endoscopic surveillance for all treatment arms. Outcome measures were life-years, quality-adjusted life years (QALYs), incident EAC cases and deaths, costs, and incremental cost-effectiveness ratios. Results Assuming 50 % reduction in EAC, chemoprevention with PPIs was a cost-effective strategy compared to no chemoprevention. In our model, administration of PPIs cost $23,000 per patient and resulted in a gain of 0.32 QALYs for an incremental cost-effectiveness ratio of $12,000/QALY. In sensitivity analyses, PPIs would be cost-effective at $50,000/QALY if they reduce EAC risk by at least 19 %. Conclusions Chemoprevention with PPIs in patients with Barrett’s esophagus without reflux is cost-effective if PPIs reduce EAC by a minimum of 19 %. The identification of subgroups of Barrett’s esophagus patients at increased risk for progression would lead to more cost-effective strategies for the prevention of esophageal adenocarcinoma. PMID:24795040

  11. LC-MS-Based Metabolomic Investigation of Chemopreventive Phytochemical-Elicited Metabolic Events.

    PubMed

    Wang, Lei; Yao, Dan; Chen, Chi

    2016-01-01

    Phytochemicals are under intensive investigation for their potential use as chemopreventive agents in blocking or suppressing carcinogenesis. Metabolic interactions between phytochemical and biological system play an important role in determining the efficacy and toxicity of chemopreventive phytochemicals. However, complexities of phytochemical biotransformation and intermediary metabolism pose challenges for studying phytochemical-elicited metabolic events. Metabolomics has become a highly effective technical platform to detect subtle changes in a complex metabolic system. Here, using green tea polyphenols as an example, we describe a workflow of LC-MS-based metabolomics study, covering the procedures and techniques in sample collection, preparation, LC-MS analysis, data analysis, and interpretation. PMID:26608291

  12. The strategies to control prostate cancer by chemoprevention approaches

    PubMed Central

    Ting, Harold; Deep, Gagan; Agarwal, Chapla; Agarwal, Rajesh

    2014-01-01

    Prostate cancer (PCA) is the most commonly diagnosed cancer in men in the United States with growing worldwide incidence. Despite intensive investment in improving early detection, PCA often escapes timely detection and mortality remains high; this malignancy being the second highest cancer-associated mortality in American men. Collectively, health care costs of PCA results in an immense financial burden that is only expected to grow. Additionally, even in cases of successful treatment, PCA is associated with long-term and pervasive effects on patients. A proactive alternative to treating PCA is to prevent its occurrence and progression prior to symptomatic malignancy. This may serve to address the issue of burgeoning healthcare costs and increasing number of sufferers. One potential regimen in service of this alternative is PCA chemoprevention. Here, chemical compounds with cancer preventive efficacy are identified on the basis of their potential in a host of categories: their historical medicinal use, correlation with reduced risk in population studies, non-toxicity, their unique chemical properties, or their role in biological systems. PCA chemopreventive agents are drawn from multiple broad classes of chemicals, themselves further subdivided based on source or potential effect, with most derived from natural products. Many such compounds have shown efficacy, varying from inhibiting deregulated PCA cell signaling, proliferation, epithelial to mesenchymal transition (EMT), invasion, metastasis, tumor growth and angiogenesis and inducing apoptosis. Overall, these chemopreventive agents show great promise in PCA pre-clinical models, though additional work remains to be done in effectively translating these findings into clinical use. PMID:24389535

  13. The Chemopreventive Phytochemical Moringin Isolated from Moringa oleifera Seeds Inhibits JAK/STAT Signaling

    PubMed Central

    Weigl, Julia; De Nicola, Gina Rosalinda; Canistro, Donatella; Paolini, Moreno; Iori, Renato; Rascle, Anne

    2016-01-01

    Sulforaphane (SFN) and moringin (GMG-ITC) are edible isothiocyanates present as glucosinolate precursors in cruciferous vegetables and in the plant Moringa oleifera respectively, and recognized for their chemopreventive and medicinal properties. In contrast to the well-studied SFN, little is known about the molecular pathways targeted by GMG-ITC. We investigated the ability of GMG-ITC to inhibit essential signaling pathways that are frequently upregulated in cancer and immune disorders, such as JAK/STAT and NF-κB. We report for the first time that, similarly to SFN, GMG-ITC in the nanomolar range suppresses IL-3-induced expression of STAT5 target genes. GMG-ITC, like SFN, does not inhibit STAT5 phosphorylation, suggesting a downstream inhibitory event. Interestingly, treatment with GMG-ITC or SFN had a limited inhibitory effect on IFNα-induced STAT1 and STAT2 activity, indicating that both isothiocyanates differentially target JAK/STAT signaling pathways. Furthermore, we showed that GMG-ITC in the micromolar range is a more potent inhibitor of TNF-induced NF-κB activity than SFN. Finally, using a cellular system mimicking constitutive active STAT5-induced cell transformation, we demonstrated that SFN can reverse the survival and growth advantage mediated by oncogenic STAT5 and triggers cell death, therefore providing experimental evidence of a cancer chemopreventive activity of SFN. This work thus identified STAT5, and to a lesser extent STAT1/STAT2, as novel targets of moringin. It also contributes to a better understanding of the biological activities of the dietary isothiocyanates GMG-ITC and SFN and further supports their apparent beneficial role in the prevention of chronic illnesses such as cancer, inflammatory diseases and immune disorders. PMID:27304884

  14. The Chemopreventive Phytochemical Moringin Isolated from Moringa oleifera Seeds Inhibits JAK/STAT Signaling.

    PubMed

    Michl, Carina; Vivarelli, Fabio; Weigl, Julia; De Nicola, Gina Rosalinda; Canistro, Donatella; Paolini, Moreno; Iori, Renato; Rascle, Anne

    2016-01-01

    Sulforaphane (SFN) and moringin (GMG-ITC) are edible isothiocyanates present as glucosinolate precursors in cruciferous vegetables and in the plant Moringa oleifera respectively, and recognized for their chemopreventive and medicinal properties. In contrast to the well-studied SFN, little is known about the molecular pathways targeted by GMG-ITC. We investigated the ability of GMG-ITC to inhibit essential signaling pathways that are frequently upregulated in cancer and immune disorders, such as JAK/STAT and NF-κB. We report for the first time that, similarly to SFN, GMG-ITC in the nanomolar range suppresses IL-3-induced expression of STAT5 target genes. GMG-ITC, like SFN, does not inhibit STAT5 phosphorylation, suggesting a downstream inhibitory event. Interestingly, treatment with GMG-ITC or SFN had a limited inhibitory effect on IFNα-induced STAT1 and STAT2 activity, indicating that both isothiocyanates differentially target JAK/STAT signaling pathways. Furthermore, we showed that GMG-ITC in the micromolar range is a more potent inhibitor of TNF-induced NF-κB activity than SFN. Finally, using a cellular system mimicking constitutive active STAT5-induced cell transformation, we demonstrated that SFN can reverse the survival and growth advantage mediated by oncogenic STAT5 and triggers cell death, therefore providing experimental evidence of a cancer chemopreventive activity of SFN. This work thus identified STAT5, and to a lesser extent STAT1/STAT2, as novel targets of moringin. It also contributes to a better understanding of the biological activities of the dietary isothiocyanates GMG-ITC and SFN and further supports their apparent beneficial role in the prevention of chronic illnesses such as cancer, inflammatory diseases and immune disorders. PMID:27304884

  15. Hedera nepalensis K. Koch: A Novel Source of Natural Cancer Chemopreventive and Anticancerous Compounds.

    PubMed

    Jafri, Laila; Saleem, Samreen; Kondrytuk, Tamara P; Haq, Ihsan-ul; Ullah, Nazif; Pezzuto, John M; Mirza, Bushra

    2016-03-01

    Traditional medicinal plants are often used for both the prevention and the treatment of local diseases. Taking into consideration the medicinal importance of Hedera nepalensis within local Pakistani traditions, the present study was undertaken to analyze the in vitro cancer chemopreventive and cytotoxic properties of the plant. The in vitro cancer chemopreventive testing was performed using nitrite assay, NFκB assay, aromatase assay, and quinone reductase 1 (QR1) assay. The cytotoxic potential was evaluated on three cancer-cell lines: MCF-7, MDA-MB-231, and HeLa using sulforhodamine B (SRB) assay. The results of cancer chemopreventive assays show that n-hexane and ethyl acetate fractions of tested plant have promising cancer chemopreventive potential. Lupeol isolated from n-hexane as well as ethyl acetate fraction showed lowest IC50 (0.20 ± 1.9 μM) in NFκB assay. Crude extract and its fractions inhibited the growth of three cancer cell lines by more than 60%, IC50 value of lupeol varied from 2.32 to 10.2 μM. HPLC-DAD-based quantification of lupeol in different plant tissues demonstrated that leaves of H. nepalensis are a rich source of lupeol (0.196 mg/100 mg dry weight). Our data have shown that H. nepalensis harbors cancer chemopreventive and cytotoxic agents. PMID:26692176

  16. Chemoprevention Trial Feasibility Using Botanicals in Exceptionally High Risk Populations for Lung Cancer

    PubMed Central

    Kumar, Nagi B; Quinn, Gwendolyn P; Alexandrow, Mark G; Gray, Jhanelle; Schell, Michael; Sutton, Steve; Haura, Eric B

    2015-01-01

    While chemoprevention with botanicals shows promise in reducing cancer risk, recruitment and retention of participants for trials continues to be costly and presents unique challenges. Knowledge of interest, willingness of target populations and evaluation of design challenges are critical to improve accrual in these chemoprevention trials. Objective The study assessed interest and willingness of former smokers to participate in a chemoprevention trial using a botanical agent. Methods An introductory letter and survey instrument were mailed to 609 consecutive, former heavy smokers, with no cancer, from a database of 826 subjects at the Moffitt Cancer Center. Results 202 (40.4%) subjects returned completed surveys. 92-96% reported interest in receiving free lung exams and knowing their lung cancer risk. 88% were interested in participating in a trial evaluating a botanical agent for lung cancer prevention. Over 92% of subjects reported willingness to comply with study requirements; multiple blood draws and trips to the Center, spiral CTs and chest x-rays. Subjects were relatively less enthusiastic (73-79%) about bronchoscopy, taking multiple study agents and assignment to placebo arm. Conclusions Our study strongly suggests feasibility, highlights potential challenges and the significant interest and willingness of this exceptionally high risk population to participate in chemoprevention trials. PMID:26101725

  17. [Chemoprevention of oral cancer--clinical and experimental studies].

    PubMed

    Szumiło, Justyna; Podlodowska, Justyna; Podlodowski, Wiktor; Starosławska, Elzbieta; Burdan, Franciszek

    2012-02-01

    Chemoprevention is one of the cancer prevention methods, applied for the oral squamous cell carcinoma and its main precursor lesions--leukoplakia and erythroplakia. Presently, the most extensive clinically studied group used in such cases are retinoids: vitamin A (retinol), 13-cis-retinic acid (isotretinoin), N-(4-hydroxyphenyl)retinamide (fenretinide) and precursor of vitamin A--beta-carotene. However, despite good short-time effectiveness, retinoids do not prevent recurrences of the lesions and insignificantly increase cancer-free survival. Moreover, they are also characterized by relatively high toxicity. Vitamin E, Bowman-Birkprotease inhibitor, Spirulina fusiformis and green tee extracts as well as traditional Chinese herbs known as ZengShengPing were also found as effective agents. Lack of activity was reported for cyclooxygenase inhibitors--ketorolac and celecoxib. More promising data was collected from animal experimental studies with chemically induced oral squamous cell carcinoma. Chemopreventive activity was revealed for various agents including plant-derived compounds like resveratrol, green and black tee polyphenols, as well as protocatechuic, ellagic and caffeic acids. PMID:22590920

  18. Ginseng Metabolites on Cancer Chemoprevention: An Angiogenesis Link?

    PubMed Central

    Wang, Chong-Zhi; Cai, Yi; Anderson, Samantha; Yuan, Chun-Su

    2015-01-01

    Cancer is a leading cause of death in the United States. Angiogenesis inhibitors have been introduced for the treatment of cancer. Based on the fact that many anticancer agents have been developed from botanical sources, there is a significant untapped resource to be found in natural products. American ginseng is a commonly used herbal medicine in the U.S., which possess antioxidant properties. After oral ingestion, natural ginseng saponins are biotransformed to their metabolites by the enteric microbiome before being absorbed. The major metabolites, ginsenoside Rg3 and compound K, showed significant potent anticancer activity compared to that of their parent ginsenosides Rb1, Rc and Rd. In this review, the molecular mechanisms of ginseng metabolites on cancer chemoprevention, especially apoptosis and angiogenic inhibition, are discussed. Ginseng gut microbiome metabolites showed significant anti-angiogenic effects on pulmonary, gastric and ovarian cancers. This review suggests that in addition to the chemopreventive effects of ginseng compounds, as angiogenic inhibitors, ginsenoside metabolites could be used in combination with other cancer chemotherapeutic agents in cancer management. PMID:26941993

  19. Neuroprotective Effects of Sulforaphane on Cholinergic Neurons in Mice with Alzheimer’s Disease-Like Lesions

    PubMed Central

    Zhang, Rui; Zhang, Jingzhu; Fang, Lingduo; Li, Xi; Zhao, Yue; Shi, Wanying; An, Li

    2014-01-01

    Alzheimer’s disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and d-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics. PMID:25196440

  20. Sulforaphane protects against rotenone-induced neurotoxicity in vivo: Involvement of the mTOR, Nrf2, and autophagy pathways

    PubMed Central

    Zhou, Qian; Chen, Bin; Wang, Xindong; Wu, Lixin; Yang, Yang; Cheng, Xiaolan; Hu, Zhengli; Cai, Xueting; Yang, Jie; Sun, Xiaoyan; Lu, Wuguang; Yan, Huaijiang; Chen, Jiao; Ye, Juan; Shen, Jianping; Cao, Peng

    2016-01-01

    Sulforaphane, a naturally occurring compound found in cruciferous vegetables, has been shown to be neuroprotective in several neurological disorders. In this study, we sought to investigate the potential protective effects and associated molecular mechanisms of sulforaphane in an in vivo Parkinson’s disease (PD) model, based on rotenone-mediated neurotoxicity. Our results showed that sulforaphane inhibited rotenone-induced locomotor activity deficiency and dopaminergic neuronal loss. Additionally, sulforaphane treatment inhibited the rotenone-induced reactive oxygen species production, malondialdehyde (MDA) accumulation, and resulted in an increased level of total glutathione and reduced glutathione (GSH): oxidized glutathione (GSSG) in the brain. Western blot analysis illustrated that sulforaphane increased the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase (NQO1), the latter two of which are anti-oxidative enzymes. Moreover, sulforaphane treatment significantly attenuated rotenone-inhibited mTOR-mediated p70S6K and 4E-BP1 signalling pathway, as well as neuronal apoptosis. In addition, sulforaphane rescued rotenone-inhibited autophagy, as detected by LC3-II. Collectively, these findings demonstrated that sulforaphane exert neuroprotective effect involving Nrf2-dependent reductions in oxidative stress, mTOR-dependent inhibition of neuronal apoptosis, and the restoration of normal autophagy. Sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing PD. PMID:27553905

  1. Sulforaphane protects against rotenone-induced neurotoxicity in vivo: Involvement of the mTOR, Nrf2, and autophagy pathways.

    PubMed

    Zhou, Qian; Chen, Bin; Wang, Xindong; Wu, Lixin; Yang, Yang; Cheng, Xiaolan; Hu, Zhengli; Cai, Xueting; Yang, Jie; Sun, Xiaoyan; Lu, Wuguang; Yan, Huaijiang; Chen, Jiao; Ye, Juan; Shen, Jianping; Cao, Peng

    2016-01-01

    Sulforaphane, a naturally occurring compound found in cruciferous vegetables, has been shown to be neuroprotective in several neurological disorders. In this study, we sought to investigate the potential protective effects and associated molecular mechanisms of sulforaphane in an in vivo Parkinson's disease (PD) model, based on rotenone-mediated neurotoxicity. Our results showed that sulforaphane inhibited rotenone-induced locomotor activity deficiency and dopaminergic neuronal loss. Additionally, sulforaphane treatment inhibited the rotenone-induced reactive oxygen species production, malondialdehyde (MDA) accumulation, and resulted in an increased level of total glutathione and reduced glutathione (GSH): oxidized glutathione (GSSG) in the brain. Western blot analysis illustrated that sulforaphane increased the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase (NQO1), the latter two of which are anti-oxidative enzymes. Moreover, sulforaphane treatment significantly attenuated rotenone-inhibited mTOR-mediated p70S6K and 4E-BP1 signalling pathway, as well as neuronal apoptosis. In addition, sulforaphane rescued rotenone-inhibited autophagy, as detected by LC3-II. Collectively, these findings demonstrated that sulforaphane exert neuroprotective effect involving Nrf2-dependent reductions in oxidative stress, mTOR-dependent inhibition of neuronal apoptosis, and the restoration of normal autophagy. Sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing PD. PMID:27553905

  2. Chemoprevention of Radiation Induced Rat Mammary Neoplasms

    NASA Technical Reports Server (NTRS)

    Huso, David L.

    1999-01-01

    Radiations encountered in space include protons and heavy ions such as iron as well as their secondaries. The relative biological effect (RBE) of these ions is not known, particularly at the doses and dose-rates expected for planetary missions. Neutrons, are not particularly relevant to space travel, but have been found experimentally to have an increase in their RBE with decreasing dose. If a similar trend of increasing RBE with decreasing dose is present for heavy ions and protons during irradiation in space, the small doses received during space travel could potentially have substantial carcinogenic risk. Clearly more investigation of the effects of heavy ions and protons is needed before accurate risk assessment for prolonged travel in space can be done. One means to mitigate the increased risk of cancer due to radiation exposure in space is by developing effective countermeasures that can reduce the incidence of tumor development. Tamoxifen has recently been shown to be an effective chemopreventive agent in both animal models and humans for the prevention of mammary tumors. Tamoxifen is a unique drug, with a highly specific mechanism of action affecting a specific radiation-sensitive population of epithelial cells in the mammary gland. In human studies, the annual incidence of a primary tumor in the contralateral breast of women with previous breast cancer is about 8 per 1000, making them an exceedingly high-risk group for the development of breast cancer. In this high risk group, treated with tamoxifen, daily, for 2 years, the incidence of a new primary tumor in the contralateral breast was approximately one third of that noted in the non-tamoxifen treatment group. Tamoxifen antagonizes the action of estrogen by competing for the nuclear receptor complex thereby altering the association of the receptor complex and nuclear binding sites. Its effects in reducing the development of breast cancer could be accomplished by controlling clinically undetectable

  3. Sulforaphane Inhibits Prostaglandin E2 Synthesis by Suppressing Microsomal Prostaglandin E Synthase 1

    PubMed Central

    Zhou, Jiping; Joplin, Denise G.; Cross, Janet V.; Templeton, Dennis J.

    2012-01-01

    Sulforaphane (SFN) is a dietary cancer preventive with incompletely characterized mechanism(s) of cancer prevention. Since prostaglandin E2 (PGE2) promotes cancer progression, we hypothesized that SFN may block PGE2 synthesis in cancer cells. We found that SFN indeed blocked PGE2 production in human A549 cancer cells not by inhibiting COX-2, but rather by suppressing the expression of microsomal prostaglandin E synthase (mPGES-1), the enzyme that directly synthesizes PGE2. We identified the Hypoxia Inducible Factor 1 alpha (HIF-1α) as the target of SFN-mediated mPGES-1 suppression. SFN suppressed HIF-1α protein expression and the presence of HIF-1α at the mPGES-1 promoter, resulting in reduced transcription of mPGES-1. Finally, SFN also reduced expression of mPGES-1 and PGE2 production in A549 xenograft tumors in mice. Together, these results point to the HIF-1α, mPGES-1 and PGE2 axis as a potential mediator of the anti-cancer effects of SFN, and illustrate the potential of SFN for therapeutic control of cancer and inflammation. Harmful side effects in patients taking agents that target the more upstream COX-2 enzyme render the downstream target mPGES-1 a significant target for anti-inflammatory therapy. Thus, SFN could prove to be an important therapeutic approach to both cancer and inflammation. PMID:23166763

  4. Risk biomarkers for assessment and chemoprevention of liver fluke-associated cholangiocarcinoma.

    PubMed

    Yongvanit, Puangrat; Pinlaor, Somchai; Loilome, Watcharin

    2014-05-01

    Human liver fluke, Opisthorchis viverrini (Ov), is the major risk factor of cholangiocarcinoma (CCA) in northeastern Thailand. Our approach focuses on genetic progression and molecular changes in the carcinogenic pathway of liver fluke-associated CCA aimed at assessing patients at risk of CCA and using chemoprevention as the secondary cancer prevention to reduce the incidence of CCA. This review summarizes altered gene expressions, biomolecules and their modification, i.e. DNA adducts, oxidized proteins, oxysterols and fibrotic markers in hamster- and human-CCA. Potential risk biomarker(s) and chemopreventive agent(s) criteria and selection were based on results from experimental and epidemiological studies identifying hepatobiliary disease, including CCA. Laboratory results reveal that oxidative stress induced by Ov infection leads to bimolecular damage, tissue remodeling especially periductal fibrosis and alteration of gene expressions, which could be involved in all steps of CCA carcinogenesis. Some of these molecules are reported to change their levels in opisthorchiasis, periductal fibrosis diagnosed by ultrasonography and CCA. Chemoprevention in experimental CCA tumorigenesis is discussed. These multiple risk biomarkers could now be explored for screening including chemopreventive intervention of subjects living in endemic areas where the prevalence of opisthorchiasis remains high. PMID:24408859

  5. Cancer chemoprevention by garlic and its organosulfur compounds-panacea or promise?

    PubMed

    Nagini, Siddavaram

    2008-04-01

    Of late medicinal plants and functional foods rich in bioactive phytochemicals have received growing attention as potential agents for cancer chemoprevention. Accumulating evidence from epidemiological studies as well as laboratory data supports the anticancer properties of garlic widely used as a medicinal herb and spice. Garlic and its organosulfur compounds (OSCs) appear to exert their anticarcinogenic effects through multiple mechanisms that include modulation of carcinogen metabolism, inhibition of DNA adduct formation, upregulation of antioxidant defences and DNA repair systems, and suppression of cell proliferation by blocking cell cycle progression and/or inducing apoptosis. Since multiple signaling pathways are dysfunctional in cancer and new oncogenic mutations accumulate with carcinogenic progression, dietary agents such as garlic with its rich array of bioactive OSCs that modulate cancer cascades offer promise as potential chemopreventive and chemotherapeutic agents. PMID:18393790

  6. Kinetic and thermodynamic studies of sulforaphane adsorption on macroporous resin.

    PubMed

    Yuanfeng, Wu; Lei, Zhang; Jianwei, Mao; Shiwang, Liu; Jun, Huang; Yuru, You; Lehe, Mei

    2016-08-15

    The adsorption equilibrium, kinetic and thermodynamic of sulforaphane (SF) adsorption onto macroporous resin in aqueous phase were studied. The SP850 resin was screened as the appropriate resin for SF purification. From the equilibrium studies, the Redlich-Peterson model was found to be the best for description of the adsorption behavior of SF onto SP850 resin, followed by the Freundlich model and the Langmuir model. Batch equilibrium experiments demonstrated that, in the examined temperature range, the equilibrium adsorption capacity of SP850 resin decreased with increasing adsorption temperature. Thermodynamics studies indicated that the adsorption of SF was a physical, exothermic, and spontaneous process. The adsorption kinetics revealed that the pseudo-second-order kinetic model was suitable to characterize the kinetics of adsorption of SF onto SP850. Finally, the intra-particle diffusion model demonstrated that SF diffused quickly into macropores, and that diffusion slowed down in the meso- and micropores. PMID:27391585

  7. Chemopreventive effect of Lagenaria siceraria in two stages DMBA plus croton oil induced skin papillomagenesis.

    PubMed

    Kumar, Navneet; Kale, Raosaheb K; Tiku, Ashu B

    2013-01-01

    Cancer chemoprevention is a dietary or therapeutic strategy to prevent, suppress, or delay carcinogenesis either at initiation or progression level with nontoxic agents. Use of natural dietary compounds has been a major chemopreventive approach to modulate tumorigenic pathways. In the present study, we have evaluated Lagenaria siceraria (bottle gourd), a common vegetable of Indian household for its chemomodulatory potential. The fruit has been used in traditional medicine for a very long time for health benefits and to cure pain, ulcers, fever, cough, asthma, and other bronchial disorders. However, despite its reported beneficial effect the chemo modulatory potential of this plant has not been reported. Therefore chemopreventive effect of bottle gourd juice (BGJ) was studied against 7,12-dimethylbenz(a)anthracene (DMBA) plus croton oil induced skin papillomagenesis in Swiss albino mice. The effect was studied both at antiinitiation and antiinitiation/promotion level followed by histopathological study. A dose of 2.5% and 5% given in drinking water showed significant decrease in papilloma number, papilloma incidence, papilloma multiplicity, papilloma latency, papilloma volume, and papilloma size in different size range. Histopathological study showed chemopreventive effect by minimizing loss of stratification, a decrease in number of epithelial layers, reducing dermal infiltration and protection for various cytoplasmic changes. Higher dose of BGJ was found to be more effective than lower dose and the chemopreventive effect was maximum for antiinitiation/promotion treatment. Altogether, this study reports the chemopreventive effect of Lagenaria siceraria on skin papillomagenesis for the first time and suggests that its consumption may help in suppression of skin cancer. PMID:23914728

  8. Ellagitannins in Cancer Chemoprevention and Therapy

    PubMed Central

    Ismail, Tariq; Calcabrini, Cinzia; Diaz, Anna Rita; Fimognari, Carmela; Turrini, Eleonora; Catanzaro, Elena; Akhtar, Saeed; Sestili, Piero

    2016-01-01

    It is universally accepted that diets rich in fruit and vegetables lead to reduction in the risk of common forms of cancer and are useful in cancer prevention. Indeed edible vegetables and fruits contain a wide variety of phytochemicals with proven antioxidant, anti-carcinogenic, and chemopreventive activity; moreover, some of these phytochemicals also display direct antiproliferative activity towards tumor cells, with the additional advantage of high tolerability and low toxicity. The most important dietary phytochemicals are isothiocyanates, ellagitannins (ET), polyphenols, indoles, flavonoids, retinoids, tocopherols. Among this very wide panel of compounds, ET represent an important class of phytochemicals which are being increasingly investigated for their chemopreventive and anticancer activities. This article reviews the chemistry, the dietary sources, the pharmacokinetics, the evidence on chemopreventive efficacy and the anticancer activity of ET with regard to the most sensitive tumors, as well as the mechanisms underlying their clinically-valuable properties. PMID:27187472

  9. Ellagitannins in Cancer Chemoprevention and Therapy.

    PubMed

    Ismail, Tariq; Calcabrini, Cinzia; Diaz, Anna Rita; Fimognari, Carmela; Turrini, Eleonora; Catanzaro, Elena; Akhtar, Saeed; Sestili, Piero

    2016-01-01

    It is universally accepted that diets rich in fruit and vegetables lead to reduction in the risk of common forms of cancer and are useful in cancer prevention. Indeed edible vegetables and fruits contain a wide variety of phytochemicals with proven antioxidant, anti-carcinogenic, and chemopreventive activity; moreover, some of these phytochemicals also display direct antiproliferative activity towards tumor cells, with the additional advantage of high tolerability and low toxicity. The most important dietary phytochemicals are isothiocyanates, ellagitannins (ET), polyphenols, indoles, flavonoids, retinoids, tocopherols. Among this very wide panel of compounds, ET represent an important class of phytochemicals which are being increasingly investigated for their chemopreventive and anticancer activities. This article reviews the chemistry, the dietary sources, the pharmacokinetics, the evidence on chemopreventive efficacy and the anticancer activity of ET with regard to the most sensitive tumors, as well as the mechanisms underlying their clinically-valuable properties. PMID:27187472

  10. [Chemoprevention of prostate cancer - a plea].

    PubMed

    Schmitz-Dräger, B J; Bismarck, E; Schöffski, O; Fischer, C

    2012-05-01

    The high disease prevalence, the presentation in older age, a frequently slowly progressing course of disease, and high costs make the diagnosis of and therapy for prostate cancer a special challenge for urologists. Effective prevention of the disease may help to improve some of the problems mentioned above. Two randomised, controlled studies have proved that effective chemoprevention of prostate cancer is viable using 5α-reductase inhibitors (finasteride, dutasteride). Furthermore, there is increasing evidence that other compounds, e. g., selective oestrogen receptor modulators (SERMs), NSAIDs and statins might also be effective. This review investigates potential risks and benefits of chemoprevention including a consideration of health economical aspects. The authors conclude that the options of chemoprevention should be investigated in an open and unbiased way. PMID:22639024

  11. Advances in prostate cancer chemoprevention: a translational perspective.

    PubMed

    Nambiar, Dhanya; Singh, Rana P

    2013-01-01

    Chemopreventive interventions are steadily emerging as an important aspect of cancer management and control. Herein, we have discussed the major epidemiological and clinical studies advocating the role of androgen inhibitors, flavonoids and antioxidants in preventing prostate cancer (PCa). Androgen inhibitors have lately been discussed not only in treatment of PCa, but also as preventive agents especially after trials with Finasteride and Dutasteride. Flavonoids such as silibinin, green tea polyphenols, genistein, curcumin have shown great promise, but avenues to improve their bioavailability are requisite. Agents with antioxidant potentials like lycopene, selenium, and vitamin E have also been explored. Antioxidant trials have yielded mixed results or benefitted only a subgroup of population, although further studies are needed to establish them as preventive agent. Although a majority of the trials resulted in positive outcomes supporting their role as preventive agents; one should be cautious of neutral or negative results as well. For clinical applicability of these agents, we need to identify the ideal target population, time of intervention, appropriate dosage, and extent of intervention required. Incoherency of data with these agents urges for a stringent study design and thorough interpretation to accurately judge the necessity and feasibility of the preventive measures. PMID:23682779

  12. Carnosol: A Phenolic Diterpene With Cancer Chemopreventive Potential

    PubMed Central

    Chun, Kyung-Soo; Kundu, Juthika; Chae, In Gyeong; Kundu, Joydeb Kumar

    2014-01-01

    Cancer is an unbeaten health challenge for the humankind. After striving for decades to find a cancer cure, attention has now been shifted to reduce the morbidity and mortality from cancer by halting the course of tumor development. Numerous bioactive phytochemicals, especially those present in edible and non-edible plant species, have been reported to reduce the risk of many cancers. Multiple lines of evidence suggest that carnosol, a phenolic diterpene present in rosemary (Rosmarinus officinalis L.), holds the promise of preventing certain types of cancer. A remarkable progress has been made in delineating the biochemical mechanisms underlying the chemopreventive effects of carnosol. Results from in vitro cell culture studies as well as animal model experiments have revealed that carnosol inhibits experimentally induced carcinogenesis and exhibits potent anti-oxidative, anti-inflammatory, antiproliferative and apoptosis inducing properties. Moreover, carnosol enhances the sensitivity of chemoresistant cancer cells to chemotherapeutic agents. The purpose of this review is to shed light on the detailed mechanistic aspects of cancer chemoprevention with carnosol. PMID:25337578

  13. The role of aspirin in colorectal cancer chemoprevention.

    PubMed

    Singh Ranger, Gurpreet

    2016-08-01

    Considerable interest has emerged over the last decade regarding the role of aspirin in prevention of colorectal cancer. This disease is one of the commonest cancers in the Western World, therefore, the existence of a simple "everyday" agent, which could have the ability to prevent the disease, represents an invaluable opportunity clinicians may be able to exploit. Evidence from case-control and cohort studies, and recent updates of randomised controlled trials have been very encouraging-indicating benefit from long term use of aspirin at low dose. Possible mechanisms of chemoprevention include inhibition of the cyclooxygenase (COX) pathway, or COX-independent mechanisms, for example, the PIK3CA pathway, or therapy-induced senescence of cancer cells. The most serious side effect of prolonged aspirin treatment is haemorrhage, especially from the GI tract. This is likely to be less of a problem with chemoprevention at lower doses. One also needs to consider the impact if aspirin resistance, an increasingly recognised clinical entity. PMID:27289249

  14. Carnosol: a phenolic diterpene with cancer chemopreventive potential.

    PubMed

    Chun, Kyung-Soo; Kundu, Juthika; Chae, In Gyeong; Kundu, Joydeb Kumar

    2014-06-01

    Cancer is an unbeaten health challenge for the humankind. After striving for decades to find a cancer cure, attention has now been shifted to reduce the morbidity and mortality from cancer by halting the course of tumor development. Numerous bioactive phytochemicals, especially those present in edible and non-edible plant species, have been reported to reduce the risk of many cancers. Multiple lines of evidence suggest that carnosol, a phenolic diterpene present in rosemary (Rosmarinus officinalis L.), holds the promise of preventing certain types of cancer. A remarkable progress has been made in delineating the biochemical mechanisms underlying the chemopreventive effects of carnosol. Results from in vitro cell culture studies as well as animal model experiments have revealed that carnosol inhibits experimentally induced carcinogenesis and exhibits potent anti-oxidative, anti-inflammatory, antiproliferative and apoptosis inducing properties. Moreover, carnosol enhances the sensitivity of chemoresistant cancer cells to chemotherapeutic agents. The purpose of this review is to shed light on the detailed mechanistic aspects of cancer chemoprevention with carnosol. PMID:25337578

  15. Chemoprevention of Endometrial Cancer in Lynch Syndrome: A Step Forward

    PubMed Central

    Stoffel, Elena M.; Walsh, Christine

    2013-01-01

    Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes. Although LS is associated with increased risk for developing colorectal, endometrial and other cancers, specialized screening, risk-reducing surgery, and chemoprevention offer promise for reducing morbidity and mortality. Frequent colonoscopic surveillance has proven effective for early detection and prevention of LS-associated colorectal cancer (CRC); however, the optimal strategy for managing endometrial cancer risks in women with germline mutations in DNA mismatch repair genes has yet to be determined. In this issue of the journal, Lu et al. report their findings of a Phase II prospective, multicenter randomized trial comparing the effects of oral contraceptive pills and Depo-Provera on endometrial proliferation in women with LS. Although short-term hormonal treatment with either modality altered endometrial proliferation indices, it remains unknown whether hormonal suppression actually reduces endometrial cancer risk in women with LS. This trial represents the first of its kind in evaluating agents, which might offer protection against LS-associated endometrial cancer and provides preliminary data regarding potential biomarkers for early detection of endometrial neoplasia. However, the investigators' experience with this trial also offers insights regarding the various technical and scientific challenges inherent in chemoprevention research. PMID:23842794

  16. Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticle-encapsulated aspirin and curcumin in combination with free sulforaphane in BALB/c mice

    PubMed Central

    Thakkar, Arvind; Chenreddy, Sushma; Thio, Astrid; Khamas, Wael; Wang, Jeffrey; Prabhu, Sunil

    2016-01-01

    Our previous studies have established the efficacy of chemopreventive regimens of aspirin and curcumin (CUR) encapsulated within solid lipid nanoparticles (SLNs) in combination with free sulforaphane (ACS combination) to prevent or delay the initiation and progression of pancreatic cancer, classified as one of the deadliest diseases with very low chances of survival upon diagnosis. Although toxicity of individual drugs and SLN has been studied previously, there are no studies in current literature that evaluate the potential toxicity of a combined regimen of ACS, especially when encapsulated within chitosan-SLNs (c-SLNs). Hence, objective of the current study was to investigate the potential toxic effects of ACS c-SLN combined chemopreventive regimens following acute (3 days), subacute (28 days), and subchronic (90 days) administrations by oral gavage in BALB/c mice. Mice were administered the following regimens: saline, blank c-SLN, low-dose ACS c-SLN (2+4.5+0.16 mg/kg), medium-dose ACS c-SLN (20+45+1.6 mg/kg), and high-dose ACS c-SLN (60+135+4.8 mg/kg). The potential toxicity was evaluated based on animal survival, body weight, hematology, blood chemistry, and organ histopathology. During 3-day, 28-day, and 90-day study periods, no animal deaths were observed. Treatment with ACS c-SLNs did not cause alteration in complete blood counts and blood chemistry data. Histopathological examination of various organ sections (pancreas, heart, liver, kidney, and brain) appeared normal. Based on the results of this study, no signs of toxicity in acute, subacute, and subchronic studies following oral administration of ACS c-SLNs were found indicating that the oral dosing regimens were safe at the levels tested for long-term administration to prevent the onset of pancreatic cancer. PMID:27499621

  17. Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticle-encapsulated aspirin and curcumin in combination with free sulforaphane in BALB/c mice.

    PubMed

    Thakkar, Arvind; Chenreddy, Sushma; Thio, Astrid; Khamas, Wael; Wang, Jeffrey; Prabhu, Sunil

    2016-01-01

    Our previous studies have established the efficacy of chemopreventive regimens of aspirin and curcumin (CUR) encapsulated within solid lipid nanoparticles (SLNs) in combination with free sulforaphane (ACS combination) to prevent or delay the initiation and progression of pancreatic cancer, classified as one of the deadliest diseases with very low chances of survival upon diagnosis. Although toxicity of individual drugs and SLN has been studied previously, there are no studies in current literature that evaluate the potential toxicity of a combined regimen of ACS, especially when encapsulated within chitosan-SLNs (c-SLNs). Hence, objective of the current study was to investigate the potential toxic effects of ACS c-SLN combined chemopreventive regimens following acute (3 days), subacute (28 days), and subchronic (90 days) administrations by oral gavage in BALB/c mice. Mice were administered the following regimens: saline, blank c-SLN, low-dose ACS c-SLN (2+4.5+0.16 mg/kg), medium-dose ACS c-SLN (20+45+1.6 mg/kg), and high-dose ACS c-SLN (60+135+4.8 mg/kg). The potential toxicity was evaluated based on animal survival, body weight, hematology, blood chemistry, and organ histopathology. During 3-day, 28-day, and 90-day study periods, no animal deaths were observed. Treatment with ACS c-SLNs did not cause alteration in complete blood counts and blood chemistry data. Histopathological examination of various organ sections (pancreas, heart, liver, kidney, and brain) appeared normal. Based on the results of this study, no signs of toxicity in acute, subacute, and subchronic studies following oral administration of ACS c-SLNs were found indicating that the oral dosing regimens were safe at the levels tested for long-term administration to prevent the onset of pancreatic cancer. PMID:27499621

  18. INDUCTION OF HEPTIC THIOREDOXIN REDUCTASE ACTIVITY BY SULFORAPHANE, BOTH IN HEPALCLC7 CELLS AND IN MALE FISHER 344 RATS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sulforaphane (SF), a glucosinolate-derived isothiocyanate found in cruciferous vegetables, is considered an anticarcinogenic component in broccoli. Sulforaphane induces a battery of detoxification enzymes that may be part of a coordinated host-defense response. The objective of the present study was...

  19. Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures

    PubMed Central

    Kumar, Nagi; Crocker, Theresa; Smith, Tiffany; Connors, Shahnjayla; Pow-Sang, Julio; Spiess, Philippe E.; Egan, Kathleen; Quinn, Gwen; Schell, Michael; Sebti, Said; Kazi, Aslam; Chuang, Tian; Salup, Raoul; Helal, Mohamed; Zagaja, Gregory; Trabulsi, Edouard; McLarty, Jerry; Fazili, Tajammul; Williams, Christopher R.; Schreiber, Fred; Anderson, Kyle

    2014-01-01

    In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention. PMID:24533253

  20. Sulforaphane, a Dietary Isothiocyanate, Induces G₂/M Arrest in Cervical Cancer Cells through CyclinB1 Downregulation and GADD45β/CDC2 Association.

    PubMed

    Cheng, Ya-Min; Tsai, Ching-Chou; Hsu, Yi-Chiang

    2016-01-01

    Globally, cervical cancer is the most common malignancy affecting women. The main treatment methods for this type of cancer include conization or hysterectomy procedures. Sulforaphane (SFN) is a natural, compound-based drug derived from dietary isothiocyanates which has previously been shown to possess potent anti-tumor and chemopreventive effects against several types of cancer. The present study investigated the effects of SFN on anti-proliferation and G₂/M phase cell cycle arrest in cervical cancer cell lines (Cx, CxWJ, and HeLa). We found that cytotoxicity is associated with an accumulation of cells in the G₂/M phases of the cell-cycle. Treatment with SFN led to cell cycle arrest as well as the down-regulation of Cyclin B1 expression, but not of CDC2 expression. In addition, the effects of GADD45β gene activation in cell cycle arrest increase proportionally with the dose of SFN; however, mitotic delay and the inhibition of proliferation both depend on the dosage of SFN used to treat cancer cells. These results indicate that SFN may delay the development of cancer by arresting cell growth in the G₂/M phase via down-regulation of Cyclin B1 gene expression, dissociation of the cyclin B1/CDC2 complex, and up-regulation of GADD45β proteins. PMID:27626412

  1. Chemopreventive Properties of Dietary Rice Bran: Current Status and Future Prospects12

    PubMed Central

    Henderson, Angela J.; Ollila, Cadie A.; Kumar, Ajay; Borresen, Erica C.; Raina, Komal; Agarwal, Rajesh; Ryan, Elizabeth P.

    2012-01-01

    Emerging evidence suggests that dietary rice bran may exert beneficial effects against several types of cancer, such as breast, lung, liver, and colorectal cancer. The chemopreventive potential has been related to the bioactive phytochemicals present in the bran portion of the rice such as ferulic acid, tricin, β-sitosterol, γ-oryzanol, tocotrienols/tocopherols, and phytic acid. Studies have shown that the anticancer effects of the rice bran–derived bioactive components are mediated through their ability to induce apoptosis, inhibit cell proliferation, and alter cell cycle progression in malignant cells. Rice bran bioactive components protect against tissue damage through the scavenging of free radicals and the blocking of chronic inflammatory responses. Rice bran phytochemicals have also been shown to activate anticancer immune responses as well as affecting the colonic tumor microenvironment in favor of enhanced colorectal cancer chemoprevention. This is accomplished through the modulation of gut microflora communities and the regulation of carcinogen-metabolizing enzymes. In addition, the low cost of rice production and the accessibility of rice bran make it an appealing candidate for global dietary chemoprevention. Therefore, the establishment of dietary rice bran as a practical food-derived chemopreventive agent has the potential to have a significant impact on cancer prevention for the global population. PMID:22983843

  2. Cervical cancer chemoprevention, vaccines, and surrogate endpoint biomarkers.

    PubMed

    Follen, Michele; Meyskens, Frank L; Alvarez, Ronald D; Walker, Joan L; Bell, Maria C; Storthz, Karen Adler; Sastry, Jagannadha; Roy, Krishnendu; Richards-Kortum, Rebecca; Cornelison, Terri L

    2003-11-01

    At the Second International Conference on Cervical Cancer, held April 11-14, 2002, experts in cervical cancer prevention, detection, and treatment reviewed the need for more research in chemoprevention, including prophylactic and therapeutic vaccines, immunomodulators, peptides, and surrogate endpoint biomarkers. Investigators and clinicians noted the need for more rigorous Phase I randomized clinical trials, more attention to the risk factors that can affect study results in this patient population, and validation of optical technologies that will provide valuable quantitative information in real time regarding disease regression and progression. They discussed the role of the human papillomavirus (HPV) in cervical cancer development and the importance of developing strategies to suppress HPV persistence and progression. Results in Phase I randomized clinical trials have been disappointing because few have demonstrated statistically significant regression attributable to the agent tested. Researchers recommended using a transgenic mouse model to test and validate new compounds, initiating vaccine and immunomodulator trials, and developing immunologic surrogate endpoint biomarkers. PMID:14603541

  3. Cancer chemoprevention by dietary phytochemicals: promises and pitfalls.

    PubMed

    Priyadarsini, Ramamurthi Vidya; Nagini, Siddavaram

    2012-01-01

    Research over the past decade has provided convincing evidence to support the premise that phytochemicals from the diet offer protection against cancer risk. A large number of dietary phytochemicals have been demonstrated to exhibit anticancer activities by interfering with multiple signaling pathways aberrant in cancer. These agents target a plethora of cellular molecules and molecular pathways including xenobiotic-metabolizing enzymes, reactive oxygen species, inflammation, cell cycle, apoptosis, invasion, angiogenesis, transcription factors, and protein kinases. In addition, dietary phytochemicals also synergize with conventional chemotherapy and radiotherapy. Thus naturally derived phytochemicals could play an important role in cancer chemoprevention and therapy owing to multitargeted mechanistic action and lack of substantial toxicity. However, more rationally designed novel clinical trials are required to translate the preclinical findings into tangible clinical benefits. PMID:21466433

  4. Repurposing old drugs to chemoprevention: the case of metformin.

    PubMed

    Heckman-Stoddard, Brandy M; Gandini, Sara; Puntoni, Matteo; Dunn, Barbara K; DeCensi, Andrea; Szabo, Eva

    2016-02-01

    Multiple epidemiologic studies have documented an association between the anti-diabetic agent metformin and reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models or more recent epidemiological studies. The purpose of this paper is to examine metformin's chemopreventive potential by reviewing relevant mechanisms of action, preclinical evidence of efficacy, updated epidemiologic evidence after correction for potential biases and confounders, and recently completed and ongoing clinical trials. Although repurposing drugs with well described mechanisms of action and safety profiles is an appealing strategy for cancer prevention, there is no substitute for well executed late phase clinical trials to define efficacy and populations that are most likely to benefit from an intervention. PMID:26970131

  5. Nanoencapsulation of pomegranate bioactive compounds for breast cancer chemoprevention.

    PubMed

    Shirode, Amit B; Bharali, Dhruba J; Nallanthighal, Sameera; Coon, Justin K; Mousa, Shaker A; Reliene, Ramune

    2015-01-01

    Pomegranate polyphenols are potent antioxidants and chemopreventive agents but have low bioavailability and a short half-life. For example, punicalagin (PU), the major polyphenol in pomegranates, is not absorbed in its intact form but is hydrolyzed to ellagic acid (EA) moieties and rapidly metabolized into short-lived metabolites of EA. We hypothesized that encapsulation of pomegranate polyphenols into biodegradable sustained release nanoparticles (NPs) may circumvent these limitations. We describe here the development, characterization, and bioactivity assessment of novel formulations of poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs loaded with pomegranate extract (PE) or individual polyphenols such as PU or EA. Monodispersed, spherical 150-200 nm average diameter NPs were prepared by the double emulsion-solvent evaporation method. Uptake of Alexa Fluor-488-labeled NPs was evaluated in MCF-7 breast cancer cells over a 24-hour time course. Confocal fluorescent microscopy revealed that PLGA-PEG NPs were efficiently taken up, and the uptake reached the maximum at 24 hours. In addition, we examined the antiproliferative effects of PE-, PU-, and/or EA-loaded NPs in MCF-7 and Hs578T breast cancer cells. We found that PE, PU, and EA nanoprototypes had a 2- to 12-fold enhanced effect on cell growth inhibition compared to their free counterparts, while void NPs did not affect cell growth. PU-NPs were the most potent nanoprototype of pomegranates. Thus, PU may be the polyphenol of choice for further chemoprevention studies with pomegranate nanoprototypes. These data demonstrate that nanotechnology-enabled delivery of pomegranate polyphenols enhances their anticancer effects in breast cancer cells. Thus, pomegranate polyphenols are promising agents for nanochemoprevention of breast cancer. PMID:25624761

  6. Nanoencapsulation of pomegranate bioactive compounds for breast cancer chemoprevention

    PubMed Central

    Shirode, Amit B; Bharali, Dhruba J; Nallanthighal, Sameera; Coon, Justin K; Mousa, Shaker A; Reliene, Ramune

    2015-01-01

    Pomegranate polyphenols are potent antioxidants and chemopreventive agents but have low bioavailability and a short half-life. For example, punicalagin (PU), the major polyphenol in pomegranates, is not absorbed in its intact form but is hydrolyzed to ellagic acid (EA) moieties and rapidly metabolized into short-lived metabolites of EA. We hypothesized that encapsulation of pomegranate polyphenols into biodegradable sustained release nanoparticles (NPs) may circumvent these limitations. We describe here the development, characterization, and bioactivity assessment of novel formulations of poly(D,L-lactic-co-glycolic acid)–poly(ethylene glycol) (PLGA–PEG) NPs loaded with pomegranate extract (PE) or individual polyphenols such as PU or EA. Monodispersed, spherical 150–200 nm average diameter NPs were prepared by the double emulsion–solvent evaporation method. Uptake of Alexa Fluor-488-labeled NPs was evaluated in MCF-7 breast cancer cells over a 24-hour time course. Confocal fluorescent microscopy revealed that PLGA–PEG NPs were efficiently taken up, and the uptake reached the maximum at 24 hours. In addition, we examined the antiproliferative effects of PE-, PU-, and/or EA-loaded NPs in MCF-7 and Hs578T breast cancer cells. We found that PE, PU, and EA nanoprototypes had a 2- to 12-fold enhanced effect on cell growth inhibition compared to their free counterparts, while void NPs did not affect cell growth. PU-NPs were the most potent nanoprototype of pomegranates. Thus, PU may be the polyphenol of choice for further chemoprevention studies with pomegranate nanoprototypes. These data demonstrate that nanotechnology-enabled delivery of pomegranate polyphenols enhances their anticancer effects in breast cancer cells. Thus, pomegranate polyphenols are promising agents for nanochemoprevention of breast cancer. PMID:25624761

  7. Sulforaphane Inhibits HIV Infection of Macrophages through Nrf2

    PubMed Central

    Furuya, Andrea Kinga Marias; Sharifi, Hamayun J.; Jellinger, Robert M.; Cristofano, Paul; Shi, Binshan; de Noronha, Carlos M. C.

    2016-01-01

    Marburg virus, the Kaposi's sarcoma-associated herpesvirus (KSHV) and Dengue virus all activate, and benefit from, expression of the transcription regulator nuclear erythroid 2-related factor 2 (Nrf2). The impact of Nrf2 activation on human immunodeficiency virus (HIV) infection has not been tested. Sulforaphane (SFN), produced in cruciferous vegetables after mechanical damage, mobilizes Nrf2 to potently reprogram cellular gene expression. Here we show for the first time that SFN blocks HIV infection in primary macrophages but not in primary T cells. Similarly SFN blocks infection in PMA-differentiated promonocytic cell lines, but not in other cell lines tested. siRNA-mediated depletion of Nrf2 boosted HIV infectivity in primary macrophages and reduced the anti-viral effects of SFN treatment. This supports a model in which anti-viral activity is mediated through Nrf2 after it is mobilized by SFN. We further found that, like the type I interferon-induced cellular anti-viral proteins SAMHD1 and MX2, SFN treatment blocks infection after entry, but before formation of 2-LTR circles. Interestingly however, neither SAMHD1 nor MX2 were upregulated. This shows for the first time that Nrf2 action can potently block HIV infection and highlights a novel way to trigger this inhibition. PMID:27093399

  8. Sulforaphane Protects against Cardiovascular Disease via Nrf2 Activation

    PubMed Central

    Bai, Yang; Wang, Xiaolu; Zhao, Song; Ma, Chunye; Cui, Jiuwei; Zheng, Yang

    2015-01-01

    Cardiovascular disease (CVD) causes an unparalleled proportion of the global burden of disease and will remain the main cause of mortality for the near future. Oxidative stress plays a major role in the pathophysiology of cardiac disorders. Several studies have highlighted the cardinal role played by the overproduction of reactive oxygen or nitrogen species in the pathogenesis of ischemic myocardial damage and consequent cardiac dysfunction. Isothiocyanates (ITC) are sulfur-containing compounds that are broadly distributed among cruciferous vegetables. Sulforaphane (SFN) is an ITC shown to possess anticancer activities by both in vivo and epidemiological studies. Recent data have indicated that the beneficial effects of SFN in CVD are due to its antioxidant and anti-inflammatory properties. SFN activates NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than a hundred cytoprotective proteins, including antioxidants and phase II detoxifying enzymes. This review will summarize the evidence from clinical studies and animal experiments relating to the potential mechanisms by which SFN modulates Nrf2 activation and protects against CVD. PMID:26583056

  9. Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts.

    PubMed

    Gabriel, Diana; Roedl, Daniela; Gordon, Leslie B; Djabali, Karima

    2015-02-01

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. PMID:25510262

  10. Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts

    PubMed Central

    Gabriel, Diana; Roedl, Daniela; Gordon, Leslie B; Djabali, Karima

    2015-01-01

    Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. PMID:25510262

  11. Sulforaphane Inhibits HIV Infection of Macrophages through Nrf2.

    PubMed

    Furuya, Andrea Kinga Marias; Sharifi, Hamayun J; Jellinger, Robert M; Cristofano, Paul; Shi, Binshan; de Noronha, Carlos M C

    2016-04-01

    Marburg virus, the Kaposi's sarcoma-associated herpesvirus (KSHV) and Dengue virus all activate, and benefit from, expression of the transcription regulator nuclear erythroid 2-related factor 2 (Nrf2). The impact of Nrf2 activation on human immunodeficiency virus (HIV) infection has not been tested. Sulforaphane (SFN), produced in cruciferous vegetables after mechanical damage, mobilizes Nrf2 to potently reprogram cellular gene expression. Here we show for the first time that SFN blocks HIV infection in primary macrophages but not in primary T cells. Similarly SFN blocks infection in PMA-differentiated promonocytic cell lines, but not in other cell lines tested. siRNA-mediated depletion of Nrf2 boosted HIV infectivity in primary macrophages and reduced the anti-viral effects of SFN treatment. This supports a model in which anti-viral activity is mediated through Nrf2 after it is mobilized by SFN. We further found that, like the type I interferon-induced cellular anti-viral proteins SAMHD1 and MX2, SFN treatment blocks infection after entry, but before formation of 2-LTR circles. Interestingly however, neither SAMHD1 nor MX2 were upregulated. This shows for the first time that Nrf2 action can potently block HIV infection and highlights a novel way to trigger this inhibition. PMID:27093399

  12. Sulforaphane Protects the Liver against CdSe Quantum Dot-Induced Cytotoxicity

    PubMed Central

    Wang, Wei; He, Yan; Yu, Guodong; Li, Baolong; Sexton, Darren W.; Wileman, Thomas; Roberts, Alexandra A.; Hamilton, Chris J.; Liu, Ruoxi; Chao, Yimin; Shan, Yujuan; Bao, Yongping

    2015-01-01

    The potential cytotoxicity of cadmium selenide (CdSe) quantum dots (QDs) presents a barrier to their use in biomedical imaging or as diagnostic and therapeutic agents. Sulforaphane (SFN) is a chemoprotective compound derived from cruciferous vegetables which can up-regulate antioxidant enzymes and induce apoptosis and autophagy. This study reports the effects of SFN on CdSe QD-induced cytotoxicity in immortalised human hepatocytes and in the livers of mice. CdSe QDs induced dose-dependent cell death in hepatocytes with an IC50 = 20.4 μM. Pre-treatment with SFN (5 μM) increased cell viability in response to CdSe QDs (20 μM) from 49.5 to 89.3%. SFN induced a pro-oxidant effect characterized by depletion of intracellular reduced glutathione during short term exposure (3–6 h), followed by up-regulation of antioxidant enzymes and glutathione levels at 24 h. SFN also caused Nrf2 translocation into the nucleus, up-regulation of antioxidant enzymes and autophagy. siRNA knockdown of Nrf2 suggests that the Nrf2 pathway plays a role in the protection against CdSe QD-induced cell death. Wortmannin inhibition of SFN-induced autophagy significantly suppressed the protective effect of SFN on CdSe QD-induced cell death. Moreover, the role of autophagy in SFN protection against CdSe QD-induced cell death was confirmed using mouse embryonic fibroblasts lacking ATG5. CdSe QDs caused significant liver damage in mice, and this was decreased by SFN treatment. In conclusion, SFN attenuated the cytotoxicity of CdSe QDs in both human hepatocytes and in the mouse liver, and this protection was associated with the induction of Nrf2 pathway and autophagy. PMID:26402917

  13. Sulforaphane produces antidepressant- and anxiolytic-like effects in adult mice.

    PubMed

    Wu, Shuhui; Gao, Qiang; Zhao, Pei; Gao, Yuan; Xi, Yanjie; Wang, Xiaoting; Liang, Ying; Shi, Haishui; Ma, Yuxia

    2016-03-15

    Increasing evidence suggests that depression is accompanied by dysregulation of neuroimmune system. Sulforaphane (SFN) is a natural compound with antioxidative, anti-inflammatory and neuroprotective activities. The present study aims to investigate the effects of SFN on depressive- and anxiety-like behaviors as well as potential neuroimmune mechanisms in mice. Repeated SFN administration (10mg/kg, i.p.) significantly decreased the immobility time in the forced swimming test (FST), tail suspension test (TST), and latency time to feeding in the novelty suppressed feeding test (NSF), and increased the time in the central zone in the open field test (OPT). Using the chronic mild stress (CMS) paradigm, we confirmed that repeated SFN (10mg/kg, i.p.) administration significantly increased sucrose preference in the sucrose preference test (SPT), and immobility time in the FST and TST of mice subjected to CMS. Also, SFN treatment significantly reversed anxiety-like behaviors (assessed by the OPT and NSF) of chronically stressed mice. Finally, ELISA analysis showed that SFN administration blocked the increase in the serum levels of corticosterone (CORT), adrenocorticotropic hormone (ACTH), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in chronically stressed mice. In summary, these findings demonstrated that SFN has antidepressant- and anxiolytic-like activities in stressed mice model of depression, which likely occurs by inhibiting the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory response to stress. These data support further exploration for developing SFN as a novel agent to treat depression and anxiety disorders. PMID:26721468

  14. Nanoparticulate delivery of novel drug combination regimens for the chemoprevention of colon cancer

    PubMed Central

    KANTHAMNENI, NAVEEN; CHAUDHARY, ABHISHEK; WANG, JEFFREY; PRABHU, SUNIL

    2010-01-01

    The purpose of this work was to assess synergistic inhibitory responses of a novel chemopreventive combination regimen of drugs namely, aspirin in combination with calcium and folic acid on two human colon cancer cell lines, HT-29 and SW-480. Subsequently, based on positive responses, nanotechnology-based formulations were developed for the targeted delivery of these combinatorial regimens to the colon for the chemoprevention of colon cancer. Additionally, conventional drug formulations using controlled release polymers chitosan, pectin and hydroxypropyl methylcellulose (HPMC) were tested for release of the drugs, for comparison purposes. Chemopreventive combination regimens demonstrated significant synergistic efficacy in both cell lines from XTT assay studies, when compared to the effects of individual agents. Approximately 45% decrease in cell viability for aspirin (15 mM) and calcium (30 mM) mixtures was observed in HT-29 cell lines, compared to ~55% decrease by the same combination in SW-480 cell lines. With combinations of aspirin (5 mM) and folic acid (1.5 mM), HT-29 cells demonstrated a 30% decrease in cell viability compared to ~38% decrease in the SW-480 cell line. Overall, all drug combinations demonstrated significant synergistic responses in the cell lines tested with the SW-480 cell line being more significantly affected by the drug regimens than the HT-29 cell line. Drug encapsulated nanoparticles demonstrated a spherical morphology, <125 nm average particle size (aspirin and folic acid) of nanoparticles and encapsulation efficiencies in the range of 80–91%. Drug release from nanoparticles was controlled with ~60% of the original amount released over a 96 h period. Conventional formulations exhibited faster kinetics of drug release when compared to the PLGA nanoparticles. Overall, the cell line studies demonstrate, for the first time, the ability of novel chemopreventive combinations to inhibit the growth of colon cancer cells whereas the

  15. Pancreatic Cancer Chemoprevention by Phytochemicals

    PubMed Central

    Boreddy, Srinivas Reddy; Srivastava, Sanjay K.

    2012-01-01

    Pancreatic cancer is fourth leading cause of cancer-related deaths in the United States of America. In spite of recent advances in the current therapeutic modalities such as surgery, radiation and chemotherapy patients, the average five year survival rate remains still less than 5%. Recently, compounds from natural sources receive ample of attention as anti-cancer agents. Many epidemiological studies published over the past few decades provide a strong correlation between consumption of vegetables, fruits or plant derived products and reduced incidence of cancer. The present review focuses on the potential antitumor effects of various natural products. PMID:23111102

  16. Pathobiology and Chemoprevention of Bladder Cancer

    PubMed Central

    Tanaka, Takuji; Miyazawa, Katsuhito; Tsukamoto, Tetsuya; Kuno, Toshiya; Suzuki, Koji

    2011-01-01

    Our understanding of the pathogenesis of bladder cancer has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies, prevention, or strategies to manage patients who are suspected to have or who have been diagnosed with bladder cancer is the ultimate goal. In particular, the chemoprevention of bladder cancer development is important, since urothelial cancer frequently recurs, even if the primary cancer is completely removed. The numerous alterations of both oncogenes and tumor suppressor genes that have been implicated in bladder carcinogenesis represent novel targets for therapy and prevention. In addition, knowledge about these genetic alterations will help provide a better understanding of the biological significance of preneoplastic lesions of bladder cancer. Animal models for investigating bladder cancer development and prevention can also be developed based on these alterations. This paper summarizes the results of recent preclinical and clinical chemoprevention studies and discusses screening for bladder cancer. PMID:21941546

  17. A new validated HPLC method for the determination of sulforaphane: application to study pharmacokinetics of sulforaphane in rats.

    PubMed

    Ong, Chau; Elbarbry, Fawzy

    2016-07-01

    A simple, accurate and reproducible high-performance liquid chromatography (HPLC) method has been developed and validated for the quantification of sulforaphane (SF) in rat plasma. The method involves a simple liquid-liquid extraction procedure to extract both SF and 7-hyrdoxycoumarin, the internal standard. The chromatographic analysis was achieved on a Shimadzu LC 20A HPLC system equipped with a Zorbax Eclipse XDB C18 column and an isocratic mobile phase consisting of 10 mm KH2 PO4 (pH 4.5) and acetonitrile HPLC grade (40:60, v/v) run at a flow rate of 1 mL/min for 10 min. The UV detection wavelength was set at 202 nm. The method exhibited good linearity (R(2) > 0.999) over the assayed concentration range (0.05-2 μg/mL) and demonstrated good intra- and inter-day precision and accuracy (relative standard deviations and the deviation from predicted values were <15%). This method was also successfully applied for studying the pharmacokinetics of SF in spontaneously hypertensive rats following single oral dietary doses of SF. The pharmacokinetics of SF show linear behavior at the dose range investigated in this study. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26542340

  18. A principal mechanism for the cancer chemopreventive activity of phenethyl isothiocyanate is modulation of carcinogen metabolism.

    PubMed

    Ioannides, Costas; Konsue, Nattaya

    2015-08-01

    Isothiocyanates are small molecules characterized by high chemical reactivity that allows them to interact readily with cellular constituents eliciting a plethora of biological activities. They are present exclusively in cruciferous vegetables, as glucosinolates, the intake of which has been associated with cancer chemoprevention. When the physical structure of these vegetables is disturbed, e.g. during mastication, the enzyme myrosinase is released and converts the glucosinolates to isothiocyanates (R-N=C=S), where R can be aliphatic or aromatic. Although sulforaphane, an aliphatic isothiocyanate, has received most attention worldwide, the most extensively studied aromatic isothiocyanate is phenethyl isothiocyanate (PEITC), and there are substantial differences in biological activity between the two sub-classes. In animal cancer models, PEITC effectively antagonized the carcinogenicity of chemicals, especially nitrosocompounds. A principal mechanism of their action is to protect the integrity of DNA by decreasing the levels of the genotoxic metabolites of chemical carcinogens. Extensive studies established that PEITC modulates the metabolism of the tobacco-specific carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by inhibiting its cytochrome P450-mediated bioactivation. Moreover, PEITC is a potent inducer of detoxification enzymes such as quinone reductase, glutathione S-transferase and glucuronosyl transferase. PEITC is rapidly absorbed and is characterized by a large bioavailability; Cmax concentrations achieved in plasma after dietary intake are sufficient to modulate carcinogen metabolism. PEITC is primarily metabolized by glutathione conjugation and is excreted in the urine and bile as the mercapturate. The ability of PEITC to perturb carcinogen metabolism through modulation of cytochrome P450 and phase II detoxification enzymes is comprehensively and critically reviewed. PMID:26119477

  19. Update from Asia. Asian studies on cancer chemoprevention.

    PubMed

    Yun, T K

    1999-01-01

    In Asia, nontoxic dietary products are considered desirable primary prevention vehicles for conquering cancer. As early as 1978, investigators in Korea carried out extensive long-term anticarcinogenicity experiments using the mouse lung tumor model and observed an anticarcinogenic effect of Panax ginseng C.A. Meyer extract in 1980. The results showed that natural products can provide hope for human cancer prevention. A newly established nine-week medium-term model using mouse lung tumors (Yun's model) could confirm the anticarcinogenicity of ginseng that varies according to its type and age. Subsequently, the ginseng was shown by epidemiological studies to be a nonorgan-specific cancer preventive agent associated with a dose-response relationship. The anticarcinogenic effects of vegetarian foods common at every dining table in Korea and some synthetics were also studied using Yun's nine-week model. In brief, ascorbic acid, soybean lecithin, capsaicin, biochanin A, Ganoderma lucidum, caffeine, and a novel synthetic 2-(allylthio)pyrazine decrease the incidence of mouse lung tumors, whereas fresh ginseng (4 years old), carrot, spinach, Sesamum indicum, beta-carotene, and 13-cis retinoic acid do not. This result regarding beta-carotene is consistent with the ineffective findings of the ATBC trial, the CARET trial, and the Physicians' Health Study. In 1983, a cancer chemoprevention study group was first established in Japan. Subsequently, (-)-epigallocatechin gallate, cryptoporic acid E, and sarcophytol A from natural products, and synthetic acyclic retinoid and canventol were shown to be anticarcinogenic or chemopreventive in human subjects. Despite the frequent consumption of tea wordwide as a beverage and current experimental evidence of anticarcinogenesis, including controversial results of epidemiological studies, more systematic clinical trials for confirmation of preventive activity of tea against cancer are needed. Placebo-controlled intervention trials of

  20. Medicinal Plants and Cancer Chemoprevention

    PubMed Central

    Desai, Avni G.; Qazi, Ghulam N.; Ganju, Ramesh K.; El-Tamer, Mahmoud; Singh, Jaswant; Saxena, Ajit K.; Bedi, Yashbir S.; Taneja, Subhash C.; Bhat, Hari K.

    2014-01-01

    Cancer is the second leading cause of death worldwide. Although great advancements have been made in the treatment and control of cancer progression, significant deficiencies and room for improvement remain. A number of undesired side effects sometimes occur during chemotherapy. Natural therapies, such as the use of plant-derived products in cancer treatment, may reduce adverse side effects. Currently, a few plant products are being used to treat cancer. However, a myriad of many plant products exist that have shown very promising anti-cancer properties in vitro, but have yet to be evaluated in humans. Further study is required to determine the efficacy of these plant products in treating cancers in humans. This review will focus on the various plant-derived chemical compounds that have, in recent years, shown promise as anticancer agents and will outline their potential mechanism of action. PMID:18781909

  1. Combination regimen with statins and NSAIDs: a promising strategy for cancer chemoprevention.

    PubMed

    Xiao, Hang; Yang, Chung S

    2008-09-01

    Statins and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed for lowering cholesterol and anti-inflammation, respectively. Recently, their potential roles as cancer chemopreventive agents have been subject to intensive studies. Human trials have not provided conclusive results on the protective effects of statins against different cancers, while more convincing results have been observed for cancer preventive effects of NSAIDs, especially on colorectal cancer. A promising strategy to enhance the cancer preventive efficacy of statins and NSAIDs is to use them in combination, which may produce synergy and lower the dose required for each agent. This strategy is of particular interest for potential use of low doses of statins and NSAIDs on a long-term basis for cancer chemoprevention; increased risks for gastrointestinal and cardiovascular side effects associated with the use of NSAIDs have been observed in colorectal cancer chemopreventive trials. This article reviews the evidence for the cancer preventive actions of statins and NSAIDs, as well as their possible synergistic action and the mechanisms involved. PMID:18548583

  2. Chemopreventive and therapeutic potential of "naringenin," a flavanone present in citrus fruits.

    PubMed

    Mir, Irfan Ahmad; Tiku, Ashu Bhan

    2015-01-01

    Cancer is one of the major causes of deaths in developed countries and is emerging as a major public health burden in developing countries too. Changes in cancer prevalence patterns have been noticed due to rapid urbanization and changing lifestyles. One of the major concerns is an influence of dietary habits on cancer rates. Approaches to prevent cancer are many and chemoprevention or dietary cancer prevention is one of them. Therefore, nutritional practices are looked at as effective types of dietary cancer prevention strategies. Attention has been given to identifying plant-derived dietary agents, which could be developed as a promising chemotherapeutic with minimal toxic side effects. Naringenin, a phytochemical mainly present in citrus fruits and tomatoes, is a frequent component of the human diet and has gained increasing interest because of its positive health effects not only in cancer prevention but also in noncancer diseases. In the last few years, significant progress has been made in studying the biological effects of naringenin at cellular and molecular levels. This review examines the cancer chemopreventive/therapeutic effects of naringenin in an organ-specific format, evaluating its limitations, and its considerable potential for development as a cancer chemopreventive/therapeutic agent. PMID:25514618

  3. Potential chemoprevention activity of pterostilbene by enhancing the detoxifying enzymes in the HT-29 cell line.

    PubMed

    Harun, Zaliha; Ghazali, Ahmad Rohi

    2012-01-01

    Detoxifying enzymes are present in most epithelial cells of the human gastrointestinal tract where they protect against xenobiotics which may cause cancer. Induction of examples such as glutathione S-transferase (GST) and its thiol conjugate, glutathione (GSH) as well as NAD(P)H: quinoneoxidoreductase (NQO1) facilitate the excretion of carcinogens and thus preventing colon carcinogenesis. Pterostilbene, an analogue of resveratrol, has demonstrated numerous pharmacological activities linked with chemoprevention. This study was conducted to investigate the potential of pterostilbene as a chemopreventive agent using the HT-29 colon cancer cell line to study the modulation of GST and NQO1 activities as well as the GSH level. Initially, our group, established the optimum dose of 24 hours pterostilbene treatment using MTT assays. Then, effects of pterostilbene (0-50 μM) on GST and NQO1 activity and GSH levels were determined using GST, NQO1 and Ellman assays, respectively. MTT assay of pterostilbene (0-100 μM) showed no cytotoxicity toward the HT-29 cell line. Treatment increased GST activity in the cell line significantly (p<0.05) at 12.5 and 25.0 μM. In addition, treatment at 50 μM increased the GSH level significantly (p<0.05). Pterostilbene also enhanced NQO1 activity significantly (p<0.05) at 12.5 μM and 50 μM. Hence, pterostilbene is a potential chemopreventive agent capable of modulation of detoxifiying enzyme levels in HT-29 cells. PMID:23464466

  4. Inhibition of Bladder Cancer by Broccoli Isothiocyanates Sulforaphane and Erucin: Characterization, Metabolism and Interconversion

    PubMed Central

    Abbaoui, Besma; Riedl, Kenneth M; Ralston, Robin A; Thomas-Ahner, Jennifer M; Schwartz, Steven J; Clinton, Steven K; Mortazavi, Amir

    2013-01-01

    Epidemiologic evidence suggests diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Our objectives are to investigate these observations and determine the role of isothiocyanates in primary or secondary bladder cancer prevention. We initially investigate the mechanisms whereby broccoli and broccoli sprout extracts and pure isothiocyanates inhibit normal, non-invasive (RT4) and invasive (J82, UMUC3) human urothelial cell viability. Sulforaphane (IC50= 5.66±1.2μM) and erucin (IC50= 8.79±1.3μM) are found to be the most potent inhibitors and normal cells are least sensitive. This observation is associated with downregulation of survivin, EGFR and HER2/neu, G2/M cell cycle accumulation and apoptosis. In a murine UMUC3 xenograft model, we fed semipurified diets containing 4% broccoli sprouts, or 2% broccoli sprout isothiocyanate extract; or gavaged pure sulforaphane or erucin (each at 295 μmol/kg, similar to dietary exposure); and report tumor weight reduction of 42% (p=0.02), 42% (p=0.04), 33% (p=0.04) and 58% (p<0.0001), respectively. Sulforaphane and erucin metabolites are present in mouse plasma (micromolar range) and tumor tissue, with N-acetyl cysteine conjugates as the most abundant. Interconversion of sulforaphane and erucin metabolites was observed. This work supports development of fully characterized, novel food products for phase I/II human studies targeting bladder cancer prevention. PMID:23038615

  5. Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response

    SciTech Connect

    Zheng, Yi; Tao, Shasha; Lian, Fangru; Chau, Binh T.; Chen, Jie; Sun, Guifan; Fang, Deyu; Lantz, R. Clark; Zhang, Donna D.

    2012-12-15

    Exposure to arsenic is associated with an increased risk of lung disease. Novel strategies are needed to reduce the adverse health effects associated with arsenic exposure in the lung. Nrf2, a transcription factor that mediates an adaptive cellular defense response, is effective in detoxifying environmental insults and prevents a broad spectrum of diseases induced by environmental exposure to harmful substances. In this report, we tested whether Nrf2 activation protects mice from arsenic-induced toxicity. We used an in vivo arsenic inhalation model that is highly relevant to low environmental human exposure to arsenic-containing dusts. Two-week exposure to arsenic-containing dust resulted in pathological alterations, oxidative DNA damage, and mild apoptotic cell death in the lung; all of which were blocked by sulforaphane (SF) in an Nrf2-dependent manner. Mechanistically, SF-mediated activation of Nrf2 alleviated inflammatory responses by modulating cytokine production. This study provides strong evidence that dietary intervention targeting Nrf2 activation is a feasible approach to reduce adverse health effects associated with arsenic exposure. -- Highlights: ► Exposed to arsenic particles and/or SF have elevated Nrf2 and its target genes. ► Sulforaphane prevents pathological alterations, oxidative damage and cell death. ► Sulforaphane alleviates infiltration of inflammatory cells into the lungs. ► Sulforaphane suppresses arsenic-induced proinflammatory cytokine production.

  6. Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs.

    PubMed

    Wang, Yian; Zhang, Zhongqiu; Garbow, Joel R; Rowland, Doug J; Lubet, Ronald A; Sit, Daniel; Law, Francis; You, Ming

    2009-07-01

    Antitumor B (ATB) is a Chinese herbal mixture of six plants. Previous studies have shown significant chemopreventive efficacy of ATB against human esophageal and lung cancers. We have recently developed a new mouse model for lung squamous cell carcinomas (SCC). In this study, lung SCC mouse model was characterized using small-animal imaging techniques (magnetic resonance imaging and computed tomography). ATB decreased lung SCC significantly (3.1-fold; P < 0.05) and increased lung hyperplastic lesions by 2.4-fold (P < 0.05). This observation suggests that ATB can block hyperplasia from progression to SCC. ATB tissue distribution was determined using matrine as a marker chemical. We found that ATB is rapidly absorbed and then distributes to various tissues including the lung. These results indicate that ATB is a potent chemopreventive agent against the development of mouse lung SCCs. PMID:19584077

  7. Neuroprotective effects of sulforaphane after contusive spinal cord injury.

    PubMed

    Benedict, Andrea L; Mountney, Andrea; Hurtado, Andres; Bryan, Kelley E; Schnaar, Ronald L; Dinkova-Kostova, Albena T; Talalay, Paul

    2012-11-01

    Traumatic spinal cord injury (SCI) leads to oxidative stress, calcium mobilization, glutamate toxicity, the release of proinflammatory factors, and depletion of reduced glutathione (GSH) at the site of injury. Induction of the Keap1/Nrf2/ARE pathway can alleviate neurotoxicity by protecting against GSH depletion, oxidation, intracellular calcium overload, mitochondrial dysfunction, and excitotoxicity. Sulforaphane (SF), an isothiocyanate derived from broccoli, is a potent naturally-occurring inducer of the Keap1/Nrf2/ARE pathway, leading to upregulation of genes encoding cytoprotective proteins such as NAD(P)H: quinone oxidoreductase 1, and GSH-regulatory enzymes. Additionally, SF can attenuate inflammation by inhibiting the nuclear factor-κB (NF-κB) pathway, and the enzymatic activity of the proinflammatory cytokine macrophage inhibitory factor (MIF). Our study examined systemic administration of SF in a rat model of contusion SCI, in an effort to utilize its indirect antioxidant and anti-inflammatory properties to decrease secondary injury. Two doses of SF (10 or 50 mg/kg) were administered at 10 min and 72 h after contusion SCI. SF (50 mg/kg) treatment resulted in both acute and long-term beneficial effects, including upregulation of the phase 2 antioxidant response at the injury site, decreased mRNA levels of inflammatory cytokines (i.e., MMP-9) in the injured spinal cord, inactivation of urinary MIF tautomerase activity, enhanced hindlimb locomotor function, and an increased number of serotonergic axons caudal to the lesion site. These findings demonstrate that SF provides neuroprotective effects in the spinal cord after injury, and could be a candidate for therapy of SCI. PMID:22853439

  8. Chemopreventive Agent Development Clinical Trials | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  9. Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma

    PubMed Central

    Liao, Chen-Yi; Lee, Ching-Chang; Tsai, Chi-chang; Hsueh, Chao-Wen; Wang, Chih-Chiang; Chen, I-Hung; Tsai, Ming-Kai; Liu, Mei-Yu; Hsieh, An-Tie; Su, Kuan-Jen; Wu, Hau-Ming; Huang, Shih-Chung; Wang, Yi-Chen; Wang, Chien-Yao; Huang, Shu-Fang; Yeh, Yen-Cheng; Ben, Ren-Jy; Chien, Shang-Tao; Hsu, Chin-Wen; Kuo, Wu-Hsien

    2015-01-01

    We would like to highlight the application of natural products to hepatocellular carcinoma (HCC). We will focus on the natural products known as flavonoids, which target this disease at different stages of hepatocarcinogenesis. In spite of the use of chemotherapy and radiotherapy in treating HCC, patients with HCC still face poor prognosis because of the nature of multidrug resistance and toxicity derived from chemotherapy and radiotherapy. Flavonoids can be found in many vegetables, fruits, and herbal medicines that exert their different anticancer effects via different intracellular signaling pathways and serve as antioxidants. In this review, we will discuss seven common flavonoids that exert different biological effects against HCC via different pathways. PMID:26858957

  10. Chemopreventive Agent Development Funding Opportunities | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  11. Chemopreventive Agent Development Staff | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  12. The tamoxifen controversy - clinical chemopreventive agent and experimental carcinogen

    SciTech Connect

    Pitot, H.C.

    1995-02-01

    While dramatic decreases in the mortality of heart disease, the major fatal disease in the United States, have occurred since 1950, there has been a slight but measurable increase in the cancer mortality rate since 1950 in this country. The reasons for the former precipitous decline in death from heart disease are a balanced combination of prevention and early detection of risk factors combined with improved treatment modalities. While improved treatment modalities of neoplasia have led to significant decreases in certain cancers such as that of testis, Hodgkin`s disease, acute lymphatic leukemia in children, and several other cancers, mortality rates from the major cancers, namely lung, breast, prostate, and colon, have either increased or not changed during this period. Since the treatment arm of cancer control has not exhibited the dramatic successes seen in, for example, heart disease therapy, many have and are advocating the importance of cancer prevention. 18 refs.

  13. Active Chemopreventive Agent Development Grants | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

  14. Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention?

    PubMed Central

    H.Dashwood, Roderick; C.Myzak, Melinda; Ho, Emily

    2008-01-01

    There is growing interest in the various mechanisms that regulate chromatin remodeling, including modulation of histone deacetylase (HDAC) activities. Competitive HDAC inhibitors disrupt the cell cycle and/or induce apoptosis via de-repression of genes such as P21 and BAX, and cancer cells appear to be more sensitive than non-transformed cells to trichostatin A and related HDAC inhibitory compounds. This apparent selectivity of action in cancer cells makes HDAC inhibitors an attractive avenue for drug development. However, in the search for potent HDAC inhibitors with cancer therapeutic potential there has been a tendency to overlook or dismiss weak ligands that could prove effective in cancer prevention, including agents present in the human diet. Recent reports have described butyrate, diallyl disulfide and sulforaphane as HDAC inhibitors, and many other dietary agents will be probably discovered to attenuate HDAC activity. Here we discuss ‘pharmacologic’ agents that potently de-repress gene expression (e.g. during therapeutic intervention) versus dietary HDAC inhibitors that, as weak ligands, might subtly regulate the expression of genes involved in cell growth and apoptosis. An important question is the extent to which dietary HDAC inhibitors, and other dietary agents that affect gene expression via chromatin remodeling, modulate the expression of genes such as P21 and BAX so that cells can respond most effectively to external stimuli and toxic insults. PMID:16267097

  15. Combination chemoprevention of experimental gastric carcinogenesis by s-allylcysteine and lycopene: modulatory effects on glutathione redox cycle antioxidants.

    PubMed

    Velmurugan, B; Nagini, S

    2005-01-01

    Combination chemoprevention by diet-derived agents is a promising strategy for protection against gastric cancer. We therefore evaluated the combined chemopreventive effect of S-allylcysteine (SAC), an organosulfur constituent of garlic, and lycopene, a major carotenoid present in tomatoes, against N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and saturated sodium chloride (S-NaCl)-induced gastric carcinogenesis in Wistar rats. The animals were divided into eight groups of six animals each. Rats in group 1 were given MNNG by intragastric intubation on days 0 and 14 as well as S-NaCl every 3 days during weeks 0-3. Animals in groups 2-4, administered MNNG and S-NaCl as in group 1, received in addition SAC and lycopene alone and in combination, respectively, three times per week starting on the day following the first exposure to MNNG. Groups 5-7 were given the chemopreventive agents alone, whereas group 8 served as controls. The animals were sacrificed after an experimental period of 21 weeks. Measurement of lipid peroxidation and antioxidants of the glutathione redox cycle in the stomach, liver, and erythrocytes was used to monitor the chemopreventive potential of SAC and lycopene. In the tumor tissue, diminished lipid peroxidation was accompanied by an increase in reduced glutathione (GSH) and GSH-dependent enzymes, whereas in the liver and erythrocytes, enhanced lipid peroxidation was associated with antioxidant depletion. Although SAC and lycopene alone significantly suppressed the development of gastric cancer, administration of SAC and lycopene in combination was more effective in inhibiting MNNG-induced stomach tumors and modulating the redox status in the tumor and host tissues. The results of the present study validate the hypothesis that diet-derived chemopreventive agents such as SAC and lycopene in combination may interact synergistically with high efficacy and lessened toxicity against gastric cancer. PMID:16379561

  16. Sulforaphane inhibits advanced glycation end product-induced pericyte damage by reducing expression of receptor for advanced glycation end products.

    PubMed

    Maeda, Sayaka; Matsui, Takanori; Ojima, Ayako; Takeuchi, Masayoshi; Yamagishi, Sho-Ichi

    2014-09-01

    Advanced glycation end products (AGEs) not only inhibit DNA synthesis but also play a role in diabetic retinopathy by evoking apoptosis and inflammation in retinal pericytes via interaction with a receptor for AGE (RAGE). Similarly, sulforaphane, which is a naturally occurring isothiocyanate that is found in widely consumed cruciferous vegetables, protects against oxidative stress-induced tissue damage. Therefore, we hypothesized that sulforaphane could inhibit AGE-induced pericytes injury through its antioxidative properties. Advanced glycation end product stimulated superoxide generation as well as RAGE gene and protein expression in bovine-cultured retinal pericytes, and these effects were prevented by the treatment with sulforaphane. Antibodies directed against RAGE also blocked AGE-evoked reactive oxygen species generation in pericytes. Sulforaphane and antibodies directed against RAGE significantly inhibited the AGE-induced decrease in DNA synthesis, apoptotic cell death, and up-regulation of monocyte chemoattractant protein 1 messenger RNA levels in pericytes. For the first time, the present study demonstrates that sulforaphane could inhibit DNA synthesis, apoptotic cell death, and inflammatory reactions in AGE-exposed pericytes, partly by suppressing RAGE expression via its antioxidative properties. Blockade of the AGE-RAGE axis in pericytes by sulforaphane might be a novel therapeutic target for the treatment of diabetic retinopathy. PMID:25241332

  17. Isothiocyanate metabolism, distribution, and interconversion in mice following consumption of thermally processed broccoli sprouts or purified sulforaphane

    PubMed Central

    Bricker, Gregory V.; Riedl, Kenneth M.; Ralston, Robin A.; Tober, Kathleen L.; Oberyszyn, Tatiana M.; Schwartz, Steven J.

    2014-01-01

    Scope Broccoli sprouts are a rich source of glucosinolates, a group of phytochemicals that when hydrolyzed, are associated with cancer prevention. Our objectives were to investigate the metabolism, distribution, and interconversion of isothiocyanates (ITCs) in mice fed thermally processed broccoli sprout powders (BSPs) or the purified ITC sulforaphane. Methods and results For 1 wk, mice were fed a control diet (n = 20) or one of four treatment diets (n = 10 each) containing nonheated BSP, 60°C mildly heated BSP, 5-min steamed BSP, or 3 mmol purified sulforaphane. Sulforaphane and erucin metabolite concentrations in skin, liver, kidney, bladder, lung, and plasma were quantified using HPLC-MS/MS. Thermal intensity of BSP processing had disparate effects on ITC metabolite concentrations upon consumption. Mild heating generally resulted in the greatest ITC metabolite concentrations in vivo, followed by the nonheated and steamed BSP diets. We observed interconversion between sulforaphane and erucin species or metabolites, and report that erucin is the favored form in liver, kidney, and bladder, even when only sulforaphane is consumed. Conclusion ITC metabolites were distributed to all tissues analyzed, suggesting the potential for systemic benefits. We report for the first time tissue-dependent ratio of sulforaphane and erucin, though further investigation is warranted to assess biological activity of individual forms. PMID:24975513

  18. An Overview of Ultraviolet B Radiation-Induced Skin Cancer Chemoprevention by Silibinin

    PubMed Central

    Kumar, Rahul; Deep, Gagan; Agarwal, Rajesh

    2015-01-01

    Skin cancer incidences are rising worldwide, and one of the major causative factors is excessive exposure to solar ultraviolet radiation (UVR). Annually, ~5 million skin cancer patients are treated in United States, mostly with nonmelanoma skin cancer (NMSC), which is also frequent in other Western countries. As sunscreens do not provide adequate protection against deleterious effects of UVR, additional and alternative chemoprevention strategies are urgently needed to reduce skin cancer burden. Over the last couple of decades, extensive research has been conducted to understand the molecular basis of skin carcinogenesis, and to identifying novel agents which could be useful in the chemoprevention of skin cancer. In this regard, several natural non-toxic compounds have shown promising efficacy in preventing skin carcinogenesis at initiation, promotion and progression stages, and are considered important in better management of skin cancer. Consistent with this, we and others have studied and established the notable efficacy of natural flavonolignan silibinin against UVB-induced skin carcinogenesis. Extensive pre-clinical animal and cell culture studies report strong anti-inflammatory, anti-oxidant, DNA damage repair, immune-modulatory and anti-proliferative properties of silibinin. Molecular studies have identified that silibinin targets pleotropic signaling pathways including mitogenic, cell cycle, apoptosis, autophagy, p53, NF-κB, etc. Overall, the skin cancer chemopreventive potential of silibinin is well supported by comprehensive mechanistic studies, suggesting its greater use against UV-induced cellular damages and photocarcinogenesis. PMID:26097804

  19. Novel aspects for the application of Curcumin in chemoprevention of various cancers.

    PubMed

    Bachmeier, Beatrice E; Killian, Peter; Pfeffer, Ulrich; Nerlich, Andreas G

    2010-01-01

    Chemoprevention of malignant tumor growth is a novel and potentially powerful approach for tumor therapy. Recent in vitro and in vivo investigations provide increasing evidence that naturally occurring substances may exhibit significant chemopreventive activities. To this regard, the spice Curcumin, widely used in Indian cuisine, has been identified to show considerable anti-tumor effects. Most interestingly, numerous studies have not shown toxic side effects of this substance. Curcumin induces tumor cell apoptosis along with a reduction of tumor cell invasion and metastasis. Recent molecular studies provide evidence that Curcumin acts via a control of the NFkappaB pathway exerting most of the various modulating and moderating effects on malignant cells. Along with these in vitro studies, ex vivo and first clinical investigations confirm the anti-tumor effects of Curcumin, either as an isolated chemoprevention substance or in combination with chemotherapeutic agents as supportive measure reducing pharmaceutical resistance of tumor cells to certain chemotherapeutics. Despite our increasing knowledge on this interesting substance there still remain many unknown effects that deserve intense investigation. PMID:20036978

  20. Chemopreventive Properties and Toxicity of Kelulut Honey in Sprague Dawley Rats Induced with Azoxymethane

    PubMed Central

    Muhamad Zali, Muhamad Firdaus Shyfiq; Mohd Ali, Razana; Zainal, Nurul Amira; Sapuan, Sarah; Tor, Yin Sim; Gopalsamy, Banulata; Syed Alwi, Sharifah Sakinah

    2016-01-01

    Ethnopharmacological Relevance. Colon cancer has been a major problem worldwide. Kelulut honey (KH) is produced by the stingless bees from Trigona species and has strong antioxidant activities that could be one of the potential chemopreventive agents from natural resources. Aim of This Study. This study investigated the chemopreventive properties and toxicity of KH in Sprague Dawley rats induced with azoxymethane (AOM). Material and Method. Twenty-four male Sprague Dawley rats aged 5 weeks were divided into 4 groups: (G1) untreated group not induced with AOM, (G2) untreated group induced with AOM, (G3) treated group induced with AOM, and (G4) treated group not induced with AOM. Injection of AOM (15 mg/kg) was via intraperitoneal route once a week for two subsequent weeks. The treatment groups were given oral administration of KH (1183 mg/kg body weight) twice daily for 8 weeks. Results. Treatment with KH significantly reduced the total number of aberrant crypt foci (ACF) and aberrant crypts (AC) and crypt multiplicity. KH was not toxic to the animals since the level of blood profile parameters, liver enzymes, and kidney functions was in normal range. Conclusions. The current finding shows that KH has chemopreventive properties in rats induced with colorectal cancer and also was found not toxic towards the animals. PMID:27525267

  1. Chemopreventive Properties and Toxicity of Kelulut Honey in Sprague Dawley Rats Induced with Azoxymethane.

    PubMed

    Saiful Yazan, Latifah; Muhamad Zali, Muhamad Firdaus Shyfiq; Mohd Ali, Razana; Zainal, Nurul Amira; Esa, Nurulaidah; Sapuan, Sarah; Ong, Yong Sze; Tor, Yin Sim; Gopalsamy, Banulata; Voon, Fui Ling; Syed Alwi, Sharifah Sakinah

    2016-01-01

    Ethnopharmacological Relevance. Colon cancer has been a major problem worldwide. Kelulut honey (KH) is produced by the stingless bees from Trigona species and has strong antioxidant activities that could be one of the potential chemopreventive agents from natural resources. Aim of This Study. This study investigated the chemopreventive properties and toxicity of KH in Sprague Dawley rats induced with azoxymethane (AOM). Material and Method. Twenty-four male Sprague Dawley rats aged 5 weeks were divided into 4 groups: (G1) untreated group not induced with AOM, (G2) untreated group induced with AOM, (G3) treated group induced with AOM, and (G4) treated group not induced with AOM. Injection of AOM (15 mg/kg) was via intraperitoneal route once a week for two subsequent weeks. The treatment groups were given oral administration of KH (1183 mg/kg body weight) twice daily for 8 weeks. Results. Treatment with KH significantly reduced the total number of aberrant crypt foci (ACF) and aberrant crypts (AC) and crypt multiplicity. KH was not toxic to the animals since the level of blood profile parameters, liver enzymes, and kidney functions was in normal range. Conclusions. The current finding shows that KH has chemopreventive properties in rats induced with colorectal cancer and also was found not toxic towards the animals. PMID:27525267

  2. Chemopreventive effect of Curcuma longa Linn on liver pathology in HBx transgenic mice.

    PubMed

    Kim, Jungsun; Ha, Hye-Lin; Moon, Hyung-Bae; Lee, Yeon-Weol; Cho, Chong-Kwan; Yoo, Hwa-Seung; Yu, Dae-Yeul

    2011-06-01

    Unlike other forms of hepatocellular carcinoma (HCC), HCC induced by hepatitis B virus (HBV) infection shows a poor prognosis after conventional therapies. HBV induces liver cirrhosis and HCC. Many researchers have made efforts to find new substances that suppress the activity of HBV. Curcuma longa Linn (CLL) has been used for traditional medicine and food in Asia, especially in India, and has shown chemopreventive effects in a HBV-related in vitro model. This in vivo study was designed to seek the chemopreventive effects of CLL and its mechanisms. CLL mixture concentrated with dextrose water by boiling was lyophilized. CLL extracts were administrated to HBV X protein (HBx) transgenic mice aged 4 weeks for 2 to 4 weeks and aged 6 months for 3 months. After administration, histological changes in the liver tissue and expression of HBx-related genes were investigated. CLL-treated mice showed less visceral fat, a smaller liver/body weight ratio and delayed liver pathogenesis. Proliferating cell nuclear antigen (PCNA) expression was also increased in CLL-treated HBx transgenic mice, indicating regeneration of damaged liver tissue. CLL treatment decreased expression of HBx and increased p21 and cyclin D1 in livers of HBx transgenic mice. In addition, p-p53 was increased after CLL treatment. These results suggest that CLL can have beneficial effects on the early and late stages of liver pathogenesis, preventing and delaying liver carcinogenesis. This drug should be considered as a potential chemopreventive agent for HBV-related hepatocarcinogenesis. PMID:21190953

  3. Anthocyans from fruits and vegetables--does bright colour signal cancer chemopreventive activity?

    PubMed

    Cooke, Darren; Steward, William P; Gescher, Andreas J; Marczylo, Tim

    2005-09-01

    Consumption of fruits and berries has been associated with decreased risk of developing cancer. The most abundant flavonoid constituents of fruits and berries are anthocyans (i.e. anthocyanins, glycosides, and their aglycons, anthocyanidins) that cause intense colouration. In this review, we describe epidemiological evidence hinting at the cancer preventive activity of anthocyan-containing foods in humans, results of chemoprevention studies in rodent models with anthocyans or anthocyan-containing fruit/vegetable extracts, and pharmacological properties of anthocyans. Anthocyanidins have been shown to inhibit malignant cell survival and confound many oncogenic signalling events in the 10(-6)-10(-4) M concentration range. Studies of the pharmacokinetics of anthocyanins after their consumption as single agents, anthocyanin mixtures or berry extracts suggest that anthocyanins reach levels of 10(-8)-10(-7) M in human blood. It is unclear whether such concentrations are sufficient to explain anticarcinogenic effects, and whether anthocyanins exert chemopreventive efficacy themselves, or if they need to undergo hydrolysis to their aglyconic counterparts. The currently available literature provides tantalising hints of the potential usefulness of anthocyans or anthocyan mixtures as cancer chemopreventive interventions. Nevertheless further studies are necessary to help adjudge the propitiousness of their clinical development. PMID:16084717

  4. Nrf2: friend or foe for chemoprevention?

    PubMed Central

    Kensler, Thomas W.; Wakabayashi, Nobunao

    2010-01-01

    Health reflects the ability of an organism to adapt to stress. Stresses—metabolic, proteotoxic, mitotic, oxidative and DNA-damage stresses—not only contribute to the etiology of cancer and other chronic degenerative diseases but are also hallmarks of the cancer phenotype. Activation of the Kelch-like ECH-associated protein 1 (KEAP1)–NF-E2-related factor 2 (NRF2)-signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whilst disruption of the pathway exacerbates these outcomes. This pathway can be induced by thiol-reactive small molecules that demonstrate protective efficacy in preclinical chemoprevention models and in clinical trials. However, mutations and epigenetic modifications affecting the regulation and fate of NRF2 can lead to constitutive dominant hyperactivation of signaling that preserves rather than attenuates cancer phenotypes by providing selective resistance to stresses. This review provides a synopsis of KEAP1–NRF2 signaling, compares the impact of genetic versus pharmacologic activation and considers both the attributes and concerns of targeting the pathway in chemoprevention. PMID:19793802

  5. Chemoprevention of prostate cancer by isoflavonoids.

    PubMed

    Aufderklamm, Stefan; Miller, Florian; Galasso, Anastasia; Stenzl, Arnulf; Gakis, Georgios

    2014-01-01

    In Europe, prostate cancer (PC) is the most common malignancy in males. There are three known risk factors strongly coherent to the development of PC: heredity, ethnical origin, and age. Migration studies have shown that environmental factors may influence the development of PC. In this context, specific nutritional components may exert an influence on the tumorigenesis of PC. Primary prevention of PC is still an important issue due to its high prevalence, treatment-associated morbidities, and long-term complications. Phytoestrogenes as flavonoids seem to play an essential role in the chemoprevention of PC which is possibly due to their hormonal function and antioxidative capability. Flavonoids and their subgroups are naturally existent in traditional asian and vegetarian nutrients as coverings of plants, fruits, and vegetables. Two of the most frequently investigated flavonoids are genistein and quercetin. These nutritional components may have therapeutic potential and may impact the development of PC. Even though these flavonoids show promising results in the chemoprevention of PC, the literature is almost experimental, epidemiological, and retrospective with a missing long-term follow-up. Therefore, randomized clinical trials are urgently needed to evaluate in depth its oncologic effects in PC. PMID:24531783

  6. Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

    SciTech Connect

    Kaur, Manjinder; Agarwal, Rajesh

    2007-11-01

    Failure and high systemic toxicity of conventional cancer therapies have accelerated the focus on the search for newer agents, which could prevent and/or slow-down cancer growth and have more human acceptability by being less or non-toxic. Silymarin is one such agent, which has been extensively used since ages for the treatment of liver conditions, and thus has possibly the greatest patient acceptability. In recent years, increasing body of evidence has underscored the cancer preventive efficacy of silymarin in both in vitro and in vivo animal models of various epithelial cancers. Apart from chemopreventive effects, other noteworthy aspects of silymarin and its active constituent silibinin in cancer treatment include their capability to potentiate the efficacy of known chemotherapeutic drugs, as an inhibitor of multidrug resistance-associated proteins and as an adjunct to the cancer therapeutic drugs due to their organ-protective efficacy specifically liver, and immunostimulatory effects. Widespread use of silymarin for liver health in humans and commercial availability of its formulations with increased bioavailability, further underscore the necessity of carrying out controlled clinical trials with these agents in cancer patients. In this review, we will briefly discuss the outcomes of clinical trials being conducted by us and others in cancer patients to provide insight into the clinical relevance of the observed chemopreventive effects of these agents in various epithelial cancer models.

  7. Chemoprevention of Lung Cancer: Prospects and Disappointments in Human Clinical Trials

    PubMed Central

    Greenberg, Alissa K.; Tsay, Jun-Chieh; Tchou-Wong, Kam-Meng; Jorgensen, Anna; Rom, William N.

    2013-01-01

    Decreasing the risk of lung cancer, or preventing its development in high-risk individuals, would have a huge impact on public health. The most effective means to decrease lung cancer incidence is to eliminate exposure to carcinogens. However, with recent advances in the understanding of pulmonary carcinogenesis and the identification of intermediate biomarkers, the prospects for the field of chemoprevention research have improved dramatically. Here we review the most recent research in lung cancer chemoprevention—focusing on those agents that have been investigated in human clinical trials. These agents fall into three major categories. First, oxidative stress plays an important role in pulmonary carcinogenesis; and therefore, antioxidants (including vitamins, selenium, green tea extracts, and isothiocyanates) may be particularly effective in preventing the development of lung cancer. Second, inflammation is increasingly accepted as a crucial factor in carcinogenesis, and many investigators have focused on anti-inflammatory agents, such as glucocorticoids, NSAIDs, statins, and PPARγ agonists. Finally, the PI3K/AKT/mTOR pathway is recognized to play a central role in tobacco-induced carcinogenesis, and inhibitors of this pathway, including myoinositol and metformin, are promising agents for lung cancer prevention. Successful chemoprevention will likely require targeting of multiple pathways to carcinogenesis—both to minimize toxicity and maximize efficacy. PMID:24216701

  8. Enhancing sulforaphane absorption and excretion in healthy men through the combined consumption of fresh broccoli sprouts and a glucoraphanin-rich powder.

    PubMed

    Cramer, Jenna M; Teran-Garcia, Margarita; Jeffery, Elizabeth H

    2012-05-01

    Sulforaphane (SF) is a chemopreventive isothiocyanate (ITC) derived from glucoraphanin (GRP) hydrolysis by myrosinase, a thioglucoside present in broccoli. The ability of broccoli powders sold as supplements to provide dietary SF is often of concern as many supplements contain GRP, but lack myrosinase. In a previous study, biomarkers of SF bioavailability from a powder rich in GRP, but lacking myrosinase, were enhanced by co-consumption of a myrosinase-containing air-dried broccoli sprout powder. Here, we studied the absorption of SF from the GRP-rich powder used in the previous study, but in combination with fresh broccoli sprouts, which are commercially available and more applicable to the human diet than air-dried sprout powder. A total of four participants each consumed four meals (separated by 1 week) consisting of dry cereal and yogurt with sprouts equivalent to 70 μmol SF, GRP powder equivalent to 120 μmol SF, both or neither. Metabolites of SF were analysed in blood and urine. The 24 h urinary SF-N-acetylcysteine recovery was 65, 60 and 24 % of the dose ingested from combination, broccoli sprout and GRP powder meals, respectively. In urine and plasma, ITC appearance was delayed following the GRP powder meal compared with the sprout and combination meals. Compared with the GRP powder or sprouts alone, combining broccoli sprouts with the GRP powder synergistically enhanced the early appearance of SF, offering insight into the combination of foods for improved health benefits of foods that reduce the risk for cancer. PMID:21910945

  9. Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling.

    PubMed

    Oh, Chang Joo; Kim, Joon-Young; Min, Ae-Kyung; Park, Keun-Gyu; Harris, Robert A; Kim, Han-Jong; Lee, In-Kyu

    2012-02-01

    Sulforaphane (SFN) is a dietary isothiocyanate that exerts chemopreventive effects via NF-E2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). This work was undertaken to evaluate the effects of SFN on hepatic fibrosis and profibrotic transforming growth factor (TGF)-β/Smad signaling, which are closely associated with oxidative stress. SFN suppressed TGF-β-enhanced expression of α-smooth muscle actin (α-SMA), a marker of hepatic stellate cell (HSC) activation, and profibrogenic genes such as type I collagen, fibronectin, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and plasminogen activator inhibitor (PAI)-1 in hTERT, an immortalized human HSC line. SFN inhibited TGF-β-stimulated activity of a PAI-1 promoter construct and (CAGA)(9) MLP-Luc, an artificial Smad3/4-specific reporter, in addition to reducing phosphorylation and nuclear translocation of Smad3. Nrf2 overexpression was sufficient to inhibit the TGF-β/Smad signaling and PAI-1 expression. Conversely, knockdown of Nrf2, but not inhibition of HO-1 or NQO1 activity, significantly abolished the inhibitory effect of SFN on (CAGA)(9) MLP-Luc activity. However, inhibition of NQO1 activity reversed repression of TGF-β-stimulated expression of type I collagen by SFN, suggesting the involvement of antioxidant activity of SFN in the suppression of Smad-independent fibrogenic gene expression. Finally, SFN treatment attenuated the development and progression of early stage hepatic fibrosis induced by bile duct ligation in mice, accompanied by reduced expression of type I collagen and α-SMA. Collectively, these results show that SFN elicits an antifibrotic effect on hepatic fibrosis through Nrf2-mediated inhibition of the TGF-β/Smad signaling and subsequent suppression of HSC activation and fibrogenic gene expression. PMID:22155056

  10. Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway.

    PubMed

    Nallasamy, Palanisamy; Si, Hongwei; Babu, Pon Velayutham Anandh; Pan, Dengke; Fu, Yu; Brooke, Elizabeth A S; Shah, Halley; Zhen, Wei; Zhu, Hong; Liu, Dongmin; Li, Yunbo; Jia, Zhenquan

    2014-08-01

    Sulforaphane, a naturally occurring isothiocyanate present in cruciferous vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of sulforaphane at physiological concentrations remain unclear. Here, we report that a sulforaphane concentration as low as 0.5 μM significantly inhibited tumor necrosis factor-α (TNF-α)-induced adhesion of monocytes to human umbilical vein endothelial cells, a key event in the pathogenesis of atherosclerosis both in static and under flow conditions. Such physiological concentrations of sulforaphane also significantly suppressed TNF-α-induced production of monocyte chemotactic protein-1 and adhesion molecules including soluble vascular adhesion molecule-1 and soluble E-selectin, key mediators in the regulation of enhanced endothelial cell-monocyte interaction. Furthermore, sulforaphane inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, Inhibitor of NF-κB alpha (IκBα) degradation and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that sulforaphane can inhibit inflammation by suppressing NF-κB signaling. In an animal study, sulforaphane (300 ppm) in a mouse diet significantly abolished TNF-α-increased ex vivo monocyte adhesion and circulating adhesion molecules and chemokines in C57BL/6 mice. Histology showed that sulforaphane treatment significantly prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization, as shown by Verhoeff-van Gieson staining. Immunohistochemistry studies showed that sulforaphane treatment also reduced vascular adhesion molecule-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, sulforaphane at physiological concentrations protects against TNF-α-induced vascular endothelial inflammation, in both in vitro and in vivo models. This anti

  11. Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway

    PubMed Central

    Nallasamy, Palanisamy; Si, Hongwei; Babu, Pon Velayutham Anandh; Pan, Dengke; Fu, Yu; Brooke, Elizabeth A.S.; Shah, Halley; Zhen, Wei; Zhu, Hong; Liu, Dongmin; Li, Yunbo; Jia, Zhenquan

    2014-01-01

    Sulforaphane, a naturally-occurring isothiocyanate present in cruciferous vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of sulforaphane at physiological concentrations remain unclear. Here, we report that a sulforaphane concentration as low as 0.5 μM significantly inhibited TNF-α-induced adhesion of monocytes to human umbilical vein endothelial cells (HUVECs), a key event in the pathogenesis of atherosclerosis both in static and under flow conditions. Such physiological concentrations of sulforaphane also significantly suppressed TNF-α-induced production of monocyte chemotactic protein-1 (MCP-1), adhesion molecule sVCAM-1 and sE-Selectin, key mediators in the regulation of enhanced endothelial cell-monocyte interaction. Furthermore, sulforaphane inhibited TNF-α-induced NF-κB transcriptional activity, IκBα degradation and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that sulforaphane can inhibit inflammation by suppressing NF-κB signaling. In an animal study, sulforaphane (300 ppm) in a mouse diet significantly abolished TNF-α-increased ex vivo monocyte adhesion and circulating adhesion molecules and chemokines in C57BL/6 mice. Histology showed that sulforaphane treatment significantly prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers’ delicate organization as shown by Verhoeff-van Gieson staining. Immunohistochemistry studies showed that sulforaphane treatment also reduced VCAM-1 and monocytes-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, sulforaphane at physiological concentrations protects against TNF-α-induced vascular endothelial inflammation, in both in vitro and in vivo models. This anti-inflammatory effect of sulforaphane may be, at least in part, associated with interfering with the NF-κB pathway. PMID:24880493

  12. Weaknesses and Pitfalls of Using Mice and Rats in Cancer Chemoprevention Studies

    PubMed Central

    Ma, Yukui; Jia, Yuping; Chen, Lichan; Ezeogu, Lewis; Yu, Baofa; Xu, Ningzhi; Liao, D. Joshua

    2015-01-01

    Many studies, using different chemical agents, have shown excellent cancer prevention efficacy in mice and rats. However, equivalent tests of cancer prevention in humans require decades of intake of the agents while the rodents' short lifespans cannot give us information of the long-term safety. Therefore, animals with a much longer lifespan should be used to bridge the lifespan gap between the rodents and humans. There are many transgenic mouse models of carcinogenesis available, in which DNA promoters are used to activate transgenes. One promoter may activate the transgene in multiple cell types while different promoters are activated at different ages of the mice. These spatial and temporal aspects of transgenes are often neglected and may be pitfalls or weaknesses in chemoprevention studies. The variation in the copy number of the transgene may widen data variation and requires use of more animals. Models of chemically-induced carcinogenesis do not have these transgene-related defects, but chemical carcinogens usually damage metabolic organs or tissues, thus affecting the metabolism of the chemopreventive agents. Moreover, many genetically edited and some chemically-induced carcinogenesis models produce tumors that exhibit cancerous histology but are not cancers because the tumor cells are still mortal, inducer-dependent, and unable to metastasize, and thus should be used with caution in chemoprevention studies. Lastly, since mice prefer an ambient temperature of 30-32°C, it should be debated whether future mouse studies should be performed at this temperature, but not at 21-23°C that cold-stresses the animals. PMID:26366220

  13. Weaknesses and Pitfalls of Using Mice and Rats in Cancer Chemoprevention Studies.

    PubMed

    Ma, Yukui; Jia, Yuping; Chen, Lichan; Ezeogu, Lewis; Yu, Baofa; Xu, Ningzhi; Liao, D Joshua

    2015-01-01

    Many studies, using different chemical agents, have shown excellent cancer prevention efficacy in mice and rats. However, equivalent tests of cancer prevention in humans require decades of intake of the agents while the rodents' short lifespans cannot give us information of the long-term safety. Therefore, animals with a much longer lifespan should be used to bridge the lifespan gap between the rodents and humans. There are many transgenic mouse models of carcinogenesis available, in which DNA promoters are used to activate transgenes. One promoter may activate the transgene in multiple cell types while different promoters are activated at different ages of the mice. These spatial and temporal aspects of transgenes are often neglected and may be pitfalls or weaknesses in chemoprevention studies. The variation in the copy number of the transgene may widen data variation and requires use of more animals. Models of chemically-induced carcinogenesis do not have these transgene-related defects, but chemical carcinogens usually damage metabolic organs or tissues, thus affecting the metabolism of the chemopreventive agents. Moreover, many genetically edited and some chemically-induced carcinogenesis models produce tumors that exhibit cancerous histology but are not cancers because the tumor cells are still mortal, inducer-dependent, and unable to metastasize, and thus should be used with caution in chemoprevention studies. Lastly, since mice prefer an ambient temperature of 30-32°C, it should be debated whether future mouse studies should be performed at this temperature, but not at 21-23°C that cold-stresses the animals. PMID:26366220

  14. New Enlightenment of Skin Cancer Chemoprevention through Phytochemicals: In Vitro and In Vivo Studies and the Underlying Mechanisms.

    PubMed

    Singh, Madhulika; Suman, Shankar; Shukla, Yogeshwer

    2014-01-01

    Skin cancer is still a major cause of morbidity and mortality worldwide. Skin overexposure to ultraviolet irradiations, chemicals, and several viruses has a capability to cause severe skin-related disorders including immunosuppression and skin cancer. These factors act in sequence at various steps of skin carcinogenesis via initiation, promotion, and/or progression. These days cancer chemoprevention is recognized as the most hopeful and novel approach to prevent, inhibit, or reverse the processes of carcinogenesis by intervention with natural products. Phytochemicals have antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification capabilities thereby considered as efficient chemopreventive agents. Considerable efforts have been done to identify the phytochemicals which may possibly act on one or several molecular targets that modulate cellular processes such as inflammation, immunity, cell cycle progression, and apoptosis. Till date several phytochemicals in the light of chemoprevention have been studied by using suitable skin carcinogenic in vitro and in vivo models and proven as beneficial for prevention of skin cancer. This revision presents a comprehensive knowledge and the main molecular mechanisms of actions of various phytochemicals in the chemoprevention of skin cancer. PMID:24757666

  15. New Enlightenment of Skin Cancer Chemoprevention through Phytochemicals: In Vitro and In Vivo Studies and the Underlying Mechanisms

    PubMed Central

    Singh, Madhulika; Suman, Shankar; Shukla, Yogeshwer

    2014-01-01

    Skin cancer is still a major cause of morbidity and mortality worldwide. Skin overexposure to ultraviolet irradiations, chemicals, and several viruses has a capability to cause severe skin-related disorders including immunosuppression and skin cancer. These factors act in sequence at various steps of skin carcinogenesis via initiation, promotion, and/or progression. These days cancer chemoprevention is recognized as the most hopeful and novel approach to prevent, inhibit, or reverse the processes of carcinogenesis by intervention with natural products. Phytochemicals have antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification capabilities thereby considered as efficient chemopreventive agents. Considerable efforts have been done to identify the phytochemicals which may possibly act on one or several molecular targets that modulate cellular processes such as inflammation, immunity, cell cycle progression, and apoptosis. Till date several phytochemicals in the light of chemoprevention have been studied by using suitable skin carcinogenic in vitro and in vivo models and proven as beneficial for prevention of skin cancer. This revision presents a comprehensive knowledge and the main molecular mechanisms of actions of various phytochemicals in the chemoprevention of skin cancer. PMID:24757666

  16. Chemoprevention of ultraviolet radiation-induced skin cancer.

    PubMed

    Ley, R D; Reeve, V E

    1997-06-01

    The use of chemical and physical sunscreening agents has increased dramatically during the last two to three decades as an effective means of preventing sunbum. The use of high sunprotection factor sunscreens has also been widely promoted for the prevention of skin cancer, including melanoma. Whereas sunscreens are undoubtedly effective in preventing sunbum, their efficacy in preventing skin cancer, especially melanoma, is currently under considerable debate. Sunscreens have been shown to prevent the induction of DNA damage that presumably results from the direct effects of ultraviolet radiation (UVR) on DNA. DNA damage has been identified as an initiator of skin cancer formation. However, both laboratory and epidemiological studies indicate that sunscreens may not block the initiation or promotion of melanoma formation. These studies suggest that the action spectrum for erythema induction is different than the action spectrum for the induction of melanoma. Indeed, recent reports on the wavelength dependency for the induction of melanoma in a fish model indicate that the efficacy of ultraviolet A wavelengths (320-400 nm) to induce melanoma is orders of magnitude higher than would be predicted from the induction of erythema in man or nonmelanoma skin tumors in mice. Other strategies for the chemoprevention of skin cancer have also been reported. Low levels and degree of unsaturation of dietary fats protect against UVR-induced skin cancer in mice humens. Compounds with antioxidant activity, including green tea extracts (polyphenols), have been reported to inhibit UVR-induced skin carcinogenesis. PMID:9255591

  17. Chemoprevention of ultraviolet radiation-induced skin cancer.

    PubMed Central

    Ley, R D; Reeve, V E

    1997-01-01

    The use of chemical and physical sunscreening agents has increased dramatically during the last two to three decades as an effective means of preventing sunbum. The use of high sunprotection factor sunscreens has also been widely promoted for the prevention of skin cancer, including melanoma. Whereas sunscreens are undoubtedly effective in preventing sunbum, their efficacy in preventing skin cancer, especially melanoma, is currently under considerable debate. Sunscreens have been shown to prevent the induction of DNA damage that presumably results from the direct effects of ultraviolet radiation (UVR) on DNA. DNA damage has been identified as an initiator of skin cancer formation. However, both laboratory and epidemiological studies indicate that sunscreens may not block the initiation or promotion of melanoma formation. These studies suggest that the action spectrum for erythema induction is different than the action spectrum for the induction of melanoma. Indeed, recent reports on the wavelength dependency for the induction of melanoma in a fish model indicate that the efficacy of ultraviolet A wavelengths (320-400 nm) to induce melanoma is orders of magnitude higher than would be predicted from the induction of erythema in man or nonmelanoma skin tumors in mice. Other strategies for the chemoprevention of skin cancer have also been reported. Low levels and degree of unsaturation of dietary fats protect against UVR-induced skin cancer in mice humens. Compounds with antioxidant activity, including green tea extracts (polyphenols), have been reported to inhibit UVR-induced skin carcinogenesis. PMID:9255591

  18. Involvement of the Electrophilic Isothiocyanate Sulforaphane in Arabidopsis Local Defense Responses1

    PubMed Central

    Andersson, Mats X.; Nilsson, Anders K.; Johansson, Oskar N.; Boztaş, Gülin; Adolfsson, Lisa E.; Pinosa, Francesco; Petit, Christel Garcia; Aronsson, Henrik; Mackey, David; Tör, Mahmut; Hamberg, Mats; Ellerström, Mats

    2015-01-01

    Plants defend themselves against microbial pathogens through a range of highly sophisticated and integrated molecular systems. Recognition of pathogen-secreted effector proteins often triggers the hypersensitive response (HR), a complex multicellular defense reaction where programmed cell death of cells surrounding the primary site of infection is a prominent feature. Even though the HR was described almost a century ago, cell-to-cell factors acting at the local level generating the full defense reaction have remained obscure. In this study, we sought to identify diffusible molecules produced during the HR that could induce cell death in naive tissue. We found that 4-methylsulfinylbutyl isothiocyanate (sulforaphane) is released by Arabidopsis (Arabidopsis thaliana) leaf tissue undergoing the HR and that this compound induces cell death as well as primes defense in naive tissue. Two different mutants impaired in the pathogen-induced accumulation of sulforaphane displayed attenuated programmed cell death upon bacterial and oomycete effector recognition as well as decreased resistance to several isolates of the plant pathogen Hyaloperonospora arabidopsidis. Treatment with sulforaphane provided protection against a virulent H. arabidopsidis isolate. Glucosinolate breakdown products are recognized as antifeeding compounds toward insects and recently also as intracellular signaling and bacteriostatic molecules in Arabidopsis. The data presented here indicate that these compounds also trigger local defense responses in Arabidopsis tissue. PMID:25371552

  19. HPLC method validation for measurement of sulforaphane level in broccoli by-products.

    PubMed

    Campas-Baypoli, O N; Sánchez-Machado, D I; Bueno-Solano, C; Ramírez-Wong, B; López-Cervantes, J

    2010-04-01

    A simple and specific analytical method was developed and tested for the determination of sulforaphane in broccoli by-products. The method includes the optimization of the conversion of glucoraphanin to sulforaphane, followed by purification of extracts using solid-phase extraction and high-performance liquid chromatography (HPLC) analysis. The response surface methodology was used to find optimum conditions for the preparation and purification procedure. Chromatographic conditions for reversed-phase HPLC with UV photodiode array detection were as follows: column, Exil ODS C(18), 25 x 0.46 cm, 5 microm; column temperature, 36 degrees C; mobile phase, a 30 : 70 (v/v) mixture of acetonitrile:water; flow rate, 0.6 mL/min. The detection wavelength was UV 202 nm. Under these conditions, excellent linearity was obtained (r(2) = 1), and the overall recovery was 97.5 and 98.1% for fresh florets and lyophilized florets, respectively. The precision results showed that the relative standard deviation of the repeatability for florets fresh and lyophilized was 3.0 and 4.0%, respectively. Sulforaphane contents were determined in the edible portion of fresh broccoli, and broccoli crop remains. PMID:19650149

  20. An effective and simple procedure to isolate abundant quantities of biologically active chemopreventive lunasin-protease inhibitor concentrate (LPIC) from soybean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lunasin is a 5-kDa soybean bioactive peptide with demonstrated anti-cancer and anti-inflammatory properties. The use of lunasin as a chemopreventive agent in large-scale animal studies and human clinical trials is hampered by the paucity of large quantities of lunasin. Recently, purification methods...

  1. Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy.

    PubMed

    Swanson, Hollie I; Njar, Vincent C O; Yu, Zhen; Castro, David J; Gonzalez, Frank J; Williams, David E; Huang, Ying; Kong, Ah-Ng T; Doloff, Joshua C; Ma, Jie; Waxman, David J; Scott, Emily E

    2010-04-01

    The primary focus of chemoprevention research is the prevention of cancer using pharmacological, biological, and nutritional interventions. Chemotherapeutic approaches that have been used successfully for both the prevention and treatment of a number of human malignancies have arisen from the identification of specific agents and appropriate molecular targets. Although drug-metabolizing enzymes have historically been targeted in attempts to block the initial, genotoxic events associated with the carcinogenic process, emerging evidence supports the idea that manipulating drug-metabolizing enzymes may also be an effective strategy to be used for treating tumor progression, invasion, and, perhaps, metastasis. This report summarizes a symposium that presents some recent progress in this area. One area of emphasis is the development of a CYP17 inhibitor for treatment of prostate cancer that may also have androgen-independent anticancer activity at higher concentrations. A second focus is the use of a mouse model to investigate the effects of aryl hydrocarbon receptor and Cyp1b1 status and chemopreventative agents on transplacental cancer. A third area of focus is the phytochemical manipulation of not only cytochrome P450 (P450) enzymes but also phase II inflammatory and antioxidant enzymes via the nuclear factor-erythroid 2-related factor 2 pathway to block tumor progression. A final highlight is the use of prodrugs activated by P450 enzymes to halt tumor growth and considerations of dosing schedule and targeted delivery of the P450 transgene to tumor tissue. In addition to highlighting recent successes in these areas, limitations and areas that should be targeted for further investigation are discussed. PMID:20233842

  2. Targeting Drug-Metabolizing Enzymes for Effective Chemoprevention and Chemotherapy

    PubMed Central

    Swanson, Hollie I.; Njar, Vincent C. O.; Yu, Zhen; Castro, David J.; Gonzalez, Frank J.; Williams, David E.; Huang, Ying; Kong, Ah-Ng T.; Doloff, Joshua C.; Ma, Jie; Waxman, David J.

    2010-01-01

    The primary focus of chemoprevention research is the prevention of cancer using pharmacological, biological, and nutritional interventions. Chemotherapeutic approaches that have been used successfully for both the prevention and treatment of a number of human malignancies have arisen from the identification of specific agents and appropriate molecular targets. Although drug-metabolizing enzymes have historically been targeted in attempts to block the initial, genotoxic events associated with the carcinogenic process, emerging evidence supports the idea that manipulating drug-metabolizing enzymes may also be an effective strategy to be used for treating tumor progression, invasion, and, perhaps, metastasis. This report summarizes a symposium that presents some recent progress in this area. One area of emphasis is the development of a CYP17 inhibitor for treatment of prostate cancer that may also have androgen-independent anticancer activity at higher concentrations. A second focus is the use of a mouse model to investigate the effects of aryl hydrocarbon receptor and Cyp1b1 status and chemopreventative agents on transplacental cancer. A third area of focus is the phytochemical manipulation of not only cytochrome P450 (P450) enzymes but also phase II inflammatory and antioxidant enzymes via the nuclear factor-erythroid 2-related factor 2 pathway to block tumor progression. A final highlight is the use of prodrugs activated by P450 enzymes to halt tumor growth and considerations of dosing schedule and targeted delivery of the P450 transgene to tumor tissue. In addition to highlighting recent successes in these areas, limitations and areas that should be targeted for further investigation are discussed. PMID:20233842

  3. Acteoside-mediates chemoprevention of experimental liver carcinogenesis through STAT-3 regulated oxidative stress and apoptosis.

    PubMed

    Peerzada, Kaiser J; Faridi, Aamir H; Sharma, Love; Bhardwaj, Subhash C; Satti, Naresh K; Shashi, Bhushan; Tasduq, Sheikh A

    2016-07-01

    In the absence of an effective therapy against Hepatocellular Carcinoma (HCC), chemoprevention remains an important strategy to circumvent morbidity and mortality. Here, we examined chemopreventive potential of Acteoside (ACT), a plant derived phenylethanoid glycoside against an environmental and dietary carcinogen, diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis. ACT treatment (0.1 and 0.3% supplemented with diet) started 2 weeks before DEN challenge and continued for 18 weeks thereafter, showed a remarkable chemopreventive activity. ACT treatment resulted in reduced HCC nodules. Histopathology showed progressive tissue damage, necrosis (5 weeks), hepatocytic injury (10 weeks), anisonucleosis with presence of prominent nucleoli, sinusidal dilations, and lymphomono nuclear inflammation (18 weeks). Biochemical analysis showed hepatocytic injury (raised ALT, p < 0.001), inflammation [IL-6, IFN-γ (p < 0.05), and TNF-α (p < 0.001)], apoptosis [elevated Caspase-3 (p < 0.001)]. ACT at 0.1 and 0.3% ameliorated DEN-induced pre-hepatocarcinogenic manifestations. Mechanistic studies of ACT chemoprevention was elucidated using Hep3B cells with an aim to develop an in vitro DEN-induced toxicity model. Hep3B was found to be a reliable and more sensitive towards DEN toxicity compared to HepG2 and HuH7 cells. ACT prevented DEN-induced cytotoxicity (p < 0.001), DNA damage, and genotoxicity (micronuclei test, DNA ladder test, Hoechst staining, cell cycle analysis). ACT significantly (p < 0.001) scavenged DEN-induced reactive oxygen species (ROS) levels and prevented mitochondrial membrane potential (MMP) loss. Immunoblotting showed ACT treatment reversed DEN-induced NF-κB, Bax, Cytochrome C, Bcl-2, and Stat-3 levels. We conclude that chemoprotective effect of ACT is mediated by STAT-3 dependent regulation of oxidative stress and apoptosis and ACT has potential to be developed as a chemopreventive agent. © 2015 Wiley Periodicals, Inc. Environ

  4. A Chemopreventive Nanodiamond Platform for Oral Cancer Treatment.

    PubMed

    Yen, Albert; Zhang, Kangyi; Daneshgaran, Giulia; Kim, Ho-Joong; Ho, Dean

    2016-02-01

    Standard oral cancer therapy generally includes a combination of surgery with chemotherapy and/or radiotherapy. This treatment paradigm has not changed in some time. In this paper, we propose a chemopreventive nanodiamond platform for the delivery of celecoxib (Celebrex) to oral cancer lesions. This innovative platform allows for sustained drug release under physiological conditions, potentially enhancing chemopreventive efficacy of celecoxib without the physical and toxicological damage associated with conventional means of drug delivery. PMID:26930755

  5. Chemoprevention of lung tumorigenesis by intranasally administered diindolylmethane in A/J mice

    PubMed Central

    Kassie, Fekadu

    2013-01-01

    The main reasons for the failure of most chemopreventive agents during clinical trials are poor in vivo bioavailability and dose-limiting side effects. One potential approach to surmount these problems in lung cancer chemoprevention trials could be direct delivery of agents into the pulmonary tissue. In this study, we assessed the efficacy of intranasally delivered bio-response diindolylmethane (BRD) against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in mice. Mice treated with NNK (two doses of 50mg/kg at an interval of a week, intraperitoneal) developed 16.3±2.9 lung tumors per mouse. Post-carcinogen administration of BRD, via intranasal instillation, for 24 weeks, twice a week, at a dose of 2mg per mouse (0.6mg pure diindolylmethane per mouse) reduced the lung tumor multiplicity to 4.6±2.2 tumors per mouse (72% reduction). Likewise, large tumors (>1mm) were almost completely abolished and multiplicities of tumors with a size of 0.5–1mm were reduced by 74%. Tumor volume was also reduced by 82%. Further studies using an in vitro model of lung tumorigenesis showed that BRD exhibited pronounced antiproliferative and apoptotic effects in premalignant and malignant bronchial cells but only minimal effects in parental immortalized cells through, at least in part, suppression of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. These results showed the potent lung tumor inhibitory activities of low doses of BRD given via intranasal instillation and, therefore, intranasal delivery of BRD holds a great promise for lung cancer chemoprevention in subjects at high risk to develop lung cancer. PMID:23239747

  6. beta-catenin-mediated signaling: a molecular target for early chemopreventive intervention.

    PubMed

    Clapper, Margie L; Coudry, Jacques; Chang, Wen-Chi L

    2004-11-01

    Dysregulation of Wnt signaling appears to be a critical event in the formation of intestinal tumors and some other cancers. Accumulating data from preclinical studies strongly suggest that targeted disruption of beta-catenin-mediated TCF signaling is a promising strategy for early chemopreventive intervention, particularly with respect to intestinal tumorigenesis. While the search for potent inhibitors is just getting underway, the ability of several synthetic and naturally occurring agents to decrease the transcriptional activity of a luciferase reporter plasmid under the control of TCF-4 regulatory elements (pTOPFLASH) has been demonstrated already. Additional enthusiasm for this approach is provided by data from several groups, which indicate that sulindac, sulindac sulfone and indomethacin can modulate the subcellular localization of beta-catenin in vivo, resulting in either decreased nuclear compartmentalization or enhanced localization of beta-catenin to the plasma membrane. Although the mechanism by which agents disrupt beta-catenin-mediated TCF signaling remains to be elucidated, possibilities include: (1) physical inhibition of the beta-catenin/TCF complex formation, (2) upregulation of the ubiquitin-mediated proteosomal degradation of beta-catenin, (3) accelerated nuclear export of beta-catenin and (4) enhanced sequestration of beta-catenin by E-cadherin. The common role of beta-catenin in both Wnt signaling and cell adhesion provides a unique opportunity to develop chemopreventive therapies that both prevent the development of cancer and delay tumor progression. PMID:15476853

  7. Chemopreventive and therapeutic potentials of thymoquinone in HepG2 cells: mechanistic perspectives.

    PubMed

    ElKhoely, Abeer; Hafez, Hafez F; Ashmawy, Abeer M; Badary, Osama; Abdelaziz, Ahmed; Mostafa, Adel; Shouman, Samia A

    2015-07-01

    Liver cancer is the fifth commonest malignancy worldwide and the third leading cause of death. Identifying novel curative and preventive therapy may improve its prognosis. In this study, thymoquinone (TQ), the most active biological ingredient of Nigella sativa Linn, was investigated for its antitumor activity. Mechanistic perspectives underlying this antitumor activity were explored by testing its effect on cell cycle, apoptosis, and angiogenesis. In addition, the chemopreventive effect of TQ was carried out by measuring its effect on phase I CYP1A1 and phase II glutathione S-transferase (GST) drug-metabolizing enzymes. The results of the present study revealed the effectiveness of TQ as an antitumor agent against different types of cancer including brain, colon, cervix and liver at both a time- and concentration-dependent manner. In HepG2 cells, it induced G2/M phase cell cycle arrest and a concentration-dependent increase in the percentage of apoptotic cells with an increase in the ratio of Bax/BCL-2. Moreover, the expression of mRNA and protein level of vascular endothelial growth factor decreased as the concentration of TQ increased. Our data showed a significant inhibition of induced phase I CYP1A1 enzyme, and elevation in the content of glutathione and activity of phase II enzyme GST, in HepG2 cells. Our results provide support for the beneficial use of TQ as a therapeutic and chemopreventive agent against liver cancer. PMID:25796541

  8. Of humans and hamsters: the hamster buccal pouch carcinogenesis model as a paradigm for oral oncogenesis and chemoprevention.

    PubMed

    Nagini, S

    2009-10-01

    Oral squamous cell carcinoma (OSCC), a common malignancy worldwide, is an important contributor to the overall international cancer burden. Squamous cell carcinomas (SCCs) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in the HBP reiterate many of the features observed in human OSCCs. The major risk factors associated with human oral cancer such as tobacco, betel quid and alcohol promote HBP carcinogenesis. SCCs induced by DMBA in the cheek pouch of Syrian hamsters are morphologically and histologically similar to human OSCC. Like human oral carcinogenesis, HBP carcinogenesis is a multistep process that involves sequential progression from hyperplasia to invasive carcinoma through varying degrees of dysplasia. In addition, HBP tumours express several biochemical and molecular markers that are also expressed in human OSCC. Multiple signaling pathways are dysfunctional in both human and hamster OSCCs. In particular, cell proliferation, apoptosis and angiogenesis are intricately interlinked in malignant transformation of the HBP mucosa by DMBA. The HBP carcinogenesis model is the best-known animal system for intervention by chemopreventive agents because of easy accessibility for examination, and follow-up of lesions. A number of synthetic and natural products have been documented to exhibit chemopreventive efficacy in the HBP model. Chemoprevention studies in the HBP model can serve as a crucial link in the potential efficacy assessment of candidate agents for oral cancer prevention and therapy. PMID:19538166

  9. Chemopreventive and antioxidant efficacy of (6)-paradol in 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis.

    PubMed

    Suresh, Kathiresan; Manoharan, Shanmugam; Vijayaanand, Mariadoss Arokia; Sugunadevi, Govindasamy

    2010-01-01

    The present study evaluated the chemopreventive potential of (6)-paradol, a pungent phenolic constituent of ginger, on 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. The mechanistic pathway for the chemopreventive potential of (6)-paradol was evaluated by measuring the status of tumor incidence, volume and burden as well as by analyzing the status of phase II detoxification agents, lipid peroxidation and antioxidants. Oral squamous cell carcinoma was induced in hamster buccal pouches by painting them with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. We observed 100% tumor formation with marked biochemical abnormalities in tumor-bearing animals compared to control animals. Oral administration of 30 mg/kg b.w. (6)-paradol to DMBA-treated hamsters on alternate days from DMBA painting for 14 weeks, significantly reduced the formation of tumors and improved the status of detoxification agents, lipid peroxidation and antioxidants. Therefore, the present study suggests that (6)-paradol has potent chemopreventive, anti-lipid peroxidative and antioxidant potentials as well as a modulating effect on phase II detoxification enzyme and reduced glutathione (GSH) in DMBA-induced hamster buccal pouch carcinogenesis. PMID:21273675

  10. Mechanism of Action of Sulforaphane as a Superoxide Radical Anion and Hydrogen Peroxide Scavenger by Double Hydrogen Transfer: A Model for Iron Superoxide Dismutase.

    PubMed

    Prasad, Ajit Kumar; Mishra, P C

    2015-06-25

    The mechanism of action of sulforaphane as a scavenger of superoxide radical anion (O2(•-)) and hydrogen peroxide (H2O2) was investigated using density functional theory (DFT) in both gas phase and aqueous media. Iron superoxide dismutase (Fe-SOD) involved in scavenging superoxide radical anion from biological media was modeled by a complex consisting of the ferric ion (Fe(3+)) attached to three histidine rings. Reactions related to scavenging of superoxide radical anion by sulforaphane were studied using DFT in the presence and absence of Fe-SOD represented by this model in both gas phase and aqueous media. The scavenging action of sulforaphane toward both superoxide radical anion and hydrogen peroxide was found to involve the unusual mechanism of double hydrogen transfer. It was found that sulforaphane alone, without Fe-SOD, cannot scavenge superoxide radical anion in gas phase or aqueous media efficiently as the corresponding reaction barriers are very high. However, in the presence of Fe-SOD represented by the above-mentioned model, the scavenging reactions become barrierless, and so sulforaphane scavenges superoxide radical anion by converting it to hydrogen peroxide efficiently. Further, sulforaphane was found to scavenge hydrogen peroxide also very efficiently by converting it into water. Thus, the mechanism of action of sulforaphane as an excellent antioxidant has been unravelled. PMID:26020652

  11. Sulforaphane controls TPA-induced MMP-9 expression through the NF-κB signaling pathway, but not AP-1, in MCF-7 breast cancer cells

    PubMed Central

    Lee, Young-Rae; Noh, Eun-Mi; Han, Ji-Hey; Kim, Jeong-Mi; Hwang, Bo-Mi; Kim, Byeong-Soo; Lee, Sung-Ho; Jung, Sung Hoo; Youn, Hyun Jo; Chung, Eun Yong; Kim, Jong-Suk

    2013-01-01

    Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)-butane] is an isothiocyanate found in some cruciferous vegetables, especially broccoli. Sulforaphane has been shown to display anti-cancer properties against various cancer cell lines. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix (ECM), plays an important role in cancer cell invasion. In this study, we investigated the effect of sulforaphane on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells. TPA-induced MMP-9 expression and cell invasion were decreased by sulforaphane treatment. TPA substantially increased NF-κB and AP-1 DNA binding activity. Pre-treatment with sulforaphane inhibited TPA-stimulated NF-κB binding activity, but not AP-1 binding activity. In addition, we found that sulforaphane suppressed NF-κB activation, by inhibiting phosphorylation of IκB in TPA-treated MCF-7 cells. In this study, we demonstrated that the inhibition of TPA-induced MMP-9 expression and cell invasion by sulforaphane was mediated by the suppression of the NF-κB pathway in MCF-7 cells. [BMB Reports 2013; 46(4): 201-206] PMID:23615261

  12. Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer

    PubMed Central

    Malik, Arshi; Afaq, Farrukh; Sarfaraz, Sami; Adhami, Vaqar M.; Syed, Deeba N.; Mukhtar, Hasan

    2005-01-01

    Prostate cancer is the most common invasive malignancy and the second leading cause of cancer-related deaths among U.S. males, with a similar trend in many Western countries. One approach to control this malignancy is its prevention through the use of agents present in diet consumed by humans. Pomegranate from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. We recently showed that pomegranate fruit extract (PFE) possesses remarkable antitumor-promoting effects in mouse skin. In this study, employing human prostate cancer cells, we evaluated the antiproliferative and proapoptotic properties of PFE. PFE (10-100 μg/ml; 48 h) treatment of highly aggressive human prostate cancer PC3 cells resulted in a dose-dependent inhibition of cell growth/cell viability and induction of apoptosis. Immunoblot analysis revealed that PFE treatment of PC3 cells resulted in (i) induction of Bax and Bak (proapoptotic); (ii) down-regulation of Bcl-XL and Bcl-2 (antiapoptotic); (iii) induction of WAF1/p21 and KIP1/p27; (iv) a decrease in cyclins D1, D2, and E; and (v) a decrease in cyclin-dependent kinase (cdk) 2, cdk4, and cdk6 expression. These data establish the involvement of the cyclin kinase inhibitor-cyclin-cdk network during the antiproliferative effects of PFE. Oral administration of PFE (0.1% and 0.2%, wt/vol) to athymic nude mice implanted with androgen-sensitive CWR22Rν1 cells resulted in a significant inhibition in tumor growth concomitant with a significant decrease in serum prostate-specific antigen levels. We suggest that pomegranate juice may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against prostate cancer in humans. PMID:16192356

  13. Cancer Prevention and Interception: A New Era for Chemopreventive Approaches.

    PubMed

    Albini, Adriana; DeCensi, Andrea; Cavalli, Franco; Costa, Alberto

    2016-09-01

    At several recent, internationally attended scientific meetings, including the American Association for Cancer Research (AACR)'s "Shaping the Future of Cancer Prevention: A Roadmap for Integrative Cancer Science and Public Health" summit in Leesburg (VA) and the AACR Annual Meeting in New Orleans, the focus on cancer prevention to reduce cancer-related deaths was extensively discussed with renewed attention and emphasis. Cancer prevention should be actively proposed even to healthy individuals, and not just to individuals with high cancer risk. We discuss evaluation of a high cancer risk versus the relatively low risk for side effects of chemopreventive agents. The concept of cancer interception, which is halting transformed cells from becoming malignant cancers, should be adopted for cancer prevention. Potential prevention/interception actions include adopting healthy life style and avoiding carcinogens, repressing inflammation and pathologic angiogenesis, controlling metabolism, correcting insulin resistance and other metabolic alterations. Current drugs with limited toxicity can be repurposed to reduce cancer incidence. Aspirin is now being recommended for the prevention of colorectal cancer and it prevents other neoplasms as well. Metformin and β-blockers could be valuable for reducing pancreatic and breast cancer onset. On the basis of the evaluation of cancer risk, we here call for personalized approaches for cancer prevention and preventive interception and we envisage a list of measures and potential guidelines for preventive and interceptive strategies to reduce cancer burden. Investment into translational research to bring these approaches into public health policies and in the clinic is urgently needed. Clin Cancer Res; 22(17); 4322-7. ©2016 AACR. PMID:27220959

  14. Trianthema portulacastrum Linn. exerts chemoprevention of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats.

    PubMed

    Bishayee, Anupam; Mandal, Animesh

    2014-10-01

    Due to limited treatment options for advanced-stage metastatic breast cancer, a high priority should be given to develop non-toxic chemopreventive drugs. The value of various natural and dietary agents to reduce the risk of developing breast cancer is well established. Trianthema portulacastrum Linn. (Aizoaceae), a dietary and medicinal plant, has been found to exert antihepatotoxic and antihepatocarcinogenic properties in rodents. This study was initiated to investigate mechanism-based chemopreventive potential of an ethanolic extract of T. portulacastrum (TPE) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary gland carcinogenesis, an experimental tumor model that closely resembles human breast cancer. Rats had access to a basal diet supplemented with TPE to yield three dietary doses of the extract, i.e., 50, 100 and 200 mg/kg body weight. Following two weeks of TPE treatment, mammary tumorigenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks after DMBA exposure), TPE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden and average tumor weight and reversed intratumor histopathological alterations. TPE dose-dependently suppressed proliferating cell nuclear antigen and cyclin D1 expression, induced apoptosis, upregulated proapoptotic protein Bax, downregulated antiapoptotic protein Bcl-2 and diminished the expression of nuclear and cytosolic β-catenin in mammary tumors. Our results clearly provide the first experimental evidence that TPE exerts chemopreventive effect in the classical DMBA model of breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through alteration of Bax/Bcl-2 ratio. Mechanistically, TPE is capable of diminishing activated canonical Wnt/β-catenin signaling to exhibit antiproliferative, proapoptotic and oncostatic effects during an early-stage breast cancer. These results may encourage further

  15. Dual Inhibition of VEGFR and EGFR is an Effective Chemopreventive Strategy in the Mouse 4-NQO Model of Oral Carcinogenesis

    PubMed Central

    Zhou, Guolin; Hasina, Rifat; Wroblewski, Kristen; Mankame, Tanmayi P.; Doçi, Colleen L.; Lingen, Mark W.

    2012-01-01

    Despite recent therapeutic advances, several factors, including field cancerization, have limited improvements in long-term survival for oral squamous cell carcinoma (OSCC). Therefore, comprehensive treatment plans must include improved chemopreventive strategies. Using the 4-Nitroquinoline 1-Oxide (4-NQO) mouse model, we tested the hypothesis that ZD6474 (Vandetanib, ZACTIMA) is an effective chemopreventive agent. CBA mice were fed 4-NQO (100 ug/ml) in their drinking water for 8 weeks and then randomized to no treatment or oral ZD6474 (25 mg/Kg/day) for 24 weeks. The percentage of animals with OSCC was significantly different between the two groups (71% in control and 12% in ZD6474 group; p≤0.001). The percentage of mice with dysplasia or OSCC was significantly different (96% in the control and 28% in the ZD6474 group; p≤0.001). Proliferation and MVD scores were significantly decreased in the ZD6474 group (p<=0.001 for both). While proliferation and MVD increased with histologic progression in control and treatment cohorts, EGFR and VEGFR-2 phosphorylation was decreased in the treatment group for each histologic diagnosis, including mice harboring tumors. OSCC from ZD6474-treated mice exhibited features of epithelial to mesenchymal transition (EMT), as demonstrated by loss E-cadherin and gain of vimentin protein expression. These data suggest that ZD6474 holds promise as an OSCC chemopreventive agent. They further suggest that acquired resistance to ZD6474 may be mediated by the expression of an EMT phenotype. Finally, the data suggests that this model is a useful pre-clinical platform to investigate the mechanisms of acquired resistance in the chemopreventive setting. PMID:20978113

  16. Sulforaphane has opposing effects on TNF-alpha stimulated and unstimulated synoviocytes

    PubMed Central

    2012-01-01

    Introduction Rheumatoid arthritis (RA) is characterized by progressive inflammation associated with rampantly proliferating synoviocytes and joint destruction due to oxidative stress. Recently, we described nuclear factor erythroid 2-related factor 2 (Nrf2) as a major requirement for limiting cartilage destruction. NF-κB and AP-1 are the main transcription factors triggering the inflammatory progression in RA. We used sulforaphane, an isothiocyanate, which is both an Nrf2 inducer and a NF-κB and AP-1 inhibitor. Methods Cultured synoviocytes were stimulated with sulforaphane (SFN) with or without TNF-α pre-treatment. NF-κB, AP-1, and Nrf2 activation was investigated via dual luciferase reporter gene assays. Matrix metalloproteinases (MMPs) were measured via zymography and luminex technique. Cytokine levels were detected using ELISA. Cell viability, apoptosis and caspase activity were studied. Cell proliferation was analysed by real-time cell analysis. Results SFN treatment decreased inflammation and proliferation dose-dependently in TNF-α-stimulated synoviocytes. SFN did not reduce MMP-3 and MMP-9 activity or expression significantly. Interestingly, we demonstrated that SFN has opposing effects on naïve and TNF-α-stimulated synoviocytes. In naïve cells, SFN activated the cytoprotective transcription factor Nrf2. In marked contrast to this, SFN induced apoptosis in TNF-α-pre-stimulated synoviocytes. Conclusions We were able to show that SFN treatment acts contrary on naïve and inflammatory synoviocytes. SFN induces the cytoprotective transcription factor Nrf2 in naïve synoviocytes, whereas it induces apoptosis in inflamed synoviocytes. These findings indicate that the use of sulforaphane might be considered as an adjunctive therapeutic strategy to combat inflammation, pannus formation, and cartilage destruction in RA. PMID:23072510

  17. In vitro cancer chemopreventive properties of polysaccharide extract from the brown alga, Sargassum latifolium.

    PubMed

    Gamal-Eldeen, Amira M; Ahmed, Eman F; Abo-Zeid, Mona A

    2009-06-01

    Polysaccharides of edible algae attracted extensive interest due to their numerous biological activities. Sargassum latifolium (Turner) C. Agardh, belongs to Sargassaceae, is a brown algae in red sea shores in Egypt. This work is a novel attempt to explore the cancer chemopreventive activity of different fractions of water-soluble polysaccharide extract derived from S. latifolium. Estimation of cancer chemopreventive activity, specifically anti-initiation, including the modulation of carcinogen metabolism and the antioxidant capacity, revealed that E1 and E4 were potent anti-initiators, where they lead not only to an inhibition in the carcinogen activator cytochrome P450 1A (IC50 2.54 and 10.30 microg/ml, respectively), but also to an induction in the carcinogen detoxification enzymes glutathione-S-transferases (144% and 225% of the control, respectively). E1 and E4 inhibited 59% and 63% of the induced-DNA damage, as measured by comet assay. Similarly both E1 and E4 possessed potential anti-promoting properties as indicated by their anti-inflammatory activity. E1 and E4 enhanced the macrophage proliferation; however they dramatically inhibited the stimulated NO (30.7% and 59.3%), TNF-alpha (38.2% and 54.9) and COX-2 (20% and 18%), respectively. E3 showed a selective cytotoxicity against lymphoblastic leukemia (1301 cells), while other fraction extracts had no cytotoxic effect against all tested cell lines. E3 led to a major disturbance in cell cycle including arrest in both S-phases in 1301 cells. This disturbance was associated with an induced-cell death due to apoptosis, but not necrosis. In conclusion, E1 and E4 are promising cancer chemopreventive fractions, since they had tumor anti- initiating activity via their protective modulation of carcinogen metabolism, and tumor anti-promoting activity via their anti-inflammatory activity, while E3 can be considered as a promising anti-cancer agent against leukemia. PMID:19306910

  18. The chemopreventive effects of Saussurea salicifolia through induction of apoptosis and phase II detoxification enzyme.

    PubMed

    Kang, Kyungsu; Lee, Hee Ju; Kim, Chul Young; Lee, Saet Byoul; Tunsag, Jigjidsuren; Batsuren, Dulamjav; Nho, Chu Won

    2007-12-01

    The ethanol extract of the aerial part of the Mongolian medicinal plant Saussurea salicifolia induced a dose-dependent cell growth inhibition in both human gastric adenocarcinoma AGS cells and mouse hepatoma Hepa 1c1c7 cells (IC(50)=30.22 and 116.96 mug/ml), respectively. The extract induced an apoptosis in AGS cells inference from the externalization of the phosphatidylserine, the increase of the sub G0/G1 content (%) and the apoptotic morphological changes including membrane blebbing, the formation of apoptotic bodies and chromatin condensation. In order to identify active substances causing the apoptosis, we further isolated major compounds present in Saussurea salicifolia and 7 compounds were isolated including a sesquiterpene lactone, cynaropicrin, 3 lignans (trachelogenin, matairesinol and arctigenin) and 3 lignan glycosides (tracheloside, matairesinoside and arctiin). In general the lignan aglycones were more cytotoxic than their lignan glycosides in both AGS cells and Hepa 1c1c7 cells. Cynaropicrin not only showed the most potent cytotoxicity among the 7 major compounds but also it induced an apoptosis and a weak G2/M arrest in AGS cells. Arctigenin had the second-best cytotoxicity among 7 major compounds, and induced an apoptosis. In order to evaluate the induction of the phase II detoxification enzyme, we measured the induction of quinone reductase activity of the extract, fractions and compounds in Hepa 1c1c7 cells. The ethyl acetate fraction and arctigenin showed the strongest cancer chemopreventive activity (chemoprevention index=9.88 and 7.57, respectively). These data suggest that the extract as well as the lignan compounds (especially arctigenin) originated from Saussurea salicifolia may be served as potential cancer chemopreventive agents for prevention or treatment of human cancers. PMID:18057725

  19. Chemoprevention of chemical-induced skin cancer by Panax ginseng root extract

    PubMed Central

    Sharma, Jyoti; Goyal, Pradeep K.

    2015-01-01

    Background Cancer has emerged as a major health problem globally as a consequence to the increased longevity of the population, changing the environment and life style. Chemoprevention is a new and promising strategy for reducing cancer burden. Recently, some natural products have been identified for their chemopreventive activity to reduce the cancer incidence. Ginseng is known for its potential to treat various ailments in human beings. The present study was designed to explore the anticancer and antioxidative potential of Panax ginseng against chemical-induced skin carcinogenesis in mammals. Methods Skin tumors were induced in Swiss albino mice by a single topical application of 7,12-dimethylbenz(a)anthracene (100 μg/100 μL acetone) and, 2 wks later, promoted by repeated applications of croton oil (thrice in a wk in 1% acetone) till the end of the experiment (i.e., 16 wk). Hydroalcoholic ginseng root extract at a dose of 25 mg/kg body weight/d was orally administered at the peri-initiation, postinitiation, and peri–post-initiation stages. Results Ginseng root extract treatment caused a significant reduction in tumor incidence, cumulative number of tumors, tumor yield, and tumor burden, as compared to the 7,12-dimethylbenz(a)anthracene–croton oil-treated control group. Further, biochemical assays revealed a significant enhancement in the levels of reduced glutathione, superoxide dismutase, catalase, vitamin C, and total proteins but a significant reduction in lipid peroxidation levels in both the liver and skin with ginseng root extract treatment, as compared to carcinogen-treated control group. Conclusion These results suggest that P. ginseng has the potential to become a pivotal chemopreventive agent that can reduce cancer in mammals. PMID:26199559

  20. Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells

    SciTech Connect

    Pei, Yanxi; Wu, Bo; Cao, Qiuhui; Wu, Lingyun; Yang, Guangdong

    2011-12-15

    Hydrogen sulfide (H{sub 2}S) is a novel gasotransmitter that regulates cell proliferation and other cellular functions. Sulforaphane (SFN) is a sulfur-containing compound that exhibits anticancer properties, and young sprouts of broccoli are particularly rich in SFN. There is consistent epidemiological evidence that the consumption of sulfur-containing vegetables, such as garlic and cruciferous vegetables, may help reduce the occurrence of prostate cancer. Here we found that a large amount of H{sub 2}S is released when SFN is added into cell culture medium or mixed with mouse liver homogenates, respectively. Both SFN and NaHS (a H{sub 2}S donor) decreased the viability of PC-3 cells (a human prostate cancer cell line) in a dose-dependent manner, and supplement of methemoglobin or oxidized glutathione (two H{sub 2}S scavengers) reversed SFN-reduced cell viability. We further found both cystathionine gamma-lyase (CSE) and cystathionine beta-synthase are expressed in PC-3 cells and mouse prostate tissues. H{sub 2}S production in prostate tissues from CSE knockout mice was only 20% of that from wild-type mice, suggesting CSE is a major H{sub 2}S-producing enzyme in prostate. CSE overexpression enhanced H{sub 2}S production and inhibited cell viability in PC-3 cells. In addition, both SFN and NaHS activated p38 mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinase (JNK). Pre-treatment of PC-3 cells with methemoglobin decreased SFN-stimulated MAPK activities. Suppression of both p38 MAPK and JNK reversed H{sub 2}S- or SFN-reduced viability of PC-3 cells. Our results demonstrated that H{sub 2}S mediates the inhibitory effect of SFN on the proliferation of PC-3 cells, which suggests that H{sub 2}S-releasing diet or drug might be beneficial in the treatment of prostate cancer. Highlights: Black-Right-Pointing-Pointer A large amount of H{sub 2}S is released from sulforaphane. Black-Right-Pointing-Pointer H{sub 2}S mediates the anti-survival effect of

  1. Chemoprevention of heterocyclic amine-induced mammary carcinogenesis in rats.

    PubMed

    Hirose, Masao; Nishikawa, Akiyoshi; Shibutani, Makoto; Imai, Toshio; Shirai, Tomoyuki

    2002-01-01

    carcinomas, and 1% green tea catechins only the mean size of mammary tumors. In a metabolic activation study of PhIP, HTHQ and caffeine clearly inhibited the formation of metabolites. In the PhIP gastric dose model, among the naturally occurring compounds examined, a plant lignan arctiin, perilla oil, which contains a large amount of n-6 alpha-linolenic acid, and CFA-S or CFA-P inhibited mammary tumor development, particularly in the postinitiation period, although a clear dose response was not observed. Treatment with 0.2% NaNO(2) in the initiation period was found to lower the volume of mammary tumors. The present results indicate that a number of compounds may be candidate chemopreventive agents against PhIP-induced mammary carcinogenesis, acting through different mechanisms and depending on the stage of carcinogenesis. PMID:11921198

  2. Chemopreventive effects of cardamom (Elettaria cardamomum L.) on chemically induced skin carcinogenesis in Swiss albino mice.

    PubMed

    Qiblawi, Samir; Al-Hazimi, Awdah; Al-Mogbel, Mohammed; Hossain, Ashfaque; Bagchi, Debasis

    2012-06-01

    The chemopreventive potential of cardamom was evaluated on 7,12-dimethylbenz[a]anthracene-initiated and croton oil-promoted mouse skin papillomagenesis. A significant reduction in the values of tumor incidence, tumor burden, and tumor yield and the cumulative number of papillomas was observed in mice treated orally with 0.5 mg of cardamom powder in suspension continuously at pre-, peri-, and post-initiational stages of papillomagenesis compared with the control group. The average weight and diameter of tumors recorded were also comparatively lower in the cardamom-treated mouse group. Treatment of cardamom suspension by oral gavage for 15 days resulted in a significant decrease in the lipid peroxidation level of the liver (P < .01). In addition, the reduced glutathione level was significantly elevated in comparison with the control group (P < .05) following cardamom suspension treatment. Taken together, these findings indicate the potential of cardamom as a chemopreventive agent against two-stage skin cancer. PMID:22404574

  3. Chemopreventive effect of a mixture of Chinese Herbs (antitumor B) on chemically induced oral carcinogenesis.

    PubMed

    Wang, Yian; Yao, Ruisheng; Gao, Song; Wen, Weidong; Du, Yinqiu; Szabo, Eva; Hu, Ming; Lubet, Ronald A; You, Ming

    2013-01-01

    In this study, we evaluated chemopreventive efficacy of Antitumor B, a Chinese herbal mixture of six plants (Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus arvensis L., Dictamnus dasycarpus, and Dioscorea bulbifera) on the development of 4-nitroquinoline-1-oxide (4NQO) induced oral squamous cell carcinomas in A/J mice. Antitumor B, delivered through diet, inhibited 4NQO-induced oral cancer development by 59.19%. The reduction of cell proliferation appears to be associated with efficacy of Antitumor B against 4NQO-induced oral cancer in A/J mice. The expression of epidermal growth factor receptor (EGFR) and phosphorylated EGFR (Tyr1173) were down-regulated by Antitumor B. Tissue distribution of Antitumor B was determined using obacunone, matrine, and maackiain as marker chemicals. We found significant amounts of obacunone, matrine, and maackiain in the blood after 1-wk treatment. The concentrations of these three compounds did not increase further at 18  wk, suggesting that plasma concentrations had reached a steady-state level at 1  wk. There was no significant body weight loss and there was no other obvious sign of toxicity in Antitumor B-treated mice. These results suggest that Antitumor B is a promising agent for human oral cancer chemoprevention. PMID:22086836

  4. Nutrient and nonnutrient components of legumes, and its chemopreventive activity: a review.

    PubMed

    Sánchez-Chino, Xariss; Jiménez-Martínez, Cristian; Dávila-Ortiz, Gloria; Álvarez-González, Isela; Madrigal-Bujaidar, Eduardo

    2015-01-01

    Legumes in combination with other products are the staple food for a large part of the world population, especially the low-income fragment, because their seeds provide valuable amounts of carbohydrates, fiber, and proteins, and have an important composition of essential amino acids, the sulphured amino acids being the limiting ones. Furthermore, legumes also have nonnutritional compounds that may decrease the absorption of nutrients or produce toxic effects; however, it has been reported that depending on the dose, these nonnutritional compounds also have different bioactivities as antioxidant, hypolipidemic, hypoglycemic, and anticarcinogenic agents, which have been proven in scientific studies. It has been observed that in countries with a high consumption of legumes, the incidence of colorectal cancer is lower. Some studies have shown that legume seeds are an alternative chemopreventive therapy against various cancers especially colon; this was verified in various animal models of induced by azoxymethane, a colon specific carcinogenic compound, in which a diet was supplemented with different concentrations of beans, lentils, chickpeas, or soybeans, mostly. These studies have proven the anticancer activity of legumes in early stages of carcinogenesis. Therefore, it is important to review the information available to elucidate the chemopreventive mechanisms of action of legume compounds. PMID:25710272

  5. Benzo(a)pyrene induced lung cancer: Role of dietary phytochemicals in chemoprevention.

    PubMed

    Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Barua, Chandana C; Sriram, Chandra Shekhar; Gogoi, Ranadeep

    2015-10-01

    Lung cancer is the major cause of overall cancer deaths, and chemoprevention is a promising strategy to control this disease. Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is one among the principal constituents of tobacco smoke that plays a key role in lung carcinogenesis. The B(a)P induced lung cancer in mice offers a relevant model to study the effect of natural products and has been widely used by many researchers and found considerable success in ameliorating the pathophysiological changes of lung cancer. Currently available synthetic drugs that constitute the pharmacological armamentarium are themselves effective in managing the condition but not without setbacks. These hunches have accelerated the requisite for natural products, which may be used as dietary supplement to prevent the progress of lung cancer. Besides, these agents also supplement the conventional treatment and offer better management of the condition with less side effects. In the context of soaring interest toward dietary phytochemicals as newer pharmacological interventions for lung cancer, in the present review, we are attempting to give a silhouette of mechanisms of B(a)P induced lung carcinogenesis and the role of dietary phytochemicals in chemoprevention. PMID:26398396

  6. Controlled-release systemic delivery - a new concept in cancer chemoprevention

    PubMed Central

    2012-01-01

    Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo. PMID:22696595

  7. Anti-Inflammatory and Anti-Superbacterial Properties of Sulforaphane from Shepherd's Purse

    PubMed Central

    Choi, Woo Jin; Kim, Seong Keun; Park, Hee Kuk; Sohn, Uy Dong

    2014-01-01

    Shepherd's purse, Capsella bursa-pastoris (L.) Medik., has been considered a health food for centuries in Asia and is known to contain the isothiocyanate compound sulforaphane. In this study, we evaluated the anti-inflammatory and antibacterial properties of a sulforaphane-containing solution (SCS) isolated from shepherd's purse. SCS had significant anti-inflammatory activity indicated by the decreased levels of nitric oxide (NO), cytokines (interleukin 1β [IL-1β], IL-6, and IL-10), and prostaglandin E2 (PGE2) in lipopolysaccharide-stimulated RAW 264.7 murine macrophages. In addition, SCS decreased the inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) levels, which confirmed the anti-inflammatory activity of SCS. Further, SCS inhibited vancomycin-resistant enterococci (VRE) and Bacillus anthracis. The minimal inhibitory concentration was 250 µg/ml for VRE and 1,000 µg/ml for B. anthracis. Taken together, these data indicate that SCS has potential anti-inflammatory and anti-superbacterial properties, and thus it can be used as a functional food or pharmaceutical. PMID:24634594

  8. Mixtures of Uncaria and Tabebuia extracts are potentially chemopreventive in CBA/Ca mice: a long-term experiment.

    PubMed

    Budán, Ferenc; Szabó, István; Varjas, Tímea; Nowrasteh, Ghodratollah; Dávid, Tamás; Gergely, Péter; Varga, Zsuzsa; Molnár, Kornélia; Kádár, Balázs; Orsós, Zsuzsa; Kiss, István; Ember, István

    2011-04-01

    A long-term experimental animal model was developed by our research group for the evaluation of potential chemopreventive effects. The inhibitory effects of agents on carcinogen (7,12-dimethylbenz[a]anthracene (DMBA) induced molecular epidemiological biomarkers, in this case the expression of key onco/suppressor genes were investigated. The expression pattern of c-myc, Ha-ras, Bcl-2, K-ras protooncogene and p53 tumour suppressor gene were studied to elucidate early carcinogenic and potential chemopreventive effects. The consumption of so-called Claw of Dragon tea (CoD™ tea) containing the bark of Uncaria guianensis, Cat's Claw (Uncaria sp. U. tomentosa) and Palmer trumpet-tree (Tabebuia sp. T. avellanedae) was able to decrease the DMBA-induced onco/suppressor gene overexpression in a short-term animal experiment. In a following study CBA/Ca mice were treated with 20 mg/kg bw DMBA intraperitoneally (i.p.) and the expression patterns of onco/suppressor genes were examined at several time intervals. According to the examined gene expression patterns in this long-term experiment the chemopreventive effect of CoD™ tea consumption could be confirmed. PMID:20799345

  9. Pharmacoproteomic analysis reveals that metapristone (RU486 metabolite) intervenes E-cadherin and vimentin to realize cancer metastasis chemoprevention

    PubMed Central

    Yu, Suhong; Yan, Cuicui; Yang, Xingtian; He, Sudang; Liu, Jian; Qin, Chongtao; Huang, Chuanzhong; Lu, Yusheng; Tian, Zhongping; Jia, Lee

    2016-01-01

    Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent by us. Despite its prominent metastasis chemopreventive effect, the underlying mechanism remains elusive. Our study, for the first time, demonstrated that metapristone had the ability to prevent breast cancer cells from migration, invasion, and interfere with their adhesion to endothelial cells. To explore the underlying mechanism of metapristone, we employed the iTRAQ technique to assess the effect of metapristone on MDA-MB-231 cells. In total, 5,145 proteins were identified, of which, 311 proteins showed significant differences in metapristone-treated cells compared to the control group (P-value < 0.05). Bioinformatic analysis showed many differentially expressed proteins (DEPs) functionally associated with post-translational modification, chaperones, translation, transcription, replication, signal transduction, etc. Importantly, many of the DEPs, such as E-cadherin, vimentin, TGF-β receptor I/II, smad2/3, β-catenin, caveolin, and dystroglycan were associated with TGF-β and Wnt signaling pathways, which were also linked to epithelial-to-mesenchymal transition (EMT) process. Further validation of the epithelial marker “E-caderin” and mesenchymal marker “vimetin” were carried out using immunoblot and immunofluorescence. These results have revealed a novel mechanism that metapristone-mediated metastasis chemoprevention is through intervening the EMT-related signaling pathways. PMID:26932781

  10. Pharmacoproteomic analysis reveals that metapristone (RU486 metabolite) intervenes E-cadherin and vimentin to realize cancer metastasis chemoprevention.

    PubMed

    Yu, Suhong; Yan, Cuicui; Yang, Xingtian; He, Sudang; Liu, Jian; Qin, Chongtao; Huang, Chuanzhong; Lu, Yusheng; Tian, Zhongping; Jia, Lee

    2016-01-01

    Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent by us. Despite its prominent metastasis chemopreventive effect, the underlying mechanism remains elusive. Our study, for the first time, demonstrated that metapristone had the ability to prevent breast cancer cells from migration, invasion, and interfere with their adhesion to endothelial cells. To explore the underlying mechanism of metapristone, we employed the iTRAQ technique to assess the effect of metapristone on MDA-MB-231 cells. In total, 5,145 proteins were identified, of which, 311 proteins showed significant differences in metapristone-treated cells compared to the control group (P-value < 0.05). Bioinformatic analysis showed many differentially expressed proteins (DEPs) functionally associated with post-translational modification, chaperones, translation, transcription, replication, signal transduction, etc. Importantly, many of the DEPs, such as E-cadherin, vimentin, TGF-β receptor I/II, smad2/3, β-catenin, caveolin, and dystroglycan were associated with TGF-β and Wnt signaling pathways, which were also linked to epithelial-to-mesenchymal transition (EMT) process. Further validation of the epithelial marker "E-caderin" and mesenchymal marker "vimetin" were carried out using immunoblot and immunofluorescence. These results have revealed a novel mechanism that metapristone-mediated metastasis chemoprevention is through intervening the EMT-related signaling pathways. PMID:26932781

  11. Sulforaphane protects against acrolein-induced oxidative stress and inflammatory responses: modulation of Nrf-2 and COX-2 expression

    PubMed Central

    Deng, Yu-Hui; Cui, Fa-Cai

    2016-01-01

    Introduction Acrolein (2-propenal) is a reactive α, β-unsaturated aldehyde which causes a health hazard to humans. The present study focused on determining the protection offered by sulforaphane against acrolein-induced damage in peripheral blood mononuclear cells (PBMC). Material and methods Acrolein-induced oxidative stress was determined through evaluating the levels of reactive oxygen species, protein carbonyl and sulfhydryl content, thiobarbituric acid reactive species, total oxidant status and antioxidant status (total antioxidant capacity, glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activity). Also, Nrf-2 expression levels were determined using western blot analysis. Acrolein-induced inflammation was determined through analyzing expression of cyclooxygenase-2 by western blot and PGE2 levels by ELISA. The protection offered by sulforaphane against acrolein-induced oxidative stress and inflammation was studied. Results Acrolein showed a significant (p < 0.001) increase in the levels of oxidative stress parameters and down-regulated Nrf-2 expression. Acrolein-induced inflammation was observed through upregulation (p < 0.001) of COX-2 and PGE2 levels. Pretreatment with sulforaphane enhanced the antioxidant status through upregulating Nrf-2 expression (p < 0.001) in PBMC. Acrolein-induced inflammation was significantly inhibited through suppression of COX-2 (p < 0.001) and PGE2 levels (p < 0.001). Conclusions The present study provides clear evidence that pre-treatment with sulforaphane completely restored the antioxidant status and prevented inflammatory responses mediated by acrolein. Thus the protection offered by sulforaphane against acrolein-induced damage in PBMC is attributed to its anti-oxidant and anti-inflammatory potential. PMID:27478470

  12. Sulforaphane effects on postinfarction cardiac remodeling in rats: modulation of redox-sensitive prosurvival and proapoptotic proteins.

    PubMed

    Fernandes, Rafael Oliveira; De Castro, Alexandre Luz; Bonetto, Jéssica Hellen Poletto; Ortiz, Vanessa Duarte; Müller, Dalvana Daneliza; Campos-Carraro, Cristina; Barbosa, Silvia; Neves, Laura Tartari; Xavier, Léder Leal; Schenkel, Paulo Cavalheiro; Singal, Pawan; Khaper, Neelam; da Rosa Araujo, Alex Sander; Belló-Klein, Adriane

    2016-08-01

    This study investigated whether sulforaphane (SFN), a compound found in cruciferous vegetables, could attenuate the progression of post-myocardial infarction (MI) cardiac remodeling. Male Wistar rats (350 g) were allocated to four groups: SHAM (n=8), SHAM+SFN (n=7), MI (n=8) and MI+SFN (n=5). On the third day after surgery, cardiac function was assessed and SFN treatment (5 mg/kg/day) was started. At the end of 25 days of treatment, cardiac function was assessed and heart was collected to measure collagen content, oxidative stress and protein kinase. MI and MI+SFN groups presented cardiac dysfunction, without signs of congestion. Sulforaphane reduced fibrosis (2.1-fold) in infarcted rats, which was associated with a slight attenuation in the cardiac remodeling process. Both infarcted groups presented increases in the oxidative markers xanthine oxidase and 4-hydroxinonenal, as well as a parallel increase in the antioxidant enzymes glutathione peroxidase and superoxide dismutase. Moreover, sulforaphane stimulated the cytoprotective heme oxygenase-1 (HO-1) (38%). Oxidative markers correlated with ERK 1/2 activation. In the MI+SFN group, up-regulation of ERK 1/2 (34%) and Akt (35%), as well as down-regulation of p38 (52%), was observed. This change in the prosurvival kinase balance in the MI+SFN group was related to a down-regulation of apoptosis pathways (Bax/Bcl-2/caspase-3). Sulforaphane was unable to modulate autophagy. Taken together, sulforaphane increased HO-1, which may generate a redox environment in the cardiac tissue favorable to activation of prosurvival and deactivation of prodeath pathways. In conclusion, this natural compound contributes to attenuation of the fibrotic process, which may contribute to mitigation against the progression of cardiac remodeling postinfarction. PMID:27288935

  13. Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation

    PubMed Central

    2014-01-01

    Background Nuclear factor-erythroid 2-related factor 2 (Nrf2) has emerged as a novel target for the prevention of colorectal cancer (CRC). Many chemopreventive compounds associated with Nrf2 activation are effective in preclinical systems and many on-going clinical trials are showing promising findings. In present study we evaluated the cytoprotective effect and chemopreventive properties of dietary digitoflavone. Method A cell based Antioxidant Response Element (ARE)-driven luciferase reporter system was applied to screen potential Nrf2 activators. Activation of Nrf2 by digitoflavone was confirmed through mRNA, protein and GSH level assay in Caco-2 cell line. The cytoprotective effect of digitoflavone was evaluated in H2O2-induced oxidative stress model and further signaling pathways analysis was used to determine the target of digitoflavone induced Nrf2 activation. An AOM-DSS induced colorectal cancer model was used to assess the chemopreventive effect of digitoflavone. Result Micromolarity (10 μM) level of digitoflavone increased Nrf2 expressing, nuclear translocation and expression of downstream phase II antioxidant enzymes. Furthermore, digitoflavone decreased H2O2-induced oxidative stress and cell death via p38 MAPK-Nrf2/ARE pathway. In vivo study, 50 mg/kg digitoflavone significantly reduced AOM-DSS induced tumor incidence, number and size. Conclusion These observations suggest that digitoflavone is a novel Nrf2 pathway activator, and protects against oxidative stress-induced cell injury. The results of the present study add further evidence of the molecular mechanisms that allow digitoflavone to exert protective effects and reaffirm its potential role as a chemopreventive agent in colorectal carcinogenesis. PMID:24602443

  14. Risk adapted chemoprevention for prostate cancer: an option?

    PubMed

    Schmitz-Dräger, Bernd J; Schöffski, Oliver; Marberger, Michael; Sahin, Sevim; Schmid, Hans-Peter

    2014-01-01

    A high disease prevalence, the presentation in older age, a frequently slowly progressing course of disease, and high costs make diagnosis and therapy of prostate cancer a special challenge for urologists. Effective prevention of the disease may help to resolve some of the problems mentioned above. Two randomised, controlled studies prove that effective chemoprevention of prostate cancer is possible using 5-α reductase inhibitors (finasteride, dutasteride) (LoE 1) both in individuals at low and those at high risk developing prostate cancer. Furthermore, there is evidence that other compounds, e.g. selective estrogen receptor modulators (SERMs), non-steroidal anti-inflammatory drugs (NSAIDs) and statins might also be effective. This review investigates potential risks and benefits of chemoprevention including a consideration of health economic aspects. The authors conclude that chemoprevention in a high risk cohort using 5-α reductase inhibitors is a viable option and may even be cost effective. In consequence, the options of chemoprevention in prostate cancer should be further explored in an open and unbiased way. PMID:24531781

  15. A novel chemopreventive mechanism for a traditional medicine: East Indian sandalwood oil induces autophagy and cell death in proliferating keratinocytes

    PubMed Central

    Dickinson, Sally E.; Olson, Erik R.; Levenson, Corey; Janda, Jaroslav; Rusche, Jadrian J.; Alberts, David S.; Bowden, G. Timothy

    2014-01-01

    One of the primary components of the East Indian sandalwood oil (EISO) is α-santalol, a molecule that has been investigated for its potential use as a chemopreventive agent in skin cancer. Although there is some evidence that α-santalol could be an effective chemopreventive agent, to date, purified EISO has not been extensively investigated even though it is widely used in cultures around the world for its health benefits as well as for its fragrance and as a cosmetic. In the current study, we show for the first time that EISO-treatment of HaCaT keratinocytes results in a blockade of cell cycle progression as well as a concentration-dependent inhibition of UV-induced AP-1 activity, two major cellular effects known to drive skin carcinogenesis. Unlike many chemopreventive agents, these effects were not mediated through an inhibition of signaling upstream of AP-1, as EISO treatment did not inhibit UV-induced Akt, or MAPK activity. Low concentrations of EISO were found to induce HaCaT cell death, although not through apoptosis as annexin V and PARP cleavage were not found to increase with EISO treatment. However, plasma membrane integrity was severely compromised in EISO-treated cells, which may have led to cleavage of LC3 and the induction of autophagy. These effects were more pronounced in cells stimulated to proliferate with bovine pituitary extract and EGF prior to receiving EISO. Together, these effects suggest that EISO may exert beneficial effects upon skin, reducing the likelihood of promotion of pre-cancerous cells to actinic keratosis (AK) and skin cancer. PMID:25004464

  16. Chemoprevention of rat mammary carcinogenesis by black tea polyphenols: modulation of xenobiotic-metabolizing enzymes, oxidative stress, cell proliferation, apoptosis, and angiogenesis.

    PubMed

    Kumaraguruparan, R; Seshagiri, P B; Hara, Y; Nagini, S

    2007-09-01

    Chemoprevention of dietary constituents has emerged as a cost-effective approach to control the incidence of breast cancer. The present study was therefore designed to evaluate the chemopreventive efficacy of black tea polyphenols (Polyphenon-B) during the preinitiation phase of 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis using xenobiotic-metabolizing enzymes, cellular redox status, cell proliferation, apoptosis, and angiogenesis as biomarkers of chemoprevention. Intragastric administration of DMBA induced adenocarcinomas that showed enhanced activities of phase I carcinogen activation and phase II detoxification enzymes with increased lipid and protein oxidation and decrease in antioxidant status. This was associated with increased cell proliferation, angiogenesis, and evasion of apoptosis as revealed by upregulation of proliferating cell nuclear antigen (PCNA), Bcl-2, and vascular endothelial growth factor (VEGF), and downregulation of Bax, caspase 3, and poly(ADP-ribose) polymerase (PARP). Dietary administration of Polyphenon-B effectively suppressed the incidence of mammary tumors as evidenced by modulation of xenobiotic-metabolizing enzymes and oxidant-antioxidant status, inhibition of cell proliferation and angiogenesis, and induction of apoptosis. The present study provides evidence that Polyphenon-B exerts multifunctional inhibitory effects on DMBA-induced mammary carcinogenesis and suggests that it can be developed as a potential chemopreventive agent. PMID:17415784

  17. Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Rexinoids with Chemopreventive Potential

    PubMed Central

    Conda-Sheridan, Martin; Park, Eun-Jung; Beck, Daniel E.; Narasimha Reddy, P. V.; Nguyen, Trung X.; Hu, Bingjie; Chen, Lian; White, Jerry J.; van Breemen, Richard B.; Pezzuto, John M.; Cushman, Mark

    2013-01-01

    Nuclear receptors, such as the retinoid X receptor (RXR), are proteins that regulate a myriad of cellular processes. Molecules that function as RXR agonists are of special interest for the prevention and control of carcinogenesis. The majority of these ligands possess an acidic moiety that is believed to be key for RXR activation. This communication presents the design, synthesis and biological evaluation of both acidic and non-acidic indenoisoquinolines as new RXR ligands. In addition, a comprehensive structure-activity relationship study is presented that identifies the important features of the indenoisoquinoline rexinoids. The ease of modification of the indenoisoquinoline core and the lack of the necessity of a carboxyl group for activity make them an attractive and unusual family of RXR agonists. This work establishes a structural foundation for the design of new and novel rexinoid cancer chemopreventive agents. PMID:23472886

  18. Chemoprevention of nonmelanoma skin cancer: experience with a polyphenol from green tea.

    PubMed

    Linden, Kenneth G; Carpenter, Philip M; McLaren, Christine E; Barr, Ronald J; Hite, Pamela; Sun, Joannie D; Li, Kou-Tung; Viner, Jaye L; Meyskens, Frank L

    2003-01-01

    Nonmelanoma skin cancer is extremely common and is increasing in incidence. It would be very useful to have forms of therapy that would prevent precancerous changes from going on to form cancer, or to reverse the precancerous changes. Epidemiologic evidence in humans, in vitro studies on human cells, and clinical experiments in animals have identified polyphenol compounds found in tea to be possibly useful in reducing the incidence of various cancers, including skin cancer. To examine the potential for a polyphenol from green tea, epigallocatechin gallate, to act as a chemopreventive agent for nonmelanoma skin cancer, a randomized, double-blind, placebo-controlled phase II clinical trial of topical epigallocatechin gallate in the prevention of nonmelanoma skin cancer was performed. PMID:12903852

  19. Breast Cancer Metabolism and Mitochondrial Activity: The Possibility of Chemoprevention with Metformin.

    PubMed

    Cazzaniga, Massimiliano; Bonanni, Bernardo

    2015-01-01

    Metabolic reprogramming refers to the ability of cancer cells to alter their metabolism in order to support the increased energy request due to continuous growth, rapid proliferation, and other characteristics typical of neoplastic cells. It has long been believed that the increase of metabolic request was independent of the mitochondrial action but recently we know that mitochondrial activity together with metabolism plays a pivotal role in the regulation of the energy needed for tumor cell growth and proliferation. For these reasons the mitochondria pathways could be a new target for therapeutic and chemopreventive intervention. Metformin in particular is actually considered a promising agent against mitochondrial activity thanks to its ability to inhibit the mitochondrial complex I. PMID:26605341

  20. [Chemoprevention of colorectal cancer for broad clinical use in the future].

    PubMed

    Mutoh, Michihiro; Ishikawa, Hideki; Wakabayashi, Keiji

    2015-05-01

    Establishment of preemptive medicine might be useful against the growing burden among colorectal cancer patients. Currently, we are trying to develop effective chemopreventive drugs not only for improving public health(i e, cancer morbidity and mortality), but also for better health economics and medical services. We have evaluated the suppressive effects of aspirin in subjects with a moderate-to-high risk of developing colorectal cancer through a randomized-controlled trial. For the first time, the efficacy of aspirin has been shown in Asian patients with adenomatous polyposis and recurrent colorectal tumors after endoscopic polypectomy. In this manuscript, we would like to show a good example of drug repositioning in cancer-preventive clinical trials and to discuss the future use of cancer-preventive agents. PMID:25981646

  1. Breast Cancer Metabolism and Mitochondrial Activity: The Possibility of Chemoprevention with Metformin

    PubMed Central

    Cazzaniga, Massimiliano; Bonanni, Bernardo

    2015-01-01

    Metabolic reprogramming refers to the ability of cancer cells to alter their metabolism in order to support the increased energy request due to continuous growth, rapid proliferation, and other characteristics typical of neoplastic cells. It has long been believed that the increase of metabolic request was independent of the mitochondrial action but recently we know that mitochondrial activity together with metabolism plays a pivotal role in the regulation of the energy needed for tumor cell growth and proliferation. For these reasons the mitochondria pathways could be a new target for therapeutic and chemopreventive intervention. Metformin in particular is actually considered a promising agent against mitochondrial activity thanks to its ability to inhibit the mitochondrial complex I. PMID:26605341

  2. Potential Chemopreventive Activity of a New Macrolide Antibiotic from a Marine-Derived Micromonospora sp

    PubMed Central

    Carlson, Skylar; Marler, Laura; Nam, Sang-Jip; Santarsiero, Bernard D.; Pezzuto, John M.; Murphy, Brian T.

    2013-01-01

    Agents capable of inducing phase II enzymes such as quinone reductase 1 (QR1) are known to have the potential of mediating cancer chemopreventive activity. As part of a program to discover novel phase II enzyme-inducing molecules, we identified a marine-derived actinomycete strain (CNJ-878) that exhibited activity with cultured Hepa 1c1c7 cells. Based on this activity, a new macrolide, juvenimicin C (1), as well as 5-O-α-l-rhamnosyltylactone (2), were isolated from the culture broth of a Micromonospora sp. Compound 1 enhanced QR1 enzyme activity and glutathione levels by two-fold with CD values of 10.1 and 27.7 μM, respectively. In addition, glutathione reductase and glutathione peroxidase activities were elevated. This is the first reported member of the macrolide class of antibiotics found to mediate these responses. PMID:23552877

  3. Chemopreventive effects of Furan-2-yl-3-pyridin-2-yl-propenone against 7,12-dimethylbenz[a]anthracene-inducible genotoxicity

    SciTech Connect

    Hwang, Yong Pil; Han, Eun Hee; Choi, Jae Ho; Kim, Hyung Gyun; Lee, Kyung Jin; Jeong, Tae Cheon; Lee, Eung Seok; Jeong, Hye Gwang

    2008-05-01

    1-Furan-2-yl-3-pyridin-2-yl-propenone (FPP-3) is an anti-inflammatory agent with a propenone moiety and chemically synthesized recently. In this study, we examined the chemopreventive effect of FPP-3 on 7,12-dimethylbenz[a]anthracene (DMBA)-induced genotoxicity in MCF-7 cells. FPP-3 reduced the formation of the DMBA-DNA adduct. DMBA-induced CYP1A1 and CYP1B1 gene expression and enzyme activity were inhibited by FPP-3. It inhibited DMBA-induced aryl hydrocarbon receptor (AhR) transactivation and DMBA-inducible nuclear localization of the AhR. Induction of detoxifying phase II genes by chemopreventive agents represents a coordinated protective response against oxidative stress and neoplastic effects of carcinogens. Transcription factor NF-E2 related factor 2 (Nrf2) regulates antioxidant response element (ARE) of phase II detoxifying and antioxidant enzymes, such as glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase (QR). FPP-3 increased the expression and enzymatic activity of GST and QR. Moreover, FPP-3 increased transcriptional activity of GST and QR. GST and QR induction and Nrf2 translocation by FPP-3 were blocked by the PKC inhibitor Goe6983, and the p38 inhibitor SB203580. These results reflected a partial role of PKC{delta} and p38 signaling in FPP-3-mediated GSTA and QR induction through nuclear translocation of Nrf2. Classically, chemopreventive agents either inhibit CYP metabolizing enzyme or induce phase II detoxifying enzymes. These results suggest that FPP-3 has a potent protective effect against DMBA-induced genotoxicity through modulating phase I and II enzymes and that it has potential as a chemopreventive agent.

  4. Data on sulforaphane treatment mediated suppression of autoreactive, inflammatory M1 macrophages

    PubMed Central

    Pal, Sanjima; Konkimalla, V. Badireenath

    2016-01-01

    Any chronic, inflammatory, autoimmune disease (e.g. arthritis) associated pathogenesis directs uncontrolled accumulation of both soluble forms of collagens in the synovial fluids and M1 macrophages around inflamed tissues. Despite of few studies demonstrating efficiency of Sulforaphane (SFN) in suppressing arthritis associated collagen restricted T cells or fibroblasts, its effects on macrophage polarity and plasticity are less understood. Recently, we reported regulation of phenotypic and functional switching by SFN in induced and spontaneously differentiating human monocytes [1]. Here, flow cytometry, western blot and ELISA derived data demonstrated that SFN inhibited in vitro inflammatory responses developed by soluble human collagens (I–IV) induced auto-reactive M1 type monocyte/macrophage model. PMID:27222853

  5. Data on sulforaphane treatment mediated suppression of autoreactive, inflammatory M1 macrophages.

    PubMed

    Pal, Sanjima; Konkimalla, V Badireenath

    2016-06-01

    Any chronic, inflammatory, autoimmune disease (e.g. arthritis) associated pathogenesis directs uncontrolled accumulation of both soluble forms of collagens in the synovial fluids and M1 macrophages around inflamed tissues. Despite of few studies demonstrating efficiency of Sulforaphane (SFN) in suppressing arthritis associated collagen restricted T cells or fibroblasts, its effects on macrophage polarity and plasticity are less understood. Recently, we reported regulation of phenotypic and functional switching by SFN in induced and spontaneously differentiating human monocytes [1]. Here, flow cytometry, western blot and ELISA derived data demonstrated that SFN inhibited in vitro inflammatory responses developed by soluble human collagens (I-IV) induced auto-reactive M1 type monocyte/macrophage model. PMID:27222853

  6. Cancer chemoprevention and cancer preventive vaccines--a call to action: leaders of diverse stakeholder groups present strategies for overcoming multiple barriers to meet an urgent need.

    PubMed

    Herberman, Ronald B; Pearce, Homer L; Lippman, Scott M; Pyenson, Bruce S; Alberts, David S

    2006-12-15

    The emerging field of cancer prevention through chemoprevention agents and cancer vaccines offers significant promise for reducing suffering and death from cancer. However, that promise may not be kept unless major barriers to progress are lowered or eliminated. Among the most significant barriers are the relatively small investment from government and industry in research and development of cancer preventive agents; a predominant emphasis of translational cancer research on therapeutic interventions for metastatic or advanced cancer; complexities of prevention trial design; a relatively uncharted Food and Drug Administration (FDA) approval process for preventive agents; insufficient public and patient understanding of the importance and potential for cancer preventive measures, with consequent unpredictable public and patient willingness to take preventive agents; an uncertain reimbursement from payors; and limitations in patent law, liability protection, and data package exclusivity that undermine the opportunity for recouping investment. Viewed individually or collectively, each of these barriers serves as a substantial deterrent to intellectual and financial investment by all sectors of the cancer community. In an effort to ultimately overcome these barriers, a Cancer Prevention Research Summit was assembled June 12-13, 2006 in Bethesda, Maryland, organized by C-Change with support from the AACR. The Summit brought together some 120 leaders from private, public, and not-for-profit entities, including cancer researchers and clinicians; federal health officials; regulatory agency representatives; pharmaceutical, biotech, and food industry leaders; patent attorneys; economists; public and private provider group executives; and advocates. Participants engaged in a detailed process to more carefully define the major barriers, identify potential solutions, and formulate initial priorities and recommendations for action. At the conclusion of this dialogue among

  7. Sulforaphane formation and bioaccessibility are more affected by steaming time than meal composition during in vitro digestion of broccoli.

    PubMed

    Sarvan, I; Kramer, E; Bouwmeester, H; Dekker, M; Verkerk, R

    2017-01-01

    Broccoli is a rich source of the glucosinolate glucoraphanin (GR). After hydrolysis of GR by the endogenous enzyme myrosinase, sulforaphane (SF) or sulforaphane nitrile (SFN) are produced, depending on environmental conditions. How the conversion of GR and bioaccessibility of released breakdown products are affected by steaming (raw, 1min, 2min and 3min steamed) and meal composition (protein or lipid addition) was studied with an in vitro digestion model (mouth, stomach, intestine, but not colonic digestion). The main formation of SF and SFN occurred during in vitro chewing. The contents of GR, SF and SFN did not change after further digestion, as the irreversible inactivated myrosinase under gastric conditions caused no further GR hydrolysis. SF concentrations were up to 10 times higher in raw and 1min steamed broccoli samples after digestion compared to longer-steamed broccoli. Protein or lipid addition had no influence on the formation and bioaccessibility of SF or SFN. PMID:27507513

  8. Nonsmall-cell lung cancer: chemoprevention studies.

    PubMed

    Karp, Daniel D; Tsao, Anne S; Kim, Edward S

    2003-10-01

    Lung cancer is the leading cause of cancer-related death in the world. Tobacco is an addictive agent producing carcinogenic effects that have been extremely difficult to prevent or detect in a curable stage. Important randomized controlled studies have been published in "healthy" smokers (primary prevention); patients with early lesions, such as mucosal dysplasia/metaplasia (secondary prevention); and those who have already had definitive treatment for their first tobacco-related malignancy (tertiary prevention). To date, the results have been generally disappointing. It is critical to remember that lung cancer is usually diagnosed decades after the patient has begun or even stopped smoking. We must intervene with more effective agents or combinations of agents and do it earlier in the process of carcinogenesis. Approximately 10% of patients with lung cancer either never smoked or only were "passive" smokers due to their environment, workplace. These "never-smokers" may actually benefit from retinoids, while current smokers have not benefited from alpha-tocopherol, retinal, N-acetylcysteine, or isotretinoin. Smokers are actually harmed by the concurrent use of beta-carotene. We now have unprecedented knowledge regarding the control of cellular growth and senescence. New diagnostic tools also allow detection of smaller lesions. We must use all our knowledge of the cancer biology, new risk models, more refined intermediate markers, and modern detection tools to focus more clearly on the pathology of lung cancer and design research to ask more probing and relevant questions so we can begin to put an end to the worldwide scourge of this terrible killer. PMID:14710383

  9. Role of saffron and its constituents on cancer chemoprevention

    PubMed Central

    Zhang, Zhiyu; Wang, Chong-Zhi; Wen, Xiao-Dong; Shoyama, Yukihiro; Yuan, Chun-Su

    2014-01-01

    Context Cancer dramatically impacts human life expectancy and quality of life. Natural substances from vegetables, herbs and spices could be beneficial in the prevention or treatment of a variety of cancers. Crocus sativus, which has been used as a folk medicine for treating diseases for ages, showed obvious cancer chemoprevention potential. Objective This article focuses on the effects of Crocus sativus and its main ingredients, such as crocin, on cancer therapeutics. Methods We reviewed research data from saffron, a spice derived from the flower of Crocus sativus, and its constituents using the major databases, viz., Web of Science, SciFinder, and PubMed. Results and conclusion Saffron possesses free radical-scavenging properties and antitumor activities. Significant cancer chemopreventive effects have been shown in both in vitro and in vivo models. Based on current data, saffron and its ingredients could be considered as a promising candidate for clinical anticancer trials. PMID:23570520

  10. The Mechanism in Gastric Cancer Chemoprevention by Allicin.

    PubMed

    Luo, Runlan; Fang, Dengyang; Hang, Hongdong; Tang, Zeyao

    2016-01-01

    Gastric cancer remains high prevalence and fatality rates in China even though its morbidity has been decreased drastically. Allicin, which is from an assistance food-garlic (Allium Sativum L), was found to be effective in gastric cancer treatment. It is a defensive substance with a board biological properties: inhibition of bacteria, fungus, virus, controlled hypertension, diabetes, and chemoprevention of several cancers, etc. Experiments have shown that allicin can be chemopreventive to gastric cancer by inhibiting the growth of cancer cells, arresting cell cycle at G2/M phase, endoplasmic reticulum (ER) stress, and mitochondria-mediated apoptosis, which includes the caspase-dependent/-independent pathways and death receptor pathway. Those mechanisms probably involve in modulating enzymatic activity, restraining DNA formation, scavenging free radicals, and affecting cell proliferation and even tumor growth. Therefore, this review is focus on the mechanism of allicin in gastric cancer. PMID:26555611

  11. Isothiocyanates: a class of bioactive metabolites with chemopreventive potential.

    PubMed

    Kumar, Gaurav; Tuli, Hardeep Singh; Mittal, Sonam; Shandilya, Jitendra Kumar; Tiwari, Anil; Sandhu, Sardul Singh

    2015-06-01

    In recent years, growing interest has been focused on the field of chemoprevention using natural therapies. The reason to turn toward "natural" remedies is associated with diverse beneficial pharmacological properties of natural compounds. Isothiocyanates (ITCs), the major pharmacological active constituents of cruciferous vegetables, are derived from the enzymatic hydrolysis of glucosinolates (GSLs). ITCs govern many intracellular targets including cytochrome P 450 (CYP) enzymes, proteins involved in antioxidant response, tumorigenesis, apoptosis, cell cycle, and metastasis. Investigation of the mechanisms of anti-cancer drugs has given important information regarding the use of natural chemopreventive compounds. This extensive review covers various molecular aspects of the interactions of ITCs with their recognized cellular targets involved in cancer treatment in order to enhance anti-tumor outcome with decreased toxicity to patients. PMID:25835976

  12. Shrimp Lipids: A Source of Cancer Chemopreventive Compounds

    PubMed Central

    López-Saiz, Carmen-María; Suárez-Jiménez, Guadalupe-Miroslava; Plascencia-Jatomea, Maribel; Burgos-Hernández, Armando

    2013-01-01

    Shrimp is one of the most popular seafoods worldwide, and its lipids have been studied for biological activity in both, muscle and exoskeleton. Free fatty acids, triglycerides, carotenoids, and other lipids integrate this fraction, and some of these compounds have been reported with cancer chemopreventive activities. Carotenoids and polyunsaturated fatty acids have been extensively studied for chemopreventive properties, in both in vivo and in vitro studies. Their mechanisms of action depend on the lipid chemical structure and include antioxidant, anti-proliferative, anti-mutagenic, and anti-inflammatory activities, among others. The purpose of this review is to lay groundwork for future research about the properties of the lipid fraction of shrimp. PMID:24135910

  13. Highly Loaded, Sustained-Release Microparticles of Curcumin for Chemoprevention

    PubMed Central

    SHAHANI, KOMAL; PANYAM, JAYANTH

    2014-01-01

    Curcumin, a dietary polyphenol, has preventive and therapeutic potential against several diseases. Because of the chronic nature of many of these diseases, sustained-release dosage forms of curcumin could be of significant clinical value. However, extreme lipophilicity and instability of curcumin are significant challenges in its formulation development. The objectives of this study were to fabricate an injectable microparticle formulation that can sustain curcumin release over a 1-month period and to determine its chemopreventive activity in a mouse model. Microparticles were fabricated using poly(D, L-lactide-co-glycolide) polymer. Conventional emulsion solvent evaporation method of preparing microparticles resulted in crystallization of curcumin outside of microparticles and poor entrapment (~1%, w/w loading). Rapid solvent removal using vacuum dramatically increased drug entrapment (~38%, w/w loading; 76% encapsulation efficiency). Microparticles sustained curcumin release over 4 weeks in vitro, and drug release rate could be modulated by varying the polymer molecular weight and/or composition. A single subcutaneous dose of microparticles sustained curcumin liver concentration for nearly a month in mice. Hepatic glutathione-s-transferase and cyclooxygenase-2 activities, biomarkers for chemoprevention, were altered following treatment with curcumin microparticles. The results of these studies suggest that sustained-release microparticles of curcumin could be a novel and effective approach for cancer chemoprevention. PMID:21547911

  14. Chemopreventive opportunities to control basal cell carcinoma: Current perspectives.

    PubMed

    Tilley, Cynthia; Deep, Gagan; Agarwal, Rajesh

    2015-09-01

    Basal cell carcinoma (BCC) is a major health problem with approximately 2.8 million new cases diagnosed each year in the United States. BCC incidences have continued to rise due to lack of effective chemopreventive options. One of the key molecular characteristics of BCC is the sustained activation of hedgehog signaling through inactivating mutations in the tumor suppressor gene patch (Ptch) or activating mutations in Smoothened. In the past, several studies have addressed targeting the activated hedgehog pathway for the treatment and prevention of BCC, although with toxic effects. Other studies have attempted BCC chemoprevention through targeting the promotional phase of the disease especially the inflammatory component. The compounds that have been utilized in pre-clinical and/or clinical studies include green and black tea, difluoromethylornithine, thymidine dinucleotide, retinoids, non-steroidal anti-inflammatory drugs, vitamin D3, and silibinin. In this review, we have discussed genetic and epigenetic modifications that occur during BCC development as well as the current state of BCC pre-clinical and clinical chemoprevention studies. PMID:26053157

  15. Nrf2 as a Chemopreventive Target in Colorectal Cancer

    PubMed Central

    Saw, Constance Lay Lay; Kong, Tony Ah-Ng

    2012-01-01

    Introduction Numerous epidemiological studies have linked consumption of cruciferous vegetables to a reduced risk of colorectal cancer (CRC) in individuals. It is currently well accepted that chronic inflammation is a contributing factor in 15-20% malignancies including CRC. Many chemopreventive compounds are effective in preclinical systems and many on-going clinical trials are showing promising findings. Many of these compounds could activate the antioxidant responsive element (ARE), a critical regulatory element for phase II protective/detoxification and anti-oxidative stress enzymes mediated by nuclear factor-erythroid 2-related factor 2 (Nrf2). Recently, Nrf2 has emerged as a novel target for the prevention of CRC. Areas covered A full literature search was performed using PubMed with the key words ‘ARE, Nrf2, colon, colorectal cancer, chemoprevention, cancer prevention’, and all relevant publications are included. Expert opinion The use of Nrf2 knockout mice has provided key insights into the toxicological and chemopreventive importance of this pathway. Mounting evidence has revealed that Nrf2 is a critical regulator of inflammation as well, a major driving force for CRC progression and formation. Targeting the Nrf2/ARE pathway may present a novel therapeutic approach for the treatment of not only colorectal inflammatory diseases but the frequent subsequent development of CRC as well. PMID:21261563

  16. Molecular aspects and chemoprevention of dimethylaminoazobenzene-induced hepatocarcinogenesis: A review.

    PubMed

    Thomas, Nisha Susan; George, Kiran; Namasivayam, Nalini

    2016-01-01

    The lipophilic azo dye dimethylaminoazobenzene (DAB) is a potent hepatocarcinogen accounted as a group-2B carcinogen causing risk to humans. DAB is commonly used as a coloring agent in food, pharmaceuticals, beverages, soap and polishes. The exploration of DAB-induced hepatocarcinogenesis in animal models helped to an extent to perceive the histological, biochemical and molecular mechanisms of DAB carcinogenesis and also the severity of DAB exposure to humans. In experimental animal models, it is well-proved that the procarcinogen DAB is predominantly metabolized by cytochrome P450 enzymes giving rise to the formation of toxic electrophiles and reactive oxygen species (ROS), which further forms DNA adducts leading to the development of hepatic tumors. Recently, research evidence suggests that dietary phytochemicals and plant polyphenols are promising agents to control the incidence of DAB-induced hepatocarcinogenesis by preventing the generation of toxic electrophiles and ROS thereby inhibiting the formation of DNA adducts. This review highlights the role of specific dietary factors, biotransformation of DAB, phenotypic and genotypic alterations, and significance of certain chemopreventive agents against DAB-induced hepatocarcinogenesis. PMID:26272071

  17. Chemopreventive Effect of Cardamom (Elettaria cardamomum L.) Against Benzo(α)Pyrene-Induced Forestomach Papillomagenesis in Swiss Albino Mice.

    PubMed

    Qiblawi, Samir; Dhanarasu, Sasikumar; Faris, Mo'ez Al-Islam

    2015-01-01

    Prevention of cancer through dietary intervention has recently gained significant recognition. Cardamom (Elettaria cardamomum), a dietary phytoproduct, is a popular spice that is regularly used as a flavoring agent in various cuisines, and is much valued for its medicinal properties. In the present study, the cancer chemopreventive potential of cardamom was investigated against benzo(α)pyrene [B(α)P]-induced forestomach papillomagenesis in mice. Results showed that treatment with cardamom [(B(α)P + cardamom] reduced tumor incidence and multiplicity significantly (P<0.001) by 41.67% and 74.55%, respectively, compared to that of the B(α)P control group. Biochemical assays revealed a significant enhancement in the hepatic activities of glutathione-S-transferases (P<0.01), superoxide dismutase (P<0.01), glutathione peroxidase (P<0.001), and catalase (P<0.001) in mice treated with cardamom compared with the control. Furthermore, the nonenzymatic antioxidant glutathione was significantly (P<0.001) increased in the cardamom-treated group, whereas the lipid peroxidation level along with lactate dehydrogenase activity exhibited a significant (P<0.01) reduction with cardamom treatment compared to the control. These results suggest that cardamom has the potential to become a pivotal chemopreventive agent against forestomach cancer. PMID:26081028

  18. Chemopreventive flavonoids from Millettia pulchra Kurz var-laxior (Dunn) Z.Wei (Yulangsan) function as Michael reaction acceptors.

    PubMed

    Wang, Wenli; Wang, Jian; Li, Ning; Zhang, Xiangrong; Zhao, Weihong; Li, Jiayuan; Si, Yingying

    2015-03-01

    Natural NQO1 [NAD(P)H quinine oxidoreductase 1] inducing agents play a critical role in cancer chemoprevention. The expression of NQO1 is regulated by Michael reaction acceptors (MRAs) via the Keap1/Nrf2/ARE signaling pathway. The aims of this study were to identify and characterize novel effective chemopreventive agents from naturally occurring products. Using bioassay-guided isolation approaches 16 bioactive MRAs from Millettia pulchra Kurz var-laxior (Dunn) Z.Wei, also called Yulangsan as a famous Zhuang medicine. The structures were elucidated as chalcone (1-7), flavonone (8-14), flavanone (15) and isoflavan (16). Their electrophilic abilities and NQO1 inducing activity were assessed using GSH (glutathione) rapid screening, and in vitro cell-based (Hepa 1c1c7 cells) assay, respectively. Compounds 3, 4, 6, 13, and 14 showed to have NQO1 inducing activity. Among them, compounds 4 and 14 interact with NQO1 at Gly 149, Gly 150, Phe 106, Typ 105 and His 161, revealed by molecular docking studies. PMID:25630222

  19. Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice.

    PubMed

    Cai, Hong; Scott, Edwina; Kholghi, Abeer; Andreadi, Catherine; Rufini, Alessandro; Karmokar, Ankur; Britton, Robert G; Horner-Glister, Emma; Greaves, Peter; Jawad, Dhafer; James, Mark; Howells, Lynne; Ognibene, Ted; Malfatti, Michael; Goldring, Christopher; Kitteringham, Neil; Walsh, Joanne; Viskaduraki, Maria; West, Kevin; Miller, Andrew; Hemingway, David; Steward, William P; Gescher, Andreas J; Brown, Karen

    2015-07-29

    Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times higher. The dose-response relationship for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels. In Apc(Min) mice (a model of colorectal carcinogenesis) that received a high-fat diet, the low resveratrol dose suppressed intestinal adenoma development more potently than did the higher dose. Efficacy correlated with activation of adenosine monophosphate-activated protein kinase (AMPK) and increased expression of the senescence marker p21. Nonlinear dose responses were observed for AMPK and mechanistic target of rapamycin (mTOR) signaling in mouse adenoma cells, culminating in autophagy and senescence. In human colorectal tissues exposed to low dietary concentrations of resveratrol ex vivo, we measured enhanced AMPK phosphorylation and autophagy. The expression of the cytoprotective NAD(P)H dehydrogenase, quinone 1 (NQO1) enzyme was also increased in tissues from cancer patients participating in our [(14)C]-resveratrol trial. These findings warrant a revision of developmental strategies for diet-derived agents designed to achieve cancer chemoprevention. PMID:26223300

  20. Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin.

    PubMed

    Dickinson, Sally E; Janda, Jaroslav; Criswell, Jane; Blohm-Mangone, Karen; Olson, Erik R; Liu, Zhonglin; Barber, Christy; Petricoin, Emanuel F; Calvert, Valerie S; Einspahr, Janine; Dickinson, Jesse E; Stratton, Steven P; Curiel-Lewandrowski, Clara; Saboda, Kathylynn; Hu, Chengcheng; Bode, Ann M; Dong, Zigang; Alberts, David S; Timothy Bowden, G

    2016-03-01

    The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here, we explored the use of topical rapamycin as a chemopreventive agent in the context of solar-simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared with controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared with vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC. PMID:26801880

  1. Inhibition of akt enhances the chemopreventive effects of topical rapamycin in mouse skin

    USGS Publications Warehouse

    Dickinson, Sally E; Janda, Jaroslav; Criswell, Jane; Blohm-Mangone, Karen; Olson, Erik R.; Liu, Zhonglin; Barber, Christie; Rusche, Jadrian J.; Petricoin, Emmanuel, III; Calvert, Valerie; Einspahr, Janine G.; Dickinson, Jesse; Stratton, Steven P.; Curiel-Lewandrowski, Clara; Saboda, Kathylynn; Hu, Chengcheng; Bode, Ann M.; Dong, Zigang; Alberts, David S.; Bowden, G. Timothy

    2016-01-01

    The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced non-melanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin, (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared to those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here we explored the use of topical rapamycin as a chemopreventive agent in the context of solar simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared to controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared to vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC.

  2. Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention

    PubMed Central

    Nagini, Siddavaram

    2012-01-01

    Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitation and hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future. PMID:22844547

  3. Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention.

    PubMed

    Nagini, Siddavaram

    2012-07-15

    Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitation and hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future. PMID:22844547

  4. Chemopreventive effect of silymarin on liver pathology in HBV X protein transgenic mice.

    PubMed

    Wu, Yi-Fang; Fu, Shu-Ling; Kao, Cheng-Heng; Yang, Chu-Wen; Lin, Chao-Hsiung; Hsu, Ming-Ta; Tsai, Ting-Fen

    2008-03-15

    There are currently limited therapeutic regimens available for effective treatment of hepatocellular carcinoma (HCC). Silymarin is a naturally derived polyphenolic antioxidant with hepatoprotective properties and is very widely used in clinical application; however, effect of silymarin on spontaneous HCC has not been studied. Silymarin was evaluated for its efficacy against spontaneous carcinogenesis using the HBV X protein (HBx) transgenic model. Silymarin was p.o. given to the HBx transgenic mice from 4 to 6 weeks of age. Our data indicated that silymarin has therapeutic effects on the early stages of liver damage, reversing fatty changes and recovering liver histopathology in a dose-dependent manner. To study the chemopreventive effects on the later stages of carcinogenesis, the mice at 13 months were split into a precancerous group and a group with significant liver carcinogenesis. After silymarin was given to the precancerous mice from 13 to 16 months of age, in contrast to an 80% incidence of HCC development in the untreated transgenic mice, no HCC was detected in any of these mice. Nonetheless, small hyperplastic nodules were detected in 86% of these precancerous mice. In the second group with notable HCC, silymarin was unable to block cancer progression. Although silymarin did not affect HBx expression, intracellular reactive oxygen species levels were decreased, cell proliferation was stimulated, and hepatocyte ultrastructure was found to significantly recover. In conclusion, silymarin exerts beneficial effects on the early stages of liver pathogenesis, preventing and delaying liver carcinogenesis. This drug should be considered as a potential chemopreventive agent for HBV-related hepatocarcinogenesis. PMID:18339886

  5. Chemopreventive effect of sinapic acid on 1,2-dimethylhydrazine-induced experimental rat colon carcinogenesis.

    PubMed

    Balaji, C; Muthukumaran, J; Nalini, N

    2014-12-01

    Sinapic acid (SA) is a naturally occurring phenolic acid found in various herbal plants which is attributed with numerous pharmacological properties. This study was aimed to investigate the chemopreventive effect of SA on 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Rats were treated with DMH injections (20 mg kg(-1) bodyweight (b.w.) subcutaneously once a week for the first 4 consecutive weeks and SA (20, 40 and 80 mg kg(-1) b.w.) post orally for 16 weeks. At the end of the 16-week experimental period, all the rats were killed, and the tissues were evaluated biochemically. Our results reveal that DMH alone treatment decreased the levels/activities of lipid peroxidation by-products such as thiobarbituric acid reactive substances, conjugated dienes and antioxidants such as superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and reduced glutathione in the intestine and colonic tissues which were reversed on supplementation with SA. Moreover, the activities of drug-metabolizing enzymes of phase I (cytochrome P450 and P4502E1) were enhanced and those of phase II (glutathione-S-transferase, DT-diaphorase and uridine diphosphate glucuronosyl transferase) were diminished in the liver and colonic mucosa of DMH alone-treated rats and were reversed on supplementation with SA. All the above changes were supported by the histopathological observations of the rat liver and colon. These findings suggest that SA at the dose of 40 mg kg(-1) b.w. was the most effective dose against DMH-induced colon carcinogenesis, and thus, SA could be used as a potential chemopreventive agent. PMID:24532707

  6. Chemopreventive effect of 18β-glycyrrhetinic acid via modulation of inflammatory markers and induction of apoptosis in human hepatoma cell line (HepG2).

    PubMed

    Hasan, Syed Kazim; Siddiqi, Aisha; Nafees, Sana; Ali, Nemat; Rashid, Summya; Ali, Rashid; Shahid, Ayaz; Sultana, Sarwat

    2016-05-01

    Hepatocellular carcinoma is one of the most common lethal diseases worldwide and there is no effective treatment till date. Natural products derived from the plants play an important role in chemoprevention and act as therapeutic antitumor agents. Licorice is a plant that has been used in food and medicine for the treatment of various diseases. 18β-Glycyrrhetinic acid (18β-GA), a pentacyclic triterpenoid obtained from the roots of licorice plant, is reported to possess various pharmacological properties such as antitumor and antiinflammatory activities. The present study was designed to elucidate the chemopreventive effect of 18β-GA through antiinflammation, antiproliferation, and induction of apoptosis in human hepatoma cell line HepG2. 18β-GA significantly inhibits the proliferation of HepG2 cell without affecting the normal liver cell line (Chang's). In the present study, 18β-GA increased the formation of reactive oxygen species, nitric oxide production, and loss of mitochondrial membrane potential, suggesting the involvement of 18β-GA in apoptosis which was also confirmed by assessing the markers involved in apoptosis like caspase-3, caspase-9, Bax:Bcl-2 ratio, and cleaved PARP. 18β-GA also downregulated the expression of inflammatory proteins such as NF-κB, iNOS, and COX-2. Keeping these data into consideration, our results suggest that 18β-GA may be used as a chemopreventive agent in liver cancer. PMID:27116616

  7. Potential of Vinca rosea extracts in modulating trace element profile: a chemopreventive approach.

    PubMed

    Mohanta, Bidhan; Sudarshan, Mathummal; Boruah, Mandira; Chakraborty, Anindita

    2007-01-01

    Diethylnitrosamine (DEN) was used as cancer-inducing agent in the experimental animals. Vinca rosea extract was supplemented with the drinking water as a chemopreventive agent. After 4 wk of treatment, animals were sacrificed and livers were excised. Nuclei and mitochondria were separated by differential centrifugation. The proton-induced X-ray emission technique has been used as the analytical method. Elemental analysis were performed for whole liver, nuclei, and mitochondria.V. rosea plant parts were also analyzed for elemental contents. Treatment with DEN caused an increase of Ni, Zn, and Cr levels in the whole liver and nuclei. There is an increase in Fe concentration in the liver, although the level decreased in mitochondria. The concentrations of Br and Ca were unchanged in the liver as a whole, but there were substantial increases of Br in nuclei and mitochondria, whereas Ca levels depleted drastically in these two organelles. Vinca extracts were effective in reverting the changes in the elemental concentration in the hepatic tissue as a whole, but were not that effective at subcellular levels. PMID:17873399

  8. VEGFR-2 Targeted Chemoprevention of Murine Lung Tumors

    PubMed Central

    Karoor, Vijaya; Le, Mysan; Merrick, Daniel; Dempsey, Edward C.; Miller, York E.

    2010-01-01

    No clinically effective chemoprevention for lung cancer has been found. Angiogenesis is an early feature of both adenocarcinoma and squamous cell lung cancer. We investigated the effects of VEGFR-2 inhibition on lung carcinogenesis in a murine model of adenocarcinoma. The VEGFR-2 tyrosine kinase inhibitor, vandetanib, was administered to FVB/N mice in chow for 7 days at varying doses in order to demonstrate pharmacologic activity by inhibition of VEGF mediated VEFGR-2 and ERK phosphorylation. Plasma levels corroborated adequate dosage. For chemoprevention experiments, mice were injected i.p. with 1 mg/gm urethane, a carcinogen found in tobacco smoke. Chow containing vandetanib, 75 mg/kg/d, or control chow was given to mice, starting 7 days after urethane administration. Sixteen weeks after urethane injection, mice were sacrificed, tumors enumerated and measured. Vandetanib resulted in reductions in tumor multiplicity (6.5 +/− 0.86 vs 1.0 +/− 0.30, p = 0.001) and average tumor volume (0.85 +/− 0.10 mm3 vs. 0.15 +/− 0.09 mm3, p = 0.001), but not incidence (71% vs. 100%, p = ns), compared to control. As vandetanib has other activities besides VEGFR-2 tyrosine kinase inhibition, we administered the anti-VEGFR-2 monoclonal antibody, DC101, for weeks 11–15 of a urethane carcinogenesis protocol with an arrest in tumor volume increase, but no change in multiplicity or incidence. Further investigation of the chemopreventive effect of vandetanib and other VEGF signaling inhibitors is needed. PMID:20647338

  9. 77 FR 28614 - Prospective Grant of Exclusive License: Development of Chemopreventive Treatments for Head and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-15

    ... Chemopreventive Treatments for Head and Neck Squamous Cell Carcinoma AGENCY: National Institutes of Health, Public... thereof entitled ``Chemopreventive of Head and Neck Squamous Cell Carcinoma'' (HHS Ref. No. E-302-2008/0... use of the Licensed Patent Rights for the prevention and treatment of head and neck cancers....

  10. Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate.

    PubMed

    Thaler, Roman; Maurizi, Antonio; Roschger, Paul; Sturmlechner, Ines; Khani, Farzaneh; Spitzer, Silvia; Rumpler, Monika; Zwerina, Jochen; Karlic, Heidrun; Dudakovic, Amel; Klaushofer, Klaus; Teti, Anna; Rucci, Nadia; Varga, Franz; van Wijnen, Andre J

    2016-03-25

    Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation viaTet1andTet2and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2,Col1a1,Bglap2,Sp7,Atf4, andAlpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-κB ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of theTet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (∼20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorptionin vivo Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis. PMID:26757819

  11. Urease from Helicobacter pylori is inactivated by sulforaphane and other isothiocyanates.

    PubMed

    Fahey, Jed W; Stephenson, Katherine K; Wade, Kristina L; Talalay, Paul

    2013-05-24

    Infections by Helicobacter pylori are very common, causing gastroduodenal inflammation including peptic ulcers, and increasing the risk of gastric neoplasia. The isothiocyanate (ITC) sulforaphane [SF; 1-isothiocyanato-4-(methylsulfinyl)butane] derived from edible crucifers such as broccoli is potently bactericidal against Helicobacter, including antibiotic-resistant strains, suggesting a possible dietary therapy. Gastric H. pylori infections express high urease activity which generates ammonia, neutralizes gastric acidity, and promotes inflammation. The finding that SF inhibits (inactivates) urease (jack bean and Helicobacter) raised the issue of whether these properties might be functionally related. The rates of inactivation of urease activity depend on enzyme and SF concentrations and show first order kinetics. Treatment with SF results in time-dependent increases in the ultraviolet absorption of partially purified Helicobacter urease in the 260-320 nm region. This provides direct spectroscopic evidence for the formation of dithiocarbamates between the ITC group of SF and cysteine thiols of urease. The potencies of inactivation of Helicobacter urease by isothiocyanates structurally related to SF were surprisingly variable. Natural isothiocyanates closely related to SF, previously shown to be bactericidal (berteroin, hirsutin, phenethyl isothiocyanate, alyssin, and erucin), did not inactivate urease activity. Furthermore, SF is bactericidal against both urease positive and negative H. pylori strains. In contrast, some isothiocyanates such as benzoyl-ITC, are very potent urease inactivators, but are not bactericidal. The bactericidal effects of SF and other ITC against Helicobacter are therefore not obligatorily linked to urease inactivation, but may reduce the inflammatory component of Helicobacter infections. PMID:23583386

  12. Sulforaphane protects Microcystin-LR-induced toxicity through activation of the Nrf2-mediated defensive response

    SciTech Connect

    Gan Nanqin; Mi Lixin; Sun Xiaoyun; Dai Guofei; Chung Funglung; Song Lirong

    2010-09-01

    Microcystins (MCs), a cyclic heptapeptide hepatotoxins, are mainly produced by the bloom-forming cyanobacerium Microcystis, which has become an environmental hazard worldwide. Long term consumption of MC-contaminated water may induce liver damage, liver cancer, and even human death. Therefore, in addition to removal of MCs in drinking water, novel strategies that prevent health damages are urgently needed. Sulforaphane (SFN), a natural-occurring isothiocyanate from cruciferous vegetables, has been reported to reduce and eliminate toxicities from xenobiotics and carcinogens. The purpose of the present study was to provide mechanistic insights into the SFN-induced antioxidative defense system against MC-LR-induced cytotoxicity. We performed cell viability assays, including MTS assay, colony formation assay and apoptotic cell sorting, to study MC-LR-induced cellular damage and the protective effects by SFN. The results showed that SFN protected MC-LR-induced damages at a nontoxic and physiological relevant dose in HepG2, BRL-3A and NIH 3 T3 cells. The protection was Nrf2-mediated as evident by transactivation of Nrf2 and activation of its downstream genes, including NQO1 and HO-1, and elevated intracellular GSH level. Results of our studies indicate that pretreatment of cells with 10 {mu}M SFN for 12 h significantly protected cells from MC-LR-induced damage. SFN-induced protective response was mediated through Nrf2 pathway.

  13. Sulforaphane reduces the alterations induced by quinolinic acid: modulation of glutathione levels.

    PubMed

    Santana-Martínez, R A; Galván-Arzáte, S; Hernández-Pando, R; Chánez-Cárdenas, M E; Avila-Chávez, E; López-Acosta, G; Pedraza-Chaverrí, J; Santamaría, A; Maldonado, P D

    2014-07-11

    Glutamate-induced excitotoxicity involves a state of acute oxidative stress, which is a crucial event during neuronal degeneration and is part of the physiopathology of neurodegenerative diseases. In this work, we evaluated the ability of sulforaphane (SULF), a natural dietary isothiocyanate, to induce the activation of transcription factor Nrf2 (a master regulator of redox state in the cell) in a model of striatal degeneration in rats infused with quinolinic acid (QUIN). Male Wistar rats received SULF (5mg/kg, i.p.) 24h and 5min before the intrastriatal infusion of QUIN. SULF increased the reduced glutathione (GSH) levels 4h after QUIN infusion, which was associated with its ability to increase the activity of glutathione reductase (GR), an antioxidant enzyme capable to regenerate GSH levels at 24h. Moreover, SULF treatment increased glutathione peroxidase (GPx) activity, while no changes were observed in γ-glutamyl cysteine ligase (GCL) activity. SULF treatment also prevented QUIN-induced oxidative stress (measured by oxidized proteins levels), the histological damage and the circling behavior. These results suggest that the protective effect of SULF could be related to its ability to preserve GSH levels and increase GPx and GR activities. PMID:24814729

  14. Sulforaphane Attenuates Contrast-Induced Nephropathy in Rats via Nrf2/HO-1 Pathway

    PubMed Central

    Zhao, Zhihong; Liao, Guixiang; Zhou, Qin; Lv, Daoyuan; Holthfer, Harry; Zou, Hequn

    2016-01-01

    Background. Oxidative stress plays an important role in the pathogenesis of contrast-induced nephropathy (CIN). The aim of this study was to investigate the antioxidant effects of sulforaphane (SFN) in a rat model of CIN and a cell model of oxidative stress in HK2 cells. Methods. Rats were randomized into four groups (n = 6 per group): control group, Ioversol group (Ioversol-induced CIN), Ioversol + SFN group (CIN rats pretreated with SFN), and SFN group (rats treated with SFN). Renal function tests, malondialdehyde (MDA), and reactive oxygen species (ROS) were measured. Western blot, real-time polymerase chain reaction analysis, and immunohistochemical analysis were performed for nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) detection. Results. Serum blood urea nitrogen (BUN), creatinine, and renal tissue MDA were increased after contrast exposure. Serum BUN, creatinine, and renal tissue MDA were decreased in the Ioversol + SFN group as compared with those in the Ioversol group. SFN increased the expression of Nrf2 and HO-1 in CIN rats and in Ioversol-induced injury HK2 cells. SFN increased cell viability and attenuated ROS level in vitro. Conclusions. SFN attenuates experimental CIN in vitro and in vivo. This effect is suggested to activate the Nrf2 antioxidant defenses pathway. PMID:27006750

  15. Sulforaphane Analogues with Heterocyclic Moieties: Syntheses and Inhibitory Activities against Cancer Cell Lines.

    PubMed

    Shi, Ye-Hui; Dai, Dong-Fang; Li, Jing; Dong, Yan-Wei; Jiang, Yin; Li, Huan-Gong; Gao, Yuan; Chong, Chuan-Ke; Li, Hui-Ying; Chu, Xiao-Qian; Yang, Cheng; Zhang, Quan; Tong, Zhong-Sheng; Bai, Cui-Gai; Chen, Yue

    2016-01-01

    Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⁺ breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⁺ subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⁺ subpopulation. PMID:27110751

  16. Cultivation conditions and selenium fertilization alter the phenolic profile, glucosinolate, and sulforaphane content of broccoli.

    PubMed

    Robbins, Rebecca J; Keck, Anna-Sigrid; Banuelos, Gary; Finley, John W

    2005-01-01

    Broccoli is a food often consumed for its potential health-promoting properties. The health benefits of broccoli are partly associated with secondary plant compounds that have bioactivity; glucosinolates and phenolic acids are two of the most abundant and important in broccoli. In an effort to determine how variety, stress, and production conditions affect the production of these bioactive components broccoli was grown in the greenhouse with and without selenium (Se) fertilization, and in the field under conventional or organic farming procedures and with or without water stress. High-performance liquid chromatography/mass spectrometry was used to separate and identify 12 primary phenolic compounds. Variety had a major effect: There was a preponderance of flavonoids in the Majestic variety, but hydroxycinnamic esters were relatively more abundant in the Legacy variety. Organic farming and water stress decreased the overall production of phenolics. Se fertilization increased glucosinolates in general, and sulforaphane in particular, up to a point; above that Se fertilization decreased glucosinolate production. Organic farming and water stress also decreased glucosinolate production. These data show environmental and genetic variation in phenolics and glucosinolates in broccoli, and warn that not all broccoli may contain all health-promoting bioactive components. They further show that selection for one bioactive component (Se) may decrease the content of other bioactive components such as phenolics and glucosinolates. PMID:16117613

  17. Urease from Helicobacter pylori is inactivated by sulforaphane and other isothiocyanates

    PubMed Central

    Fahey, Jed W.; Stephenson, Katherine K.; Wade, Kristina L.; Talalay, Paul

    2013-01-01

    Infections by Helicobacter pylori are very common, causing gastroduodenal inflammation including peptic ulcers, and increasing the risk of gastric neoplasia. The isothiocyanate (ITC) sulforaphane [SF; 1-isothiocyanato-4-(methylsulfinyl)butane] derived from edible crucifers such as broccoli is potently bactericidal against Helicobacter, including antibiotic-resistant strains, suggesting a possible dietary therapy. Gastric H. pylori infections express high urease activity which generates ammonia, neutralizes gastric acidity, and promotes inflammation. The finding that SF inhibits (inactivates) urease (jack bean and Helicobacter) raised the issue of whether these properties might be functionally related. The rates of inactivation of urease activity depend on enzyme and SF concentrations and show first order kinetics. Treatment with SF results in time-dependent increases in the ultraviolet absorption of partially purified Helicobacter urease in the 280–340 nm region. This provides direct spectroscopic evidence for the formation of dithiocarbamates between the ITC group of SF and cysteine thiols of urease. The potencies of inactivation of Helicobacter urease by isothiocyanates structurally related to SF were surprisingly variable. Natural isothiocyanates closely related to SF, previously shown to be bactericidal (berteroin, hirsutin, phenethyl isothiocyanate, alyssin, and erucin), did not inactivate urease activity. Furthermore, SF is bactericidal against both urease positive and negative H. pylori strains. In contrast, some isothiocyanates such as benzoyl-ITC, are very potent urease inactivators, but are not bactericidal. The bactericidal effects of SF and other ITC against Helicobacter are therefore not obligatorily linked to urease inactivation, but may reduce the inflammatory component of Helicobacter infections. PMID:23583386

  18. Sulforaphane promotes murine hair growth by accelerating the degradation of dihydrotestosterone.

    PubMed

    Sasaki, Mari; Shinozaki, Shohei; Shimokado, Kentaro

    2016-03-25

    Dihydrotestosterone (DHT) causes the regression of human hair follicles in the parietal scalp, leading to androgenic alopecia (AGA). Sulforaphane (SFN) increases the expression of DHT degrading enzymes, such as 3α-hydroxysteroid dehydrogenases (3α-HSDs), and, therefore, SFN treatment may improve AGA. To determine the effects of SFN on hair growth, we administered SFN (10 mg/kg BW, IP) or vehicle (DMSO) to ob/ob mice for six weeks and examined hair regeneration and the plasma levels of testosterone and DHT. We also tested the effects of SFN on the expression of two forms of 3α-HSD, aldo-keto reductase 1c21 and dehydrogenase/reductase (SDR family) member 9, both in vitro and in vivo. SNF significantly enhanced hair regeneration in ob/ob mice. The mice treated with SFN showed lower plasma levels of testosterone and DHT than those treated with vehicle. SFN increased the mRNA and protein levels of the two forms of 3α-HSD in the liver of the mice and in cultured murine hepatocyte Hepa1c1c7 cells. These results suggest that SFN treatment increases the amount of 3α-HSDs in the liver, accelerates the degradation of blood DHT, and subsequently blocks the suppression of hair growth by DHT. PMID:26923074

  19. Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon

    PubMed Central

    Al-Henhena, Nawal; Khalifa, Shaden A. M.; Ying, Rozaida Poh Yuen; Hassandarvish, Pouya; Rouhollahi, Elham; Al-Wajeeh, Nahla Saeed; Ali, Habibah Mohd; Abdulla, Mahmood Ameen; El-Seedi, Hesham R.

    2015-01-01

    In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and β-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content. PMID:26307342

  20. Raman spectroscopic investigation of the chemopreventive response of naringenin and its nanoparticles in DMBA-induced oral carcinogenesis

    NASA Astrophysics Data System (ADS)

    Krishnakumar, N.; Sulfikkarali, N. K.; Manoharan, S.; Venkatachalam, P.

    2013-11-01

    Raman spectroscopy is a vibrational spectroscopic technique that can be used to optically probe the biomolecular changes associated with tumor progression. The aim of the present study is to investigate the biomolecular changes in chemopreventive response of prepared naringenin-loaded nanoparticles (NARNPs) relative to efficacy of free naringenin (NAR) during 7,12-dimethyl benz(a)anthracene (DMBA)-induced oral carcinogenesis by Fourier Transform Raman (FT-Raman) spectroscopy. Oral squamous cell carcinoma (OSCC) was developed in the buccal pouch of golden Syrian hamsters by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. Raman spectra differed significantly between the control and tumor tissues, with tumors showing higher percentage signals for nucleic acids, phenylalanine and tryptophan and a lower in the percentage of phospholipids. Moreover, oral administration of free NAR and NARNPs significantly increased phospholipids and decreased the levels of tryptophan, phenylalanine and nucleic acid contents. On a comparative basis, NARNPs was found to have a more potent antitumor effect than free NAR in completely preventing the formation of squamous cell carcinoma and in improving the biochemical status to a normal range in DMBA-induced oral carcinogenesis. The present study further suggest that Raman spectroscopy could be a valuable tool for rapid and sensitive detection of specific biomolecular changes in response to chemopreventive agents.

  1. Chemopreventive effects of aloin against 1,2-dimethylhydrazine-induced preneoplastic lesions in the colon of Wistar rats.

    PubMed

    Hamiza, O O; Rehman, M U; Khan, R; Tahir, M; Khan, A Q; Lateef, A; Sultana, S

    2014-02-01

    Chemoprevention opens new window in the prevention of all types of cancers including colon cancer. Aloin, an anthracycline in plant pigment, can be utilized as a protective agent in cancer induction. In the present study, we have evaluated the chemopreventive efficacy of aloin against 1,2-dimethylhydrazine (DMH)-induced preneoplastic lesions in the colon of Wistar rats. DMH-induced aberrant crypt foci (ACF) and mucin-depleted foci (MDF) have been used as biomarkers of colon cancer. Efficacy of aloin against the colon toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, lipid peroxidation, ACF, MDF, histopathological changes, and expression levels of molecular markers of inflammation and tumor promotion. Aloin pretreatment ameliorates the damaging effects induced by DMH through a protective mechanism that involved reduction in increased oxidative stress enzymes (p < 0.001), ACF, MDF, cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6, proliferating cell nuclear antigen protein expression, and tumor necrosis factor-α (p < 0.001) release. From the results, it could be concluded that aloin clearly protects against chemically induced colon toxicity and acts reasonably by inducing antioxidant level, anti-inflammatory and antiproliferative markers. PMID:23928829

  2. Antioxidative and Chemopreventive Properties of Vernonia amygdalina and Garcinia biflavonoid

    PubMed Central

    Farombi, Ebenezer O.; Owoeye, Olatunde

    2011-01-01

    Recently, considerable attention has been focused on dietary and medicinal phytochemicals that inhibit, reverse or retard diseases caused by oxidative and inflammatory processes. Vernonia amygdalina is a perennial herb belonging to the Asteraceae family. Extracts of the plant have been used in various folk medicines as remedies against helminthic, protozoal and bacterial infections with scientific support for these claims. Phytochemicals such as saponins and alkaloids, terpenes, steroids, coumarins, flavonoids, phenolic acids, lignans, xanthones, anthraquinones, edotides and sesquiterpenes have been extracted and isolated from Vernonia amygdalina. These compounds elicit various biological effects including cancer chemoprevention. Garcinia kola (Guttiferae) seed, known as “bitter kola”, plays an important role in African ethnomedicine and traditional hospitality. It is used locally to treat illnesses like colds, bronchitis, bacterial and viral infections and liver diseases. A number of useful phytochemicals have been isolated from the seed and the most prominent of them is the Garcinia bioflavonoids mixture called kolaviron. It has well-defined structure and an array of biological activities including antioxidant, antidiabetic, antigenotoxic and hepatoprotective properties. The chemopreventive properties of Vernonia amygdalina and Garcinia biflavonoids have been attributed to their abilities to scavenge free radicals, induce detoxification, inhibit stress response proteins and interfere with DNA binding activities of some transcription factors. PMID:21776245

  3. Uptake of exemestane chemoprevention in postmenopausal women at increased risk for breast cancer.

    PubMed

    Aktas, Bilge; Sorkin, Mia; Pusztai, Lajos; Hofstatter, Erin W

    2016-01-01

    Despite their efficacy, uptake of selective estrogen receptor modulators for breast cancer chemoprevention remains low. Exemestane, an aromatase inhibitor, has recently been identified as a potential chemopreventive option with fewer serious side effects compared with selective estrogen receptor modulators in postmenopausal women. The purpose of this study was to assess the uptake of exemestane in a breast cancer prevention clinic. A retrospective chart review was conducted to capture chemoprevention uptake by postmenopausal women presenting to the Yale Breast Cancer Prevention Clinic between November 2011 and November 2012. Descriptive statistics of the study population have been presented. Statistical analyses were carried out using SAS 9.3 (SAS Institute Inc., Cary, North Carolina, USA) between December 2012 and February 2013. Of 90 postmenopausal women, 56 were eligible for chemoprevention. Their mean age was 56.8 years. Among the women, 39% had osteopenia or osteoporosis. Thirteen women chose to start chemoprevention medication (23%). Although 31% of the chemopreventive medication administered included exemestane, only four of 56 postmenopausal women opted for exemestane (7%). Chemoprevention uptake rates of postmenopausal women in the setting of a breast cancer prevention clinic are higher than that reported in the general population; however, they remain low overall despite the inclusion of exemestane as an option. A significant proportion of postmenopausal women have decreased bone density, which is a potential barrier to exemestane uptake. The results provide practical implications suggesting that exemestane may have limited impact on breast cancer chemoprevention uptake. Further investigations should focus on understanding the factors that influence, predict, and increase chemoprevention uptake. PMID:25642790

  4. Uptake of exemestane chemoprevention in postmenopausal women at increased risk for breast cancer

    PubMed Central

    Sorkin, Mia; Pusztai, Lajos; Hofstatter, Erin W.

    2016-01-01

    Despite their efficacy, uptake of selective estrogen receptor modulators for breast cancer chemoprevention remains low. Exemestane, an aromatase inhibitor, has recently been identified as a potential chemopreventive option with fewer serious side effects compared with selective estrogen receptor modulators in postmenopausal women. The purpose of this study was to assess the uptake of exemestane in a breast cancer prevention clinic. A retrospective chart review was conducted to capture chemoprevention uptake by postmenopausal women presenting to the Yale Breast Cancer Prevention Clinic between November 2011 and November 2012. Descriptive statistics of the study population have been presented. Statistical analyses were carried out using SAS 9.3 (SAS Institute Inc., Cary, North Carolina, USA) between December 2012 and February 2013. Of 90 postmenopausal women, 56 were eligible for chemoprevention. Their mean age was 56.8 years. Among the women, 39% had osteopenia or osteoporosis. Thirteen women chose to start chemoprevention medication (23%). Although 31% of the chemopreventive medication administered included exemestane, only four of 56 postmenopausal women opted for exemestane (7%). Chemoprevention uptake rates of postmenopausal women in the setting of a breast cancer prevention clinic are higher than that reported in the general population; however, they remain low overall despite the inclusion of exemestane as an option. A significant proportion of postmenopausal women have decreased bone density, which is a potential barrier to exemestane uptake. The results provide practical implications suggesting that exemestane may have limited impact on breast cancer chemoprevention uptake. Further investigations should focus on understanding the factors that influence, predict, and increase chemoprevention uptake. PMID:25642790

  5. Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells.

    PubMed

    Pei, Yanxi; Wu, Bo; Cao, Qiuhui; Wu, Lingyun; Yang, Guangdong

    2011-12-15

    Hydrogen sulfide (H(2)S) is a novel gasotransmitter that regulates cell proliferation and other cellular functions. Sulforaphane (SFN) is a sulfur-containing compound that exhibits anticancer properties, and young sprouts of broccoli are particularly rich in SFN. There is consistent epidemiological evidence that the consumption of sulfur-containing vegetables, such as garlic and cruciferous vegetables, may help reduce the occurrence of prostate cancer. Here we found that a large amount of H(2)S is released when SFN is added into cell culture medium or mixed with mouse liver homogenates, respectively. Both SFN and NaHS (a H(2)S donor) decreased the viability of PC-3 cells (a human prostate cancer cell line) in a dose-dependent manner, and supplement of methemoglobin or oxidized glutathione (two H(2)S scavengers) reversed SFN-reduced cell viability. We further found both cystathionine gamma-lyase (CSE) and cystathionine beta-synthase are expressed in PC-3 cells and mouse prostate tissues. H(2)S production in prostate tissues from CSE knockout mice was only 20% of that from wild-type mice, suggesting CSE is a major H(2)S-producing enzyme in prostate. CSE overexpression enhanced H(2)S production and inhibited cell viability in PC-3 cells. In addition, both SFN and NaHS activated p38 mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinase (JNK). Pre-treatment of PC-3 cells with methemoglobin decreased SFN-stimulated MAPK activities. Suppression of both p38 MAPK and JNK reversed H(2)S- or SFN-reduced viability of PC-3 cells. Our results demonstrated that H(2)S mediates the inhibitory effect of SFN on the proliferation of PC-3 cells, which suggests that H(2)S-releasing diet or drug might be beneficial in the treatment of prostate cancer. PMID:22005276

  6. Sulforaphane attenuates the development of atherosclerosis and improves endothelial dysfunction in hypercholesterolemic rabbits.

    PubMed

    Shehatou, George S G; Suddek, Ghada M

    2016-02-01

    The aim of the present work was to explore possible protective effects of sulforaphane (SFN) against atherosclerosis development and endothelial dysfunction in hypercholesterolemic rabbits. Rabbits were assigned to three groups of five: group I fed normal chow diet for four weeks, group II fed 1% high cholesterol diet (HCD) and group III fed HCD + SFN (0.25 mg/kg/day). Blood samples were collected for measurement of serum triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), lactate dehydrogenase (LDH) and C-reactive protein (CRP). Aortic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and total nitrite/nitrate (NOx) were measured. Vascular reactivity and intima/media (I/M) ratio were analyzed. Nuclear factor-kappa B (NF-κB) activation in aortic endothelial cells was identified immunohistochemically. HCD induced significant increases in serum TGs, TC, LDL-C, LDH, and CRP, and aortic MDA and SOD. Moreover, HCD caused significant reductions in serum HDL-C, aortic GSH and NOx. SFN administration significantly decreased HCD-induced elevations in serum TC, LDL-C, CRP, and LDH. while significantly increased HDL-C and GSH levels and normalized aortic SOD and NOx. Additionally, SFN significantly improved rabbit aortic endothelium-dependent relaxation to acetylcholine. Moreover, SFN significantly reduced the elevation in I/M ratio. This effect was confirmed by aortic histopathologic examination. The expression of NF-κB in aortic tissue showed a marked reduction upon treatment with SFN. In conclusion, this study reveals that SFN has the ability to ameliorate HCD-induced atherosclerotic lesions progression and vascular dysfunction, possibly via its lipid-lowering and antioxidant effects and suppression of NF-κB-mediated inflammation. PMID:26490346

  7. Benzoquinone toxicity is not prevented by sulforaphane in CD-1 mouse fetal liver cells.

    PubMed

    Philbrook, Nicola A; Winn, Louise M

    2016-08-01

    Benzene is an environmental pollutant known to cause leukemia in adults, and may be associated with childhood leukemia. While the mechanisms of benzene-mediated carcinogenicity have not been fully elucidated, increased reactive oxygen species (ROS) and DNA damage are implicated. Sulforaphane (SFN) induces nuclear factor erythroid 2-related factor 2 (Nrf2), which contributes to SFN-mediated protection against carcinogenesis. We exposed cultured CD-1 mouse fetal liver cells to the benzene metabolite, benzoquinone, to determine its potential to cause DNA damage and alter DNA repair. Cells were also exposed to SFN to determine potential protective effects. Initially, cells were exposed to benzoquinone to confirm increased ROS and SFN to confirm Nrf2 induction. Subsequently, cells were treated with benzoquinone (with or without SFN) and levels of ROS, 8-hydroxy-2-deoxyguanosine (8-OHdG; marker of oxidative DNA damage), gamma histone 2A variant X (γH2AX; marker of DNA double-stranded breaks; DSBs) and transcript levels of genes involved in DNA repair were measured. Benzoquinone exposure led to a significant increase in ROS, which was not prevented by pretreatment with SFN or the antioxidative enzyme, catalase. DNA damage was increased after benzoquinone exposure, which was not prevented by SFN. Benzoquinone exposure significantly decreased the transcript levels of the critical base excision repair gene, 8-oxoguanine glycosylase (Ogg1), which was not prevented by SFN. The findings of this study demonstrate for the first time that DNA damage and altered DNA repair are a consequence of benzoquinone exposure in CD-1 mouse fetal liver cells and that SFN conferred little protection in this model. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26456483

  8. Sulforaphane Decreases Endothelial Cell Apoptosis in Fuchs Endothelial Corneal Dystrophy: A Novel Treatment

    PubMed Central

    Ziaei, Alireza; Schmedt, Thore; Chen, Yuming; Jurkunas, Ula V.

    2013-01-01

    Purpose. Fuchs endothelial corneal dystrophy (FECD) is an oxidative stress disorder that leads to age-related and gradual loss of corneal endothelial cells resulting in corneal edema and loss of vision. To date, other than surgical intervention, there are no treatment options for patients with FECD. We have shown that in FECD, there is a deficiency in nuclear factor erythroid 2-related factor 2 (Nrf2)–regulated antioxidant defense due to decreased Nrf2 nuclear translocation and activation of antioxidant response element (ARE). In this study, we used sulforaphane (SFN) and D3T to investigate a strategy of targeting Nrf2-ARE in FECD. Methods. FECD and normal ex vivo corneas and human corneal endothelial cell lines were pretreated with SFN or D3T and exposed to oxidative stress with tert-Butyl hydroperoxide (tBHP). Apoptosis was detected with TUNEL. Cellular localization of Nrf2 and p53 was assessed by immunohistochemistry. Effect of SFN was determined by using DCFDA assay, Western blot and real-time PCR. Results. After pretreatment with SFN, oxidative stress was induced with tBHP. In ex vivo FECD specimens, SFN decreased CEC apoptosis by 55% in unstressed group and by 43% in tBHP-treated specimens. SFN enhanced nuclear translocation of Nrf2 in FECD specimens and decreased p53 staining under oxidative stress. Pretreatment with SFN enhanced cell viability by decreasing intracellular reactive oxygen species production. Upregulation of Nrf2 levels led to increased synthesis of DJ-1, heme oxygenase 1, and nicotinamide adenine dinucleotide quinone oxidoreductase-1. SFN significantly upregulated major ARE-dependent antioxidants and ameliorated oxidative stress–induced apoptosis in FECD. Conclusions. Our results suggest that targeting Nrf2-ARE pathway may arrest degenerative cell loss seen in FECD. PMID:24030461

  9. Sulforaphane is not an effective antagonist of the human Pregnane X-Receptor in vivo

    PubMed Central

    Poulton, Emma Jane; Levy, Lisa; Lampe, Johanna W.; Shen, Danny D.; Tracy, Julia; Shuhart, Margaret C.; Thummel, Kenneth E.; Eaton, David L.

    2012-01-01

    Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand – rifampicin (300 mg/d) was given alone for 7 days in arm 1, or in daily combination with 450 µmoles SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology. PMID:23153560

  10. The dietary histone deacetylase inhibitor sulforaphane induces human β-defensin-2 in intestinal epithelial cells

    PubMed Central

    Schwab, Markus; Reynders, Veerle; Loitsch, Stefan; Steinhilber, Dieter; Schröder, Oliver; Stein, Jürgen

    2008-01-01

    Antimicrobial peptides like human β-defensin-2 (HBD-2) play an important role in the innate immune system protecting the intestinal mucosa against bacterial invasion. The dietary histone deacetylase (HDAC) inhibitors sulforaphane (SFN) and butyrate have received a great deal of attention because of their ability to simultaneously modulate multiple cellular targets involved in cellular protection. In this study the influence of SFN and butyrate on HBD-2 expression as well as the molecular pathways involved in SFN-mediated induction of HBD-2 were scrutinized. Treatment of Caco-2, HT-29 and SW480 cells with SFN led to a time- and dose-dependent upregulation of HBD-2 mRNA expression as determined by semi-quantitative reverse transcription–polymerase chain reaction. Moreover, HBD-2 protein production increased in response to SFN, measured by enzyme-linked immunosorbent assay. Induction of HBD-2 was also observed in response to butyrate. Immunofluorescence analysis revealed that the protein was localized in the cytosol. Coincubation of SFN with a vitamin D receptor (VDR), or an extracellular-regulated kinase 1/2 or a nuclear factor-κB inhibitor all reduced HBD-2 mRNA upregulation. In contrast, transfection of cells with a dominant-negative peroxisome proliferator-activated receptor γ (PPARγ) mutant vector to inhibit PPARγ wild-type action and inhibition of p38 mitogen-activated protein kinase (MAPK) signalling did not affect SFN-mediated upregulation of HBD-2 mRNA. Moreover, SFN induced the expression of VDR, PPARγ and phosphorylated ERK1/2 but did not affect p38 MAPK activation. The data clearly demonstrate for the first time that the dietary HDAC inhibitor SFN is able to induce antimicrobial peptides in colonocytes. In this process HBD-2 expression is regulated via VDR, mitogen-activated protein kinase kinase/extracellular-regulated kinase and nuclear factor-κB signalling. PMID:18373608

  11. Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A

    PubMed Central

    Erzinger, Melanie M.; Bovet, Cédric; Hecht, Katrin M.; Senger, Sabine; Winiker, Pascale; Sobotzki, Nadine; Cristea, Simona; Beerenwinkel, Niko; Shay, Jerry W.; Marra, Giancarlo; Wollscheid, Bernd; Sturla, Shana J.

    2016-01-01

    The chemoprotective properties of sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobiotic-metabolizing and antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of cancer therapy through the modulation of drug-metabolizing enzymes. To identify proteins modulated by a low concentration of SF, we treated HT29 colon cancer cells with 2.5 μM SF. Protein abundance changes were detected by stable isotope labeling of amino acids in cell culture. Among 18 proteins found to be significantly up-regulated, aldo-keto reductase 1C3 (AKR1C3), bioactivating the DNA cross-linking prodrug PR-104A, was further characterized. Preconditioning HT29 cells with SF reduced the EC50 of PR-104A 3.6-fold. The increase in PR-104A cytotoxicity was linked to AKR1C3 abundance and activity, both induced by SF in a dose-dependent manner. This effect was reproducible in a second colon cancer cell line, SW620, but not in other colon cancer cell lines where AKR1C3 abundance and activity were absent or barely detectable and could not be induced by SF. Interestingly, SF had no significant influence on PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of PR-104A after preconditioning with SF was apparent only in cancer cells provided that AKR1C3 is expressed, while its expression in non-cancerous cells did not elicit such a response. Therefore, a subset of cancers may be susceptible to combined food-derived component and prodrug treatments with no harm to normal tissues. PMID:26950072

  12. Sulforaphane prevents microcystin-LR-induced oxidative damage and apoptosis in BALB/c mice

    SciTech Connect

    Sun Xiaoyun; Mi Lixin; Liu Jin; Song Lirong; Chung Funglung; Gan Nanqin

    2011-08-15

    Microcystins (MCs), the products of blooming algae Microcystis, are waterborne environmental toxins that have been implicated in the development of liver cancer, necrosis, and even fatal intrahepatic bleeding. Alternative protective approaches in addition to complete removal of MCs in drinking water are urgently needed. In our previous work, we found that sulforaphane (SFN) protects against microcystin-LR (MC-LR)-induced cytotoxicity by activating the NF-E2-related factor 2 (Nrf2)-mediated defensive response in human hepatoma (HepG2) and NIH 3T3 cells. The purpose of this study was to investigate and confirm efficacy the SFN-induced multi-mechanistic defense system against MC-induced hepatotoxicity in an animal model. We report that SFN protected against MC-LR-induced liver damage and animal death at a nontoxic and physiologically relevant dose in BALB/c mice. The protection by SFN included activities of anti-cytochrome P450 induction, anti-oxidation, anti-inflammation, and anti-apoptosis. Our results suggest that SFN may protect mice against MC-induced hepatotoxicity. This raises the possibility of a similar protective effect in human populations, particularly in developing countries where freshwaters are polluted by blooming algae. - Graphical abstract: Display Omitted Research Highlights: > SFN protected against MC-LR-induced liver damage and animal death in BALB/c mice. > The dose of SFN is at a nontoxic and physiologically relevant dose. > The protection included activities of anti-oxidation, anti-inflammation, and anti-apoptosis. > SFN may protect mice against MC-induced hepatotoxicity.

  13. Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease

    PubMed Central

    Doss, Jennifer F.; Jonassaint, Jude C.; Garrett, Melanie E.; Ashley-Koch, Allison E.; Telen, Marilyn J.; Chi, Jen-Tsan

    2016-01-01

    Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption. We observed an increase in the mean relative whole blood mRNA levels for the NRF2 target HMOX1 (p = 0.02) on the last day of BSH treatment, compared to pre-treatment. We also observed a trend toward increased mean relative mRNA levels of the NRF2 target HBG1 (p = 0.10) from baseline to end of treatment, but without significant changes in HbF protein. We conclude that BSH, in the provided doses, is safe in stable SCD patients and may induce changes in gene expression levels. We therefore propose investigation of more potent NRF2 inducers, which may elicit more robust physiological changes and offer clinical benefits to SCD patients. Trial Registration: ClinicalTrials.gov NCT01715480 PMID:27071063

  14. Sulforaphane Restores Cellular Glutathione Levels and Reduces Chronic Periodontitis Neutrophil Hyperactivity In Vitro

    PubMed Central

    Dias, Irundika H. K.; Chapple, Ian L. C.; Milward, Mike; Grant, Melissa M.; Hill, Eric; Brown, James; Griffiths, Helen R.

    2013-01-01

    The production of high levels of reactive oxygen species by neutrophils is associated with the local and systemic destructive phenotype found in the chronic inflammatory disease periodontitis. In the present study, we investigated the ability of sulforaphane (SFN) to restore cellular glutathione levels and reduce the hyperactivity of circulating neutrophils associated with chronic periodontitis. Using differentiated HL60 cells as a neutrophil model, here we show that generation of extracellular O2. - by the nicotinamide adenine dinucleotide (NADPH) oxidase complex is increased by intracellular glutathione depletion. This may be attributed to the upregulation of thiol regulated acid sphingomyelinase driven lipid raft formation. Intracellular glutathione was also lower in primary neutrophils from periodontitis patients and, consistent with our previous findings, patients neutrophils were hyper-reactive to stimuli. The activity of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of the antioxidant response, is impaired in circulating neutrophils from chronic periodontitis patients. Although patients’ neutrophils exhibit a low reduced glutathione (GSH)/oxidised glutathione (GSSG) ratio and a higher total Nrf2 level, the DNA-binding activity of nuclear Nrf2 remained unchanged relative to healthy controls and had reduced expression of glutamate cysteine ligase catalytic (GCLC), and modifier (GCLM) subunit mRNAs, compared to periodontally healthy subjects neutrophils. Pre-treatment with SFN increased expression of GCLC and GCM, improved intracellular GSH/GSSG ratios and reduced agonist-activated extracellular O2. - production in both dHL60 and primary neutrophils from patients with periodontitis and controls. These findings suggest that a deficiency in Nrf2-dependent pathways may underpin susceptibility to hyper-reactivity in circulating primary neutrophils during chronic periodontitis. PMID:23826097

  15. Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease.

    PubMed

    Doss, Jennifer F; Jonassaint, Jude C; Garrett, Melanie E; Ashley-Koch, Allison E; Telen, Marilyn J; Chi, Jen-Tsan

    2016-01-01

    Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption. We observed an increase in the mean relative whole blood mRNA levels for the NRF2 target HMOX1 (p = 0.02) on the last day of BSH treatment, compared to pre-treatment. We also observed a trend toward increased mean relative mRNA levels of the NRF2 target HBG1 (p = 0.10) from baseline to end of treatment, but without significant changes in HbF protein. We conclude that BSH, in the provided doses, is safe in stable SCD patients and may induce changes in gene expression levels. We therefore propose investigation of more potent NRF2 inducers, which may elicit more robust physiological changes and offer clinical benefits to SCD patients. Trial registration: ClinicalTrials.gov NCT01715480. PMID:27071063

  16. Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A.

    PubMed

    Erzinger, Melanie M; Bovet, Cédric; Hecht, Katrin M; Senger, Sabine; Winiker, Pascale; Sobotzki, Nadine; Cristea, Simona; Beerenwinkel, Niko; Shay, Jerry W; Marra, Giancarlo; Wollscheid, Bernd; Sturla, Shana J

    2016-01-01

    The chemoprotective properties of sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobiotic-metabolizing and antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of cancer therapy through the modulation of drug-metabolizing enzymes. To identify proteins modulated by a low concentration of SF, we treated HT29 colon cancer cells with 2.5 μM SF. Protein abundance changes were detected by stable isotope labeling of amino acids in cell culture. Among 18 proteins found to be significantly up-regulated, aldo-keto reductase 1C3 (AKR1C3), bioactivating the DNA cross-linking prodrug PR-104A, was further characterized. Preconditioning HT29 cells with SF reduced the EC50 of PR-104A 3.6-fold. The increase in PR-104A cytotoxicity was linked to AKR1C3 abundance and activity, both induced by SF in a dose-dependent manner. This effect was reproducible in a second colon cancer cell line, SW620, but not in other colon cancer cell lines where AKR1C3 abundance and activity were absent or barely detectable and could not be induced by SF. Interestingly, SF had no significant influence on PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of PR-104A after preconditioning with SF was apparent only in cancer cells provided that AKR1C3 is expressed, while its expression in non-cancerous cells did not elicit such a response. Therefore, a subset of cancers may be susceptible to combined food-derived component and prodrug treatments with no harm to normal tissues. PMID:26950072

  17. Chemopreventive effects of Ginkgo biloba extract in estrogen-negative human breast cancer cells.

    PubMed

    Park, Yong Joo; Kim, Mi Jie; Kim, Ha Ryong; Yi, Min Sun; Chung, Kyu Hyuck; Oh, Seung Min

    2013-01-01

    Excessive level of estrogen is considered as a main cause of breast cancer, therefore, many studies have focused on estrogen receptor (ER)-positive breast cancer, even though ER-negative cancer has a poor prognosis than ER-positive breast cancer. We evaluated the anti-cancer effects of Ginkgo biloba extract (GBE) in estrogen-independent breast cancer. GBE has been traditionally used as a platelet activating factor, a circulatory stimulant, a tonic, and anti-asthmatic drug, and anti-cancer agent. However, anti-cancer effects of GBE on ER-negative breast cancer have not been proved yet. In this study, we tested chemotherapeutic potential of GBE in the MDA-MB-231 (ER-negative) human breast cancer cell line. Our results showed that cytotoxicity effects of GBE in MDA-MB-231 lead to DNA fragmentation at high concentrations (500 and 1,000 μg/ml). Caspase-3 was significantly activated and mRNA levels of apoptosis-related genes (Bcl-2 and Bax) were altered. These results indicate that GBE induces apoptosis in MDA-MB-231 cells. It is presumed that GBE has chemopreventive effects in ER-independent breast cancer through anti-proliferation and apoptosis-inducing activities. PMID:23335025

  18. Targeting of chemoprevention to high-risk potentially malignant oral lesions: Challenges and opportunities

    PubMed Central

    Martinez, Victor D.; MacCaulay, Calum E.; Guillaud, Martial; Lam, Wan L; Zhang, Lewei; Corbett, Kitty; Rosin, Miriam P.

    2014-01-01

    Worldwide, oral cancer is responsible for 170,000 deaths per year. Intervention to prevent this disease is a long sought after goal. Chemoprevention studies have focused on clinicopathological features of potentially malignant lesions (PML) in an effort to prevent their progression to cancer. However, prediction of future behavior for such lesions is difficult and remains a major challenge to such intervention. Different approaches to this problem have been tested in the past 20 years. Early genetic progression models identified critical regions of allelic imbalance at 3p and 9p, and provided the basis for molecular markers to identify progressing PMLs. Subsequently, technological advances, such as genome-wide high-throughput array platforms, computer imaging, visualization technology and next generation sequencing, have broadened the scope for marker development and have the potential of further improving our ability to identify high-risk lesions in the near future either alone or in combination. In this article, we examine the milestones in the development of markers for PML progression. We emphasize the critical importance of networks among scientists, health professionals and community to facilitate the validation and application of putative markers into clinical practice. With a growing number of new agents to validate, it is necessary to coordinate the design and implementation of strategies for patient recruitment, integration of marker assessment, and the final translation of such approaches into clinical use. PMID:25240917

  19. Biochemical basis of cancer chemoprevention and/or chemotherapy with ginsenosides (Review).

    PubMed

    Choi, Joon-Seok; Chun, Kyung-Soo; Kundu, Juthika; Kundu, Joydeb Kumar

    2013-12-01

    Cancer still imposes a global threat to public health. After decades of research on cancer biology and enormous efforts in developing anticancer therapies, we now understand that the majority of cancers can be prevented. Bioactive phytochemicals present in edible plants have been shown to reduce the risk of various types of cancer. Ginseng (Panax ginseng C.A. Meyer), which contains a wide variety of saponins, known as ginsenosides, is an age-old remedy for human ailments, including cancer. Numerous laboratory-based studies have revealed the anticancer properties of ginsenosides, which compel tumor cells to commit suicide, arrest the proliferation of cancer cells in culture and inhibit experimentally-induced tumor formation in laboratory animals. Ginsenosides have been reported to inhibit tumor angiogenesis, as well as the invasion and metastasis of various types of cancer cells. Moreover, ginsenosides as combination therapy enhance the sensitivity of chemoresistant tumors to clinically used chemotherapeutic agents. This review sheds light on the molecular mechanisms underlying the cancer chemopreventive and/or chemotherapeutic activity of ginsenosides and their intestinal metabolites with particular focus on the modulation of cell signaling pathways associated with oxidative stress, inflammation, cell proliferation, apoptosis, angiogenesis and the metastasis of cancer cells. PMID:24126942

  20. Curcumin: A Novel Stat 3 Pathway Inhibitor for Chemoprevention of Lung Cancer

    PubMed Central

    Alexandrow, Mark G.; Song, Lanxi J.; Altiok, Soner; Gray, Jhanelle; Haura, Eric B.; Kumar, Nagi B.

    2011-01-01

    curcumin treatment, concomitant with a reduction in cell proliferation, supporting our hypothesis that inhibition of the Stat3 pathway represents at least one important mechanism by which curcumin elicits its effects on the bronchoepithelium. These data provide a rationale for the use of curcumin as a promising chemopreventive agent in high risk populations such as former smokers. PMID:22156994

  1. Women victims of sexual violence: adherence to chemoprevention of HIV.

    PubMed

    Diniz, Normélia Maria Freire; de Almeida, Lílian Conceição Guimarães; dos S Ribeiro, Bárbara Cristina; de Macêdo, Valéria Góes

    2007-01-01

    This study aimed to investigate the adherence of women victims of sexual violence, to AIDS chemoprevention treatment. A quantitative study was carried out at a care service to victims of sexual violence in Salvador (Bahia, Brazil). Study participants were 172 women. Data were collected through interviews with forms and consultation of patient files. The results showed that 45.4% of the abused women were teenagers and 40.7% of the attended women were raped. Only 54% of the women were advised to use antiretrovirals to prevent HIV. Adherence to treatment occurred in 57.4% of cases and discontinuity corresponded to 42.6%. Non-adherence to treatment was attributed to psychological or emotional disorders and non-understanding of the established treatment. Therefore, it is important that professionals pay careful attention in order to perceive the conditions that might increase women's vulnerability to the infection. PMID:17375226

  2. Participants' perceptions of a phase I colon cancer chemoprevention trial.

    PubMed

    Hudmon, K S; Stoltzfus, C; Chamberlain, R M; Lorimor, R J; Steinbach, G; Winn, R J

    1996-12-01

    To assess participants' perceptions of a phase I colon cancer chemoprevention trial using a calcium intervention, questionnaires were mailed to trial participants at the conclusion of the study. Responses to questionnaire items reported here include (1) perceived benefits and barriers of participation, (2) interest in participating in future trials, (3) willingness to pay trial expenses out of pocket, and (4) posttrial continuation of the calcium regimen. The study found that the most highly rated trial benefit was the perception of potential colon cancer prevention; the trial barrier reported to be the most troublesome was inappropriate or mistaken billing for study visits. Three fourths of the subjects expressed an interest in future trials of the same duration. For trials of longer duration, this percentage decreased to 66%. Approximately half did not object to participation in future trials involving placebos, and just over one third indicated that they would either definitely (8%) or probably (27%) have joined the calcium trial even if they had to pay some study expenses out of pocket. Over 90% indicated they would continue taking the calcium pills if calcium is shown to be effective. The level of perceived benefits was positively associated with reported interest in participating in future trials of the same and longer durations, and the level of reported difficulty with trial pills and procedures was inversely related to interest in future placebo-controlled trials. The results of this study, in conjunction with results of prospective studies of trial participation, may be applied in future chemoprevention trials to facilitate recruitment, reduce attrition, and promote positive trial experiences for participants by emphasizing frequently reported benefits and minimizing frequently reported barriers. PMID:8974209

  3. Augmentation of natural killer cell and antibody-dependent cellular cytotoxicity in BALB/c mice by sulforaphane, a naturally occurring isothiocyanate from broccoli through enhanced production of cytokines IL-2 and IFN-gamma.

    PubMed

    Thejass, P; Kuttan, G

    2006-01-01

    Effect of sulforaphane on cell-mediated immune (CMI) response was studied in normal as well as Ehrlich ascites tumor-bearing BALB/c mice. Administration of sulforaphane significantly enhanced natural killer (NK) cell activity in both normal as well as tumor-bearing animals, and the activity was observed earlier than in tumor-bearing control animals. Antibody-dependent cellular cytotoxicity (ADCC) also was enhanced significantly in both normal as well as tumor-bearing animals after sulforaphane administration compared with untreated control tumor-bearing animals. An early antibody-dependent complement-mediated cytotoxicity (ACC) also was observed in sulforaphane-treated normal and tumor-bearing animals. Administration of sulforaphane significantly enhanced the production of Interleukin-2 and Interferon-gamma in normal as well as tumor-bearing animals. In addition, sulforaphane significantly enhanced the proliferation of splenocytes, bone marrow cells, and thymocytes by stimulating the mitogenic potential of various mitogens such as concanavalin A, phytohaemagglutinin, poke weed mitogen, and lipopolysaccharide. PMID:16997793

  4. Chemopreventive effect of raw and cooked lentils (Lens culinaris L) and soybeans (Glycine max) against azoxymethane-induced aberrant crypt foci.

    PubMed

    Faris, Mo'ez Al-Islam E; Takruri, Hamed R; Shomaf, Maha S; Bustanji, Yasser K

    2009-05-01

    Although lentils (Lens culinaris L) contain several bioactive compounds that have been linked to the prevention of cancer, the in vivo chemopreventive ability of lentils against chemically induced colorectal cancer has not been examined. Our present study examined the hypothesis that lentils could suppress the early carcinogenesis in vivo by virtue of their bioactive micro- and macroconstituents and that culinary thermal treatment could affect their chemopreventive potential. To accomplish this goal, we used raw whole lentils (RWL), raw split lentils (RSL), cooked whole lentils (CWL), and cooked split lentils (CSL). Raw soybeans (RSB; Glycine max) were used for the purpose of comparison with a well-studied chemopreventive agent. Sixty weanling Fischer 344 male rats, 4 to 5 weeks of age, were randomly assigned to 6 groups (10 rats/group): the control group (C) received AIN-93G diet, and treatment leguminous groups of RWL, CWL, RSL, CSL, and RSB received the treatment diets containing AIN-93G+5% of the above-mentioned legumes. After acclimatization for 1 week (at 5th to 6th week of age), all animals were put on the control and treatment diets separately for 5 weeks (from 6th to 11th week of age). At the end of the 5th week of feeding (end of 11th week of age), all rats received 2 subcutaneous injections of azoxymethane carcinogen at 15 mg/kg rat body weight per dose once a week for 2 consecutive weeks. After 17 weeks of the last azoxymethane injection (from 12th to 29th week of age), all rats were euthanized. Chemopreventive ability was assessed using colonic aberrant crypt foci and activity of hepatic glutathione-S-transferases. Significant reductions (P < .05) were found in total aberrant crypt foci number (mean +/- SEM) for RSB (27.33 +/- 4.32), CWL (33.44 +/- 4.56), and RSL (37.00 +/- 6.02) in comparison with the C group (58.33 +/- 8.46). Hepatic glutathione-S-transferases activities increased significantly (P < .05) in rats fed all treatment diets (from 51

  5. Phytoconstituents as apoptosis inducing agents: strategy to combat cancer.

    PubMed

    Kumar, Manish; Kaur, Varinder; Kumar, Subodh; Kaur, Satwinderjeet

    2016-08-01

    Advancement in the field of cancer molecular biology has aided researchers to develop various new chemopreventive agents which can target cancer cells exclusively. Cancer chemopreventive agents have proficiency to inhibit, reverse and delay process of carcinogenesis during its early and later course. Chemopreventive agents can act as antioxidative, antimutagenic/antigenotoxic, anti-inflammatory agents or via aiming various molecular targets in a cell to induce cell death. Apoptosis is a kind of cell death which shows various cellular morphological alterations such as cell shrinkage, blebbing of membrane, chromatin condensation, DNA fragmentation, formation of apoptotic bodies etc. Nowadays, apoptosis is being one of the new approaches for the identification and development of novel anticancer therapies. For centuries, plants are known to play part in daily routine from providing food to management of human health. In the last two decades, diverse phytochemicals and various botanical formulations have been characterized as agents that possess potential to execute cancer cells via inducing apoptosis. Data obtained from the research carried out globally pointed out that natural products are the potential candidates which have capability to combat cancer. In the present review, we surveyed literature on natural products which throws light on the mechanism through which these phytochemicals induce apoptosis in cancer cells. PMID:26239338

  6. Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo

    SciTech Connect

    Poulton, Emma Jane; Levy, Lisa; Lampe, Johanna W.; Shen, Danny D.; Tracy, Julia; Shuhart, Margaret C.; Thummel, Kenneth E.; Eaton, David L.

    2013-01-01

    Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand — rifampicin (300 mg/d) was given alone for 7 days in arm 1, or in daily combination with 450 μmol SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology. -- Highlights: ► The effects of SFN on PXR mediated CYP3A4 induction in humanized PXR mice and humans were examined. ► SFN had no effect on rifampicin mediated CYP3A4 induction in humans or humanized mice. ► SFN had a modest effect on basal CYP3A4 activity among subjects with higher baseline activity. ► Humanized PXR

  7. NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid has enhanced chemo-preventive properties compared to aspirin, is gastrointestinal safe with all the classic therapeutic indications.

    PubMed

    Kodela, Ravinder; Chattopadhyay, Mitali; Velázquez-Martínez, Carlos A; Kashfi, Khosrow

    2015-12-15

    Aspirin is chemopreventive; however, side effects preclude its long-term use. NOSH-aspirin (NBS-1120), a novel hybrid that releases nitric oxide and hydrogen sulfide, was designed to be a safer alternative. Here we compare the gastrointestinal safety, anti-inflammatory, analgesic, anti-pyretic, anti-platelet, and chemopreventive properties of aspirin and NBS-1120 administered orally to rats at equimolar doses. Gastrointestinal safety: 6h post-administration, the number and size of hemorrhagic lesions in stomachs were counted; tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5h. Analgesic: time-dependent analgesic effects were evaluated by carrageenan-induced hyperalgesia. Antiplatelet: anti-aggregatory effects were studied on collagen-induced platelet aggregation of human platelet-rich plasma. Chemoprevention: nude mice were gavaged daily for 25 days with vehicle, aspirin or NBS-1120. After one week, each mouse was inoculated subcutaneously in the right flank with HT-29 human colon cancer cells. Both agents reduced PGE2 levels in stomach tissue; however, NBS-1120 did not cause any stomach ulcers, whereas aspirin caused significant bleeding. Lipid peroxidation induced by aspirin was higher than that exerted by NBS-1120. SOD activity was significantly inhibited by aspirin but increased by NBS-1120. Both agents showed similar anti-inflammatory, analgesic, anti-pyretic, and anti-platelet activities. Aspirin increased plasma TNFα more than NBS-1120-treated animals. NBS-1120 was better than aspirin as a chemopreventive agent; it dose-dependently inhibited tumor growth and tumor mass. PMID:26394025

  8. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced Hamster Cheek Pouch Carcinogenesis by a 5-Lipoxygenase Inhibitor, Garcinol

    PubMed Central

    Shim, Joong-Youn; Sang, Shengmin; Sun, Zheng; Chen, Xiaoxin

    2013-01-01

    Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis, and can be targeted for cancer prevention. In order to develop potent topical agents for oral cancer chemoprevention, five known 5-Lox inhibitors from dietary and synthetic sources, Zileuton, ABT-761, Licofelone, Curcumin and Garcinol, were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis. PMID:23137051

  9. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol.

    PubMed

    Chen, Xin; Zhang, Xinyan; Lu, Ye; Shim, Joong-Youn; Sang, Shengmin; Sun, Zheng; Chen, Xiaoxin

    2012-01-01

    Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis. PMID:23137051

  10. Less is more for cancer chemoprevention: evidence of a non-linear dose response for the protective effects of resveratrol in humans and mice

    PubMed Central

    Scott, Edwina; Cai, Hong; Kholghi, Abeer; Andreadi, Catherine; Rufini, Alessandro; Karmokar, Ankur; Britton, Robert G.; Horner-Glister, Emma; Greaves, Peter; Jawad, Dhafer; James, Mark; Howells, Lynne; Ognibene, Ted; Malfatti, Mike; Goldring, Christopher; Kitteringham, Neil; Walsh, Joanne; Viskaduraki, Maria; West, Kevin; Miller, Andrew; Hemingway, David; Steward, William P.; Gescher, Andreas J.

    2016-01-01

    Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials assessing efficacy. To challenge the assumption that ‘more is better’ we compared the pharmacokinetics and activity of a dietary dose with an intake 200-times higher. The dose response relationship and metabolite profile of [14C]-resveratrol in colorectal tissue of patients helped define clinically achievable concentrations. In ApcMin mice receiving a high-fat diet the low dose supressed intestinal adenoma development more potently than the higher dose. Efficacy correlated with increased AMP-activated protein kinase (AMPK) activation and the senescence marker p21. Non-linear dose responses were observed for AMPK and mTOR signalling in adenoma cells, culminating in autophagy and senescence. In human tissues low dietary exposures caused enhanced AMPK phosphorylation, autophagy and expression of the cytoprotective enzyme NQO1. These findings warrant revision of developmental strategies for diet-derived agents for cancer chemoprevention. PMID:26223300

  11. Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone.

    PubMed

    Roy, H K; Karolski, W J; Ratashak, A

    2001-05-15

    Use of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention of colon cancer has been hindered by their potential gastro-intestinal toxicity. Nabumetone, which is approximately 10 to 36 times safer than conventional NSAIDs, was evaluated in 2 models of experimental colon carcinogenesis. In azoxymethane (AOM)-treated Fisher 344 rats, nabumetone caused dose-dependent inhibition of aberrant crypt foci (ACF), with 750 and 1,500 ppm resulting in 15% and 37% reductions, respectively (p < 0.05). Moreover, complex ACF were reduced by 48% in the latter group. MIN mice studies confirmed the chemopreventive efficacy of nabumetone, with 900 ppm suppressing approximately half of the intestinal tumors. Interestingly, inhibition of intermediate biomarkers in both models was markedly greater in the distal than the proximal bowel. To mechanistically evaluate this regional selectivity, we assessed cyclo-oxygenase-2 (COX-2) expression in the uninvolved mucosa and demonstrated a 3- to 4-fold excess in the distal relative to the proximal bowel in both MIN mice and AOM-treated rats. We then investigated another putative NSAID target, peroxisome proliferator-activated receptor-delta (PPAR-delta) and demonstrated up-regulation during AOM-induced colonic tumorigenesis. Furthermore, in pre-neoplastic mucosa, there was a 3-fold excess of PPAR-delta in the distal colon. We demonstrate that nabumetone is an effective protective agent in both experimental models of colon carcinogenesis. The striking distal predilection of nabumetone may be, at least partially, explained by distal bowel over-expression of COX-2 and PPAR-delta. PMID:11304699

  12. Increased chemopreventive effect by combining arctigenin, green tea polyphenol and curcumin in prostate and breast cancer cells.

    PubMed

    Wang, Piwen; Wang, Bin; Chung, Seyung; Wu, Yanyuan; Henning, Susanne M; Vadgama, Jaydutt V

    2014-08-01

    The low bioavailability of most flavonoids limits their application as anti-carcinogenic agents in humans. A novel approach of treatment with a mixture of bioactive compounds that share molecular anti-carcinogenic targets may enhance the effect on these targets at low concentrations of individual compound, thereby overcoming the limitations of reduced bioavailability. We therefore investigated whether a combination of three natural products arctigenin (Arc), a novel anti-inflammatory lignan from the seeds of Arctium lappa, green tea polyphenol (-)-epigallocatechin gallate (EGCG) and curcumin (Cur) increases the chemopreventive potency of individual compounds. LNCaP prostate cancer and MCF-7 breast cancer cells were treated with 2-4 mg/L (about 5-10μM) Cur, 1μM Arc and 40μM EGCG alone or in combination for 48h. In both cell lines treatment with the mixture of Cur, Arc and EGCG synergistically increased the antiproliferative effect. In LNCaP cells both Arc and EGCG increased the pro-apoptotic effect of Cur. Whereas in MCF-7 cells Arc increased the cell apoptosis of Cur while EGCG enhanced cell cycle arrest of Cur at G0/G1 phase. The strongest effects on cell cycle arrest and apoptosis were achieved by combining all three compounds in both cell lines. The combination treatment significantly increased the ratio of Bax to Bcl-2 proteins, decreased the activation of NFκB, PI3K/Akt and Stat3 pathways and cell migration compared to individual treatment. These results warrant in vivo studies to confirm the efficacy of this novel regimen by combining Arc and EGCG with Cur to enhance chemoprevention in both prostate and breast cancer. PMID:25243063

  13. Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/beta-catenin signaling.

    PubMed

    Roy, Hemant K; Kunte, Dhananjay P; Koetsier, Jennifer L; Hart, John; Kim, Young L; Liu, Yang; Bissonnette, Marc; Goldberg, Michael; Backman, Vadim; Wali, Ramesh K

    2006-08-01

    Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1-beta-catenin-mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because beta-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf)-TOPFLASH reporter assay to show that PEG markedly inhibited beta-catenin transcriptional activity. PEG did not alter total beta-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of beta-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect. PMID:16928827

  14. Evaluation of the chemopreventive response of naringenin-loaded nanoparticles in experimental oral carcinogenesis using laser-induced autofluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    Sulfikkarali, N. K.; Krishnakumar, N.

    2013-04-01

    The aim of the present study is to investigate the chemopreventive effects of prepared naringenin-loaded nanoparticles (NARNPs) relative to the efficacy of free naringenin (NAR) in modifying the carcinogenic process and to study the changes in the endogenous fluorophores during DMBA-induced hamster buccal pouch (HBP) carcinogenesis by laser-induced autofluorescence (LIAF) spectroscopy. LIAF emission spectra from the hamster buccal mucosa of the control and experimental groups of animals were recorded in the 350-700 nm spectral range on a miniature fiber optic spectrometer from different anatomical sites of each group, with excitation at 404 nm from a diode laser. Oral squamous cell carcinoma (OSCC) was developed in the buccal pouch of golden Syrian hamsters by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. DMBA-painted animals revealed morphological changes, hyperplasia, dysplasia and well-differentiated squamous cell carcinoma. LIAF emission spectra showed significant difference between the control and tumor tissues. The tumor tissues are characterized by an increase in the emission of porphyrins and a decrease in the emission of nicotinamide adenine dinucleotide hydrogenase (NADH) and flavin adenine nucleotide (FAD) when compared to the control tissues. Furthermore, oral administration of NAR and its nanoparticulates restored the status of endogenous fluorophores in the buccal mucosa of DMBA-painted animals. On a comparative basis, the treatment of nanoparticulate naringenin was found to be more effective than free naringenin in completely preventing the formation of squamous cell carcinoma and in improving the status of endogenous porphyrins to a normal range in DMBA-induced hamster buccal pouch carcinogenesis. The result of the present study further suggests that LIAF spectroscopy may be a very valuable tool for rapid and sensitive detection of endogenous fluorophore changes in response to chemopreventive agents.

  15. Chemopreventive and anti-leukemic effects of ethanol extracts of Moringa oleifera leaves on wistar rats bearing benzene induced leukemia.

    PubMed

    Akanni, E O; Adedeji, A L; Adedosu, O T; Olaniran, O I; Oloke, J K

    2014-01-01

    Pharmacological exploitation of natural compounds has continued to lead to development of non-synthetic and non-toxic anticancer agents that are promising at ameliorating the menace of neoplastic diseases such as leukemia. This study is an attempt to determine the chemopreventive and antileukemic activities of ethanol extracts of Moringa oleifera leaves on benzene induced leukemia bearing rats. Leukemia was induced by intravenous injection of 0.2 mL benzene solution 48 hourly for 4 weeks in appropriate rat groups. Ethanol extract of Moringa oleifera (EMO) leaves was administered at 0.2 mL of 100 mg/mL to respective treatment rat groups. A standard antileukemic drug (cyclophosphamide) was also used to treat appropriate rat groups. Clinical examination of liver and spleen with hematological parameters were employed to assess the leukemia burden following analysis of the rat blood samples on Sysmex KX-21N automated instrument. Leukemia induction reflected in severe anemia and a marked leukocytosis over the control/baseline group. Liver and spleen enlargements were also observed in group exposed to benzene carcinogen. The in vivo antioxidative potential of EMO was evaluated using Malondialdehyde (MDA) and reduced glutathione (GSH) levels. The liver MDA and GSH levels obtained in benzene induced leukemic rats treated with EMO compared favorably with those obtained in similar treatments with the standard drug (p< 0.05). The extract demonstrated chemopreventive and anti-leukemic activities as much as the standard anti-leukemic drug (p>0.05) by ameliorating the induced leukemic condition in the affected rat groups owing to its bioactive constituents. This study reveals that the extract might be an active, natural and non-toxic anticancer drug lead. PMID:25051949

  16. Increased chemopreventive effect by combining arctigenin, green tea polyphenol and curcumin in prostate and breast cancer cells

    PubMed Central

    Wang, Piwen; Wang, Bin; Chung, Seyung; Wu, Yanyuan; Henning, Susanne M.; Vadgama, Jaydutt V.

    2014-01-01

    The low bioavailability of most flavonoids limits their application as anti-carcinogenic agents in humans. A novel approach of treatment with a mixture of bioactive compounds that share molecular anti-carcinogenic targets may enhance the effect on these targets at low concentrations of individual compound, thereby overcoming the limitations of reduced bioavailability. We therefore investigated whether a combination of three natural products arctigenin (Arc), a novel anti-inflammatory lignan from the seeds of Arctium lappa, green tea polyphenol (−)-epigallocatechin gallate (EGCG) and curcumin (Cur) increases the chemopreventive potency of individual compounds. LNCaP prostate cancer and MCF-7 breast cancer cells were treated with 2–4 mg/L (about 5–10μM) Cur, 1μM Arc and 40μM EGCG alone or in combination for 48h. In both cell lines treatment with the mixture of Cur, Arc and EGCG synergistically increased the antiproliferative effect. In LNCaP cells both Arc and EGCG increased the pro-apoptotic effect of Cur. Whereas in MCF-7 cells Arc increased the cell apoptosis of Cur while EGCG enhanced cell cycle arrest of Cur at G0/G1 phase. The strongest effects on cell cycle arrest and apoptosis were achieved by combining all three compounds in both cell lines. The combination treatment significantly increased the ratio of Bax to Bcl-2 proteins, decreased the activation of NFκB, PI3K/Akt and Stat3 pathways and cell migration compared to individual treatment. These results warrant in vivo studies to confirm the efficacy of this novel regimen by combining Arc and EGCG with Cur to enhance chemoprevention in both prostate and breast cancer. PMID:25243063

  17. Sulforaphane-cysteine suppresses invasion via downregulation of galectin-1 in human prostate cancer DU145 and PC3 cells.

    PubMed

    Tian, Hua; Zhou, Yan; Yang, Gaoxiang; Geng, Yang; Wu, Sai; Hu, Yabin; Lin, Kai; Wu, Wei

    2016-09-01

    Our previous study showed that sulforaphane (SFN) inhibits invasion in human prostate cancer DU145 cells; however, the underlying mechanisms were not profoundly investigated. In the present study, we found that sulforaphane-cysteine (SFN-Cys), as a metabolite of SFN, inhibits invasion and possesses a novel mechanism in prostate cancer DU145 and PC3 cells. The scratch and Transwell assays showed that SFN-Cys (15 µM) inhibited both migration and invasion, with cell morphological changes, such as cell shrinkage and pseudopodia shortening. The cell proliferation (MTS) assay indicated that cell viability was markedly suppressed with increasing concentrations of SFN‑Cys. Furthermore, the Transwell assay showed that inhibition of SFN‑Cys‑triggered invasion was tightly linked to the sustained extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Western blot analysis revealed that SFN-Cys downregulated galectin-1 protein, an invasion‑related protein, and that the galectin‑1 reduction could be blocked by ERK1/2 inhibitor PD98059 (25 µM). Moreover, immunofluorescence staining showed that the expression level of galectin-1 protein was significantly reduced in the cells treated with SFN‑Cys. Hence, SFN‑Cys‑inhibited invasion resulted from the sustained ERK1/2 phosphorylation and ERK1/2‑triggered galectin-1 downregulation, suggesting that galectin-1 is a new SFN-Cys target inhibiting invasion apart from ERK1/2, in the treatment of prostate cancer. PMID:27430422

  18. Biotransformation of the chemopreventive agent 2',4',4-trihydroxychalcone (isoliquiritigenin) by UDP-glucuronosyltransferases.

    PubMed

    Guo, Jian; Liu, Ang; Cao, Hongmei; Luo, Yan; Pezzuto, John M; van Breemen, Richard B

    2008-10-01

    2',4',4-trihydroxychalcone (isoliquiritigenin), a chalcone found in licorice root and shallots, exhibits antioxidant, estrogenic, and antitumor activities. To complement our previous studies concerning the phase 1 metabolism of isoliquiritigenin, the phase 2 transformation of isoliquiritigenin by human hepatocytes and pooled human liver microsomes (HLMs) was investigated using liquid chromatography/tandem mass spectrometry and UV absorbance. Five glucuronides were detected corresponding to monoglucuronides of isoliquiritigenin and liquiritigenin, but no sulfate conjugates were observed. The UDP-glucuronosyltransferases (UGTs) involved in the formation of the major glucuronide conjugates were identified using recombinant human UGTs in combination with liquid chromatography/mass spectrometry. UGT1A1 and UGT1A9 were the major enzymes responsible for the formation of the most abundant conjugate, isoliquiritigenin 4'-O-glucuronide (MG5), with Km values of 4.30+/-0.47 and 3.15+/-0.24 microM, respectively. UGT1A1 and UGT1A10 converted isoliquiritigenin to the next most abundant phase 2 metabolite, isoliquiritigenin 2'-O-glucuronide (MG4), with Km values of 2.98+/-0.8 and 25.8+/-1.3 microM, respectively. In addition, isoliquiritigenin glucuronides MG4 and MG5 were formed by pooled human intestine and kidney microsomes, respectively. Based on the in vitro determination of a 25.3-min half-life for isoliquiritigenin when incubated with HLMs, the intrinsic clearance of isoliquiritigenin was estimated to be 36.4 ml/min/kg. These studies indicate that isoliquiritigenin will be conjugated rapidly in the liver to form up to five monoglucuronides. PMID:18653743

  19. Chemopreventive effect of apple and berry fruits against colon cancer

    PubMed Central

    Jaganathan, Saravana Kumar; Vellayappan, Muthu Vignesh; Narasimhan, Gayathri; Supriyanto, Eko; Octorina Dewi, Dyah Ekashanti; Narayanan, Aqilah Leela T; Balaji, Arunpandian; Subramanian, Aruna Priyadarshini; Yusof, Mustafa

    2014-01-01

    Colon cancer arises due to the conversion of precancerous polyps (benign) found in the inner lining of the colon. Prevention is better than cure, and this is very true with respect to colon cancer. Various epidemiologic studies have linked colorectal cancer with food intake. Apple and berry juices are widely consumed among various ethnicities because of their nutritious values. In this review article, chemopreventive effects of these fruit juices against colon cancer are discussed. Studies dealing with bioavailability, in vitro and in vivo effects of apple and berry juices are emphasized in this article. A thorough literature survey indicated that various phenolic phytochemicals present in these fruit juices have the innate potential to inhibit colon cancer cell lines. This review proposes the need for more preclinical evidence for the effects of fruit juices against different colon cancer cells, and also strives to facilitate clinical studies using these juices in humans in large trials. The conclusion of the review is that these apple and berry juices will be possible candidates in the campaign against colon cancer. PMID:25493015

  20. [Chemoprevention of esophageal squamous cell carcinoma--clinical trials].

    PubMed

    Szumiło, Justyna

    2008-09-01

    Esophageal squamous cell carcinoma is one of the most lethal malignances of digestive tract. Epidemiological data confirmed influence of the diet especially Mediterranean one that decreases the risk of cancer. High consumption of fresh vegetables and fruits, mainly citrus and tea drinking, also has a beneficial effect on decreasing incidence of the cancer. High intake of various antioxidants and natural fibers found in the plant diet as well as prolonged administration of cyclooxygenase-inhibitors, especially aspirin, plays also a protective role. Results of sparse, prospective, randomized trials on chemoprevention of esophageal squamous cell carcinoma are not so unequivocal. Supplementation of six traditional Chinese herbs, retinamide and riboflavin provided the most promising effects, but intake of multiple vitamins and minerals, including calcium and decaffeinated green tea, was ineffective. However, the studies were performed on small populations inhabiting select Chinese provinces known for their high esophageal cancer incidence. Due to a number of limitations, the collected data cannot be compared directly to other populations who are exposed to different environmental factors and with different genetic predispositions. PMID:19112850

  1. Crocus sativus L. (saffron) for cancer chemoprevention: A mini review

    PubMed Central

    Bhandari, Prasan R.

    2015-01-01

    Cancer is one of the most feared diseases globally and there has been a sustained rise in its incidence in both developing and developed countries. Despite the growing therapeutic options for patients with cancer, their efficacy is time-limited and non-curative. Hence to overcome these drawbacks, an incessant screening for superior and safer drugs has been ongoing for numerous decades, resulting in the detection of anti-cancer properties of several phytochemicals. Chemoprevention using readily available natural substances from vegetables, fruits, herbs and spices is one of the significantly important approaches for cancer prevention in the present era. Among the spices, Crocus sativus L. (saffron; 番紅花 fān hóng huā) has generated interest because pharmacological experiments have established numerous beneficial properties including radical scavenging, anti-mutagenic and immuno-modulating effects. The more powerful components of saffron are crocin, crocetin and safranal. Studies in animal models and with cultured human malignant cell lines have demonstrated antitumor and cancer preventive activities of saffron and its main ingredients. This review provides a brief insight into the anticancer properties of saffron and its components. PMID:26151016

  2. Cancer chemopreventive and therapeutic activities of red ginseng.

    PubMed

    Xiaoguang, C; Hongyan, L; Xiaohong, L; Zhaodi, F; Yan, L; Lihua, T; Rui, H

    1998-02-01

    Red ginseng extract A and B are the active components of Panax ginseng. Red ginseng is a classical traditional Chinese medicine. Among Chinese herbs, red ginseng has been considered as one of the tonics. Many studies indicated that red ginseng could enhance immune function of the human body. The effects of red ginseng extracts on transplantable tumors, proliferation of lymphocyte, two-stage model and rat liver lipid peroxidation were studied. In a two-stage model, red ginseng extracts had a significant cancer chemoprevention. At 50-400 mg/kg, they could inhibit DMBA/Croton oil-induced skin papilloma in mice, decrease the incidence of papilloma, prolong the latent period of tumor occurrence and reduce tumor number per mouse in a dose-dependent manner. Red ginseng extract B could effectively inhibit the Fe2+/cysteine-induced lipid peroxidation of rat liver microsome, suggesting that red ginseng extract B has a stronger antioxidative effect than that of extract A. The results indicated that red ginseng extracts (50 approximately 400 mg/kg) could significantly inhibit the growth of transplantable mouse sarcoma S180 and melanoma B16. Red ginseng extracts A (0.5 mg/ml) and B (0.1 and 0.25 mg/ml) might effectively promote the transformation of T lymphocyte, but there was no influence on lymphocyte proliferation stimulated by concanavalin A. This suggests that red ginseng extracts have potent tumor therapeutic activity and improve the cell immune system. PMID:9533434

  3. Spicing up a vegetarian diet: chemopreventive effects of phytochemicals.

    PubMed

    Lampe, Johanna W

    2003-09-01

    Thousands of chemical structures have been identified in plant foods. Many are found in spices. Typically, spices are the dried aromatic parts of plants-generally the seeds, berries, roots, pods, and sometimes leaves-that mainly, but not invariably, grow in hot countries. Given the wide range of botanical species and plant parts from which spices are derived, they can contribute significant variety and complexity to the human diet. In the past, the medicinal uses of spices and herbs were often indistinguishable from their culinary uses, and for good reason: people have recognized for centuries both the inherent value, as well as the potential toxicity, of phytochemicals in relation to human health. Plants have the capacity to synthesize a diverse array of chemicals, and understanding how phytochemicals function in plants may further our understanding of the mechanisms by which they benefit humans. In plants, these compounds function to attract beneficial and repel harmful organisms, serve as photoprotectants, and respond to environmental changes. In humans, they can have complementary and overlapping actions, including antioxidant effects, modulation of detoxification enzymes, stimulation of the immune system, reduction of inflammation, modulation of steroid metabolism, and antibacterial and antiviral effects. Embracing a cuisine rich in spice, as well as in fruit and vegetables, may further enhance the chemopreventive capacity of one's diet. PMID:12936952

  4. Chemopreventive effect of resveratrol, sesamol, sesame oil and sunflower oil in the Epstein-Barr virus early antigen activation assay and the mouse skin two-stage carcinogenesis.

    PubMed

    Kapadia, Govind J; Azuine, Magnus A; Tokuda, Harukuni; Takasaki, Midori; Mukainaka, Teruo; Konoshima, Takao; Nishino, Hoyoku

    2002-06-01

    Resveratrol, sesamol, sesame oil and sunflower oil are known natural dietary components with intrinsic cancer chemopreventive potentials. As a part of our study of dietary constituents as potential cancer chemopreventive agents, we have assessed the anti-cancer potentials of these products in the promotion stage of cancer development employing the in vitro Epstein-Barr virus early antigen activation assay induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, we studied the activities of these compounds in the brine shrimp cytotoxicity assay as well as on the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging bioassay with a view to comparing some of the mechanisms of their anti-cancer activity. Finally, we compared the observed chemoprotective capabilities of the four products in the in vivo 7,12 dimethylbenz(a)anthracene initiated and TPA-promoted mouse skin two-stage carcinogenesis protocols. All the products tested showed a profound inhibitory effect on the Epstein-Barr virus early antigen induction using Raji cells. Comparatively, sesame oil was the most potent followed by sesamol and then resveratrol. Only sesamol and resveratrol showed a remarkable cytotoxic activity in the brine shrimp lethality assays as well as profound free radical scavenging activity in the DPPH bioassay. In both test systems, sesamol exhibited a more remarkable activity than resveratrol while sesame oil and sunflower oil did not exhibit any appreciable activity even at the highest concentrations tested (4000 microg ml(-1) ). In our in vivo assay at a 50-fold molar ratio to TPA, sesamol offered 50% reduction in mouse skin papillomas at 20 weeks after promotion with TPA. Under an identical molar ratio to TPA, resveratrol offered a 60% reduction in the papillomas in mouse at 20 weeks. Thus sesamol seems to be an almost equally potent chemopreventive agent. Sesame oil and sunflower oil offered 20 and 40% protection, respectively, in the mouse

  5. The chemopreventive activity of the histone deacetylase inhibitor tributyrin in colon carcinogenesis involves the induction of apoptosis and reduction of DNA damage

    SciTech Connect

    Heidor, Renato; Furtado, Kelly Silva; Ortega, Juliana Festa; Oliveira, Tiago Franco de; Tavares, Paulo Eduardo Latorre Martins; Vieira, Alessandra; Miranda, Mayara Lilian Paulino; Purgatto, Eduardo; Moreno, Fernando Salvador

    2014-04-15

    The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis. The animals were treated with TB (TB group: 200 mg/100 g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300 mg/100 g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40 mg/kg b.w.) twice a week. After 9 weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p < 0.05) as well as the ACF with ≥ 4 crypts (p < 0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts. The TB group also showed a higher apoptotic index (p < 0.05) and reduced DNA damage (p < 0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p < 0.05). TB administration resulted in increased colonic tissue concentrations of BA (p < 0.05) compared with the control animals. These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those that were more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB. - Highlights: • Tributyrin is a chemopreventive agent for rat colon aberrant crypt foci. • Tributyrin increased apoptosis in an experimental rat colon carcinogenesis model. • Tributyrin treatment in a rat colon carcinogenesis model decreased DNA damage. • Tributyrin treatment induced H3K9 acetylation in a rat colon carcinogenesis model.

  6. Quantitative profiling of glucosinolates by LC-MS analysis reveals several cultivars of cabbage and kale as promising sources of sulforaphane.

    PubMed

    Sasaki, Katsunori; Neyazaki, Makiko; Shindo, Kazutoshi; Ogawa, Toshiya; Momose, Masaki

    2012-08-15

    Sulforaphane is an isothiocyanate well known for its potential health benefits. With the aim of finding sulforaphane supply sources, its precursor, glucoraphanin, was widely searched for among Brassica oleracea varieties. Quantitative profiling of seven glucosinolates by LC-MS analysis was performed on 6 cultivars of broccoli, 32 of cabbage and 24 cultivars of kale. The glucoraphanin levels found in three cultivars of cabbage and six cultivars of kale were comparable with, or even higher than, the highest of broccoli (119.4 mg/100g FW). The most promising group belonged to the black kale, Cavolo nero. Use of a C30 column and an ammonium formate buffer in LC-MS and a micro plate solid phase extraction technique was highly effective. PMID:22857862

  7. Polyethylene glycol-mediated colorectal cancer chemoprevention: roles of epidermal growth factor receptor and Snail.

    PubMed

    Wali, Ramesh K; Kunte, Dhananjay P; Koetsier, Jennifer L; Bissonnette, Marc; Roy, Hemant K

    2008-09-01

    Polyethylene glycol (PEG) is a clinically widely used agent with profound chemopreventive properties in experimental colon carcinogenesis. We reported previously that Snail/beta-catenin signaling may mediate the suppression of epithelial proliferation by PEG, although the upstream events remain unclear. We report herein the role of epidermal growth factor receptor (EGFR), a known mediator of Snail and overexpressed in approximately 80% of human colorectal cancers, on PEG-mediated antiproliferative and hence antineoplastic effects in azoxymethane (AOM) rats and HT-29 colon cancer cells. AOM rats were randomized to either standard diet or one with 10% PEG-3350 and euthanized 8 weeks later. The colonic samples were subjected to immunohistochemical or Western blot analyses. PEG decreased mucosal EGFR by 60% (P < 0.001). Similar PEG effects were obtained in HT-29 cells. PEG suppressed EGFR protein via lysosmal degradation with no change in mRNA levels. To show that EGFR antagonism per se was responsible for the antiproliferative effect, we inhibited EGFR by either pretreating cells with gefitinib or stably transfecting with EGFR-short hairpin RNA and measured the effect of PEG on proliferation. In either case, PEG effect was blunted, suggesting a vital role of EGFR. Flow cytometric analysis revealed that EGFR-short hairpin RNA cells, besides having reduced membrane EGFR, also expressed low Snail levels (40%), corroborating a strong association. Furthermore, in EGFR silenced cells, PEG effect on EGFR or Snail was muted, similar to that on proliferation. In conclusion, we show that EGFR is the proximate membrane signaling molecule through which PEG initiates antiproliferative activity with Snail/beta-catenin pathway playing the central intermediary function. PMID:18790788

  8. Cancer chemopreventive activities of S-3-1, a synthetic derivative of danshinone.

    PubMed

    Chen, X G; Li, Y; Yan, C H; Li, L N; Han, R

    2001-01-01

    Salvia miltiorrhiza is a traditional Chinese medicine which has been well documented for its anti-cancer effects. Based on the structure of danshinone, one of the active compounds derived from Salvia miltiorrhiza, we synthesized a simplified phenolic analog, S-3-1, and tried to explore its possible actions in preventing the development of cancer. With the Ames test, S-3-1 was found to efficiently suppress the mutagenicity of benzo[alpha]pyrene. This result is consistent with the inhibitory effect of S-3-1 on the activation of benzo[alpha]pyrene by hepatic microsomal enzymes. Besides the anti-initiation effects, S-3-1 could significantly inhibit the croton oil-induced increase of mouse skin epithermal ornithine decarboxylase activity. Moreover, S-3-1 quenched both superoxide and hydroxyl free radicals whereas it inhibited lipid peroxidation in the in vitro model. These results suggest that S-3-1 might act as anti-initiation and anti-promotion agents through reversing the biochemical alterations induced by carcinogen during carcinogenesis. Therefore, we further investigated the effects of S-3-1 on carcinogenesis. In vitro, S-3-1 inhibited the benzo[alpha]pyrene-induced transformation of V79 Chinese hamster lung fibroblasts. At 10-40 mg/kg, S-3-1 was found to inhibit the development of DMBA/croton oil-induced skin papilloma in mice through decreasing the incidence of papilloma, prolonging the latent period of tumor occurrence and reducing tumor number per mouse in a dose-dependent manner. We concluded from this study that S-3-1 might be developed as a new chemopreventive drug. PMID:11355772

  9. Dietary factors and cancer chemoprevention: an overview of obesity-related malignancies.

    PubMed

    Murthy, N S; Mukherjee, S; Ray, G; Ray, A

    2009-01-01

    Obesity is a growing health problem in developed nations and in countries that are in the process of westernization like India. Obesity is linked with several health disorders such as hypertension and cardiovascular diseases, Type 2 diabetes, dyslipidemia and certain cancers. Currently, obesity-related malignancies, e.g., cancers of the breast, prostate and colon are the leading cancers in the industrialized societies. An increased amount of fat or adipose tissue in an overweight or obese person probably influences the development of cancer by releasing several hormone-like factors or adipokines. The majority of adipokines are pro-inflammatory, which promote pathological conditions like insulin resistance and cancer. On the other hand, many recent studies have shown that adiponectin, an anti-inflammatory adipokine, has anti-cancer and insulin-sensitizing effects. Adiponectin exerts its physiological functions chiefly by activation of AMP kinase via adiponectin receptors. Interestingly, several fruits and vegetables may contain adiponectin-like molecules or may increase the biosynthesis of adiponectin in our body. Studies on adiponectin analogues or adiponectin receptor agonists are a promising area of cancer chemoprevention research. In general, fruits and vegetables contain various dietary substances such as vitamins, minerals (like calcium and selenium), fiber and phytochemicals or phenolic compounds (like flavonoids and vanilloids), which may act as anti-cancer agents. Similarly, several dietary constituents including phytochemicals may have anti-obesity effects. Consumption of such dietary compounds along with caloric restriction and physical activity may be helpful in preventing obesity-related cancers. For this review article, we searched PubMed primarily to get the relevant literature. PMID:19242081

  10. In vitro and In vivo Studies on Stilbene Analogs as Potential Treatment Agents for Colon Cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Based upon the potential of resveratrol as a cancer chemopreventive agent, 27 stilbenes analogs were synthesized and tested against colon cancer cell line HT-29. Among these compounds, amino derivative (Z)-4-(3,5-dimethoxystyryl) aniline (4), (Z)-methyl 4-(3,5-dimethoxystyryl) benzoate (6) and (Z)-1...

  11. Sulforaphane-rich broccoli sprout extract improves hepatic abnormalities in male subjects

    PubMed Central

    Kikuchi, Masahiro; Ushida, Yusuke; Shiozawa, Hirokazu; Umeda, Rumiko; Tsuruya, Kota; Aoki, Yudai; Suganuma, Hiroyuki; Nishizaki, Yasuhiro

    2015-01-01

    AIM: To evaluate effects of dietary supplementation of sulforaphane (SF)-rich broccoli sprout (BS) extract on hepatic abnormalities in Japanese male participants. METHODS: In a randomized, placebo-controlled, double blind trial, male participants with fatty liver received either BS capsules containing glucoraphanin [GR; a precursor of SF (n = 24)] or placebo (n = 28) for 2 mo. Liver function markers, serum levels of aspartate and alanine aminotransferases (AST and ALT, respectively) and γ-glutamyl transpeptidase (γ-GTP) and an oxidative stress marker, urinary levels of 8-hydroxydeoxyguanosine (8-OHdG), were measured and compared in participants before and after the trial period. In an animal model, chronic liver failure was induced in Sprague-Dawley rats by successive intraperitoneal injection with N-nitrosodimethylamine (NDMA) for 4 wk. Concomitantly, rats received AIN-76 diets supplemented with or without BS extract. Thereafter, rats were sacrificed, and their sera and livers were collected to measure serum liver function markers and hepatic levels of thiobarbituric acid reactive substances (TBARS) levels and hepatic glutathione S-transferase (GST) activity, a prototypical phase 2 antioxidant enzyme. RESULTS: Dietary supplementation with BS extract containing SF precursor GR for 2 mo significantly decreased serum levels of liver function markers, ALT [median (interquartile range), before: 54.0 (34.5-79.0) vs after supplementation: 48.5 (33.3-65.3) IU/L, P < 0.05] and γ-GTP [before: 51.5 (40.8-91.3) vs after: 50.0 (37.8-85.3) IU/L, P < 0.05], as well as the alkali phosphatase activity. Placebo showed no significant effects on the markers. The urinary level of 8-OHdG, an established oxidative stress marker, was significantly reduced in participants who had received BS capsules but not the placebo [before: 6.66 (5.51-9.03) vs after: 5.49 (4.89-6.66) ng/mg-creatinine, P < 0.05]. The reduction of urinary 8-OHdG was significantly correlated with decreased levels of

  12. Cost-effectiveness of prostate cancer chemoprevention among high-risk men.

    PubMed

    Zeliadt, Steven B; Ramsey, Scott D

    2010-10-01

    EVALUATION OF: Earnshaw SR, McDade CL, Black LK, Bell CF, Kattan MW. Cost effectiveness of 5-α reductase inhibitors for the prevention of prostate cancer in multiple patient populations. Pharmacoeconomics 28(6), 489-505 (2010). Chemoprevention with 5-α reductase inhibitors (5ARIs) has been shown in clinical trials to reduce the incidence of prostate cancer. Although avoiding or delaying a diagnosis of prostate cancer through chemoprevention is attractive, it is unknown whether 5ARI chemoprevention reduces the number of prostate cancer deaths. Prior cost-effectiveness studies have found the adoption of 5ARIs in the general population to not be cost effective owing to the high costs of 5ARIs and multiple years of treatment required before gains are realized. The current study examines the cost-effectiveness of 5ARIs for men with multiple risk factors, including an elevated prostate-specific antigen and a prior negative biopsy. The analysis consistently observes under multiple assumptions that chemoprevention in the subgroup of high-risk men is cost effective and represents a good value for money, while chemoprevention among men from the general population appears to not be cost effective. PMID:20950065

  13. Chemopreventive effect of resveratrol and apocynin on pancreatic carcinogenesis via modulation of nuclear phosphorylated GSK3β and ERK1/2

    PubMed Central

    Kato, Akihisa; Naiki-Ito, Aya; Nakazawa, Takahiro; Hayashi, Kazuki; Naitoh, Itaru; Miyabe, Katsuyuki; Shimizu, Shuya; Kondo, Hiromu; Nishi, Yuji; Yoshida, Michihiro; Umemura, Shuichiro; Hori, Yasuki; Mori, Toshio; Tsutsumi, Masahiro; Kuno, Toshiya; Suzuki, Shugo; Kato, Hiroyuki; Ohara, Hirotaka; Joh, Takashi; Takahashi, Satoru

    2015-01-01

    Despite progress in clinical cancer medicine in multiple fields, the prognosis of pancreatic cancer has remained dismal. Recently, chemopreventive strategies using phytochemicals have gained considerable attention as an alternative in the management of cancer. The present study aimed to evaluate the chemopreventive effects of resveratrol (RV) and apocynin (AC) in N-Nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamster. RV- and AC-treated hamsters showed significant reduction in the incidence of pancreatic cancer with a decrease in Ki-67 labeling index in dysplastic lesions. RV and AC suppressed cell proliferation of human and hamster pancreatic cancer cells by inhibiting the G1 phase of the cell cycle with cyclin D1 downregulation and inactivation of AKT-GSK3β and ERK1/2 signaling. Further, decreased levels of GSK3βSer9 and ERK1/2 phosphorylation and cyclin D1 expression in the nuclear fraction were observed in cells treated with RV or AC. Nuclear expression of phosphorylated GSK3βSer9 was also decreased in dysplastic lesions and adenocarcinomas of hamsters treated with RV or AC in vivo. These results suggest that RV and AC reduce phosphorylated GSK3βSer9 and ERK1/2 in the nucleus, resulting in inhibition of the AKT-GSK3β and ERK1/2 signaling pathways and cell cycle arrest in vitro and in vivo. Taken together, the present study indicates that RV and AC have potential as chemopreventive agents for pancreatic cancer. PMID:26556864

  14. Chemopreventive effects of diverse dietary phytochemicals against DMBA-induced hamster buccal pouch carcinogenesis via the induction of Nrf2-mediated cytoprotective antioxidant, detoxification, and DNA repair enzymes.

    PubMed

    Kavitha, K; Thiyagarajan, P; Rathna Nandhini, J; Mishra, Rajakishore; Nagini, S

    2013-08-01

    Identifying agents that activate nuclear factor erythroid-2 related factor-2 (Nrf2), a key regulator of various cytoprotective antioxidant, and detoxifying enzymes has evolved as a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary supplementation of structurally diverse phytochemicals- astaxanthin, blueberry, chlorophyllin, ellagic acid, and theaphenon-E on Nrf2 signaling, and xenobiotic-metabolizing and antioxidant enzymes in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model. We observed that these phytochemicals induce nuclear accumulation of Nrf2 while downregulating its negative regulator, Keap-1. This was associated with reduced expression of CYP1A1 and CYP1B1, the cytochrome P450 isoforms involved in the activation of DMBA, and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine coupled with upregulation of the phase II detoxification enzymes glutathione S-transferases and NAD(P)H:quinone oxidoreductase 1 and the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. In addition, these dietary phytochemicals also enhanced the DNA repair enzymes 8-oxoguanine glycosylase 1 (OGG1), xeroderma pigmentosum D (XPD), xeroderma pigmentosum G (XPG), and x-ray repair cross complementing group 1 (XRCC1). Our data provide substantial evidence that the dietary phytochemicals inhibit the development of HBP carcinomas through the activation of Nrf2/Keap-1 signaling and by upregulating cytoprotective enzymes. The extent of the chemopreventive effects of the phytochemicals was in the order: chlorophyllin > blueberry > ellagic acid > astaxanthin > theaphenon-E. Thus these dietary phytochemicals that function as potent activators of Nrf2 and its orchestrated response are novel candidates for cancer chemoprevention. PMID:23707664

  15. Microbiome and potential targets for chemoprevention of esophageal adenocarcinoma.

    PubMed

    Neto, Antonio Galvao; Whitaker, April; Pei, Zhiheng

    2016-02-01

    Esophageal cancer is one of the deadliest cancers, with a dismal prognosis. It is increasingly recognized that esophageal cancer is a heterogeneous disease. It can be subdivided into two distinct groups: squamous cell carcinoma and adenocarcinoma, based on histological appearance. In the Western world, the incidence of squamous cell carcinoma was considerably higher than esophageal adenocarcinoma (EA) until the 1990s when, due to a dramatic increase, the incidence of EA surpassed that of squamous cell carcinoma. EA typically follows a well-established stepwise evolution from chronic inflammation due to reflux esophagitis (RE) that progresses to metaplasia (Barrett's esophagus [BE]) to dysplasia, which often culminates in EA. The pathophysiology of EA is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms. The current understanding of the etiology of EA is mainly derived from epidemiological studies of risk factors such as cigarette smoking, obesity, gastroesophageal reflux disorders (GERD), and low fruit and vegetable consumption. Numerous studies have been done, but the factors that drive the dynamic increase in the incidence of EA remain elusive. The advent of widespread antibiotic use occurred in the 1950s, preceding the surge of EA. Based on this temporal sequence, it has been hypothesized that antibiotics alter the microbiome to which the esophagus is exposed in patients who have GERD and that chronic exposure to this abnormal microbiome (ie, changes in species diversity or abundance) accounts for the increase in EA. If changes in the proposed factors alter the stepwise progression (RE-BE-dysplasia-EA), they may represent potential targets for chemoprevention. New discoveries will help improve our understanding of the biology and pathogenesis of these cancers, and aid in finding novel therapeutic

  16. Chemopreventive and Anticancer Activities of Allium victorialis var. platyphyllum Extracts

    PubMed Central

    Kim, Hyun-Jeong; Park, Min Jeong; Park, Hee-Juhn; Chung, Won-Yoon; Kim, Ki-Rim; Park, Kwang-Kyun

    2014-01-01

    Background: Allium victorialis var. platyphyllum is an edible perennial herb and has been used as a vegetable or as a Korean traditional medicine. Allium species have received much attention owing to their diverse pharmacological properties, including antioxidative, anti-inflammatory, and anticancer activities. However, A. victorialis var. platyphyllum needs more study. Methods: The chemopreventive potential of A. victorialis var. platyphyllum methanol extracts was examined by measuring 12-O-tetra-decanoylphorbol 13-acetate (TPA)-induced superoxide anion production in the differentiated HL-60 cells, TPA-induced mouse ear edema, and Ames/Salmonella mutagenicity. The apoptosis-inducing capabilities of the extracts were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, 4’,6-diamidino-2-phenylindole staining, and the DNA fragmentation assay in human colon cancer HT-29 cells. Antimetastatic activities of the extracts were also investigated in an experimental mouse lung metastasis model. Results: The methanol extracts of A. victorialis var. platyphyllum rhizome (AVP-R) and A. victorialis var. platyphyllum stem (AVP-S) dose-dependently inhibited the TPA-induced generation of superoxide anion in HL-60 cells and TPA-induced ear edema in mice, as well as 7,12-dimethylbenz[a]anthracene (DMBA) and tert-butyl hydroperoxide (t-BOOH) -induced bacterial mutagenesis. AVP-R and AVP-S reduced cell viability in a dose-related manner and induced apoptotic morphological changes and internucleosomal DNA fragmentation in HT-29 cells. In the experimental mouse lung metastasis model, the formation of tumor nodules in lung tissue was significantly inhibited by the treatment of the extracts. Conclusions: AVP-R and AVP-S possess antioxidative, anti-inflammatory, antimutagenic, proapoptotic, and antimetastatic activities. Therefore, these extracts can serve as a beneficial supplement for the prevention and treatment of cancer. PMID:25337587

  17. Investigation of the chemopreventive potential of neem leaf subfractions in the hamster buccal pouch model and phytochemical characterization.

    PubMed

    Manikandan, Palrasu; Ramalingam, Senthil Murugan; Vinothini, Govindarajah; Ramamurthi, Vidya Priyadarsini; Singh, Inder Pal; Anandan, Rangasamy; Gopalakrishnan, Mannathusamy; Nagini, Siddavaram

    2012-10-01

    Chemoprevention by medicinal plants has evolved as a practical strategy to control the incidence of cancer. Azadirachta indica (neem) containing various bioactive components is a promising candidate for chemoprevention. The present study was undertaken to evaluate the chemopreventive efficacy of the bioactive subfractions ethyl acetate chloroform insoluble fraction (ECIF) and the methanol ethyl acetate insoluble fraction (MEIF) following activity-guided fractionation of neem leaf extract. Analysis of the mechanism of chemoprevention revealed multitargeted mode of action that involved modulation of xenobiotic-metabolizing enzymes, inhibition of cell proliferation, induction of mitochondrial apoptosis, and abrogation of NF-κB signaling. HP-TLC, GC-MS and LC-MS analyses indicated the presence of several polar phytochemical entities in the neem leaf subfractions that might be responsible for their potent chemopreventive efficacy. PMID:22939101

  18. Dietary flavonoids as cancer prevention agents.

    PubMed

    Yao, Hua; Xu, Weizheng; Shi, Xianglin; Zhang, Zhuo

    2011-01-01

    Dietary agents identified from fruits and vegetables contribute to keeping balanced cell proliferation and preventing cell carcinogenesis. Dietary flavonoids, combined with other components such as various vitamins, play an important role in cancer prevention. Flavonoids act on reactive oxygen species, cell signal transduction pathways related to cellular proliferation, apoptosis, and angiogenesis. Many studies demonstrate that flavonoids are responsible for chemoprevention, although mechanisms of action remain to be investigated. Overall, exciting data show that dietary flavonoids could be considered as a useful cancer preventive approach. This review summarizes recent advancements on potential cancer preventive effects and mechanic insight of dietary flavonoids. PMID:21424974

  19. Effect of gallic acid on xenobiotic metabolizing enzymes in 1,2-dimethyl hydrazine induced colon carcinogenesis in Wistar rats--a chemopreventive approach.

    PubMed

    Giftson Senapathy, J; Jayanthi, S; Viswanathan, P; Umadevi, P; Nalini, N

    2011-04-01

    Colon cancer risk may be influenced by phase I and II xenobiotic-metabolizing enzyme systems. The chemopreventive agent gallic acid (GA), a plant polyphenol, is found in various natural products. Our aim was to evaluate the potential role of GA on drug-metabolizing enzymes in 1,2-dimethyl hydrazine (DMH) induced rat colon carcinogenesis. The total experimental duration was 30 weeks. The effect of GA (50 mg/kg b.w.) on the activities of phase I enzymes (cytochrome P450 and cytochrome b5) and phase II enzymes (glutathione S-transferase, DT-diaphorase and gamma glutamyl transpeptidase) were assessed in the liver and colonic mucosa and the colons were also examined visually. In DMH induced rats, there was a decrease in the activities of phase II enzymes and an increase in the activities of phase I enzymes. On GA supplementation, there was a significant increase in the activities of phase II enzymes and a significant decrease in the activities of phase I enzymes, in addition to the decreased tumor incidence. Histopathological changes also confirm this. Thus, the marked potential of GA in modulating the phase I and II xenobiotic-metabolizing enzymes suggests that GA may have a major impact on colon cancer chemoprevention. PMID:21172399

  20. Ferrocene incorporated selenoureas as anticancer agents.

    PubMed

    Hussain, Raja Azadar; Badshah, Amin; Pezzuto, John M; Ahmed, Nadeem; Kondratyuk, Tamara P; Park, Eun-Jung

    2015-07-01

    For a compound to be a best chemopreventive agent it should be a descent DNA binder and at the same time should be active against any of the three stages of carcinogenesis i.e. cancer initiation, cancer propagation and tumor growth. Most of the problems associated with chemotherapy can be overcome if the chemopreventive agent is active against all the three stages of cancer development. Cancer may be initiated by higher concentration of free radicals, inflammating agents and phase I enzymes (Cytochrome P450) in the body. Cancer propagation can be very efficiently controlled by inducing the phase II enzymes (glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases) in the body and cancer termination depends on the killing of the faulty cells i.e. cytotoxic actions. This article reports comprehensively the comparative DNA binding studies (with, cyclic voltammetry, UV-vis spectroscopy and viscometry), antioxidant activities (DPPH scavenging), anti-inflammatory activities (nitrite inhibition), phase I enzyme inhibition activities (aromatase inhibition), phase II enzyme induction studies (quinone reductase induction) and cytotoxic studies against neuroblastoma (MYCN2 and SK-N-SH), liver cancer (Hepa 1c1c7) and breast cancer (MCF-7) of seventeen ferrocene incorporated selenoureas. PMID:25966308

  1. Comparative effectiveness of chemopreventive interventions for colorectal cancer: protocol for a systematic review and network meta-analysis of randomised controlled trials

    PubMed Central

    Veettil, Sajesh K.; Saokaew, Surasak; Lim, Kean Ghee; Ching, Siew Mooi; Phisalprapa, Pochamana

    2016-01-01

    Background Colorectal cancer (CRC) is the third most common cancer worldwide and is associated with substantial socioeconomic burden. Despite considerable research, including numerous randomised controlled trials (RCTs) and systematic reviews assessed the effect of various chemopreventive interventions for CRC, there remains uncertainty regarding the comparative effectiveness of these agents. No network meta-analytic study has been published to evaluate the efficacies of these agents for CRC. Therefore, the aim of this study is to summarise the direct and indirect evidence for these interventions to prevent CRC in average-high risk individuals, and to rank these agents for practical consideration. Methods We will acquire eligible studies through a systematic search of MEDLINE, EMBASE, the Cochrane Central Registry of Controlled Trials, CINAHL plus, IPA and clinicaltrials.gov website. The Cochrane Risk of Bias Tool will be used to assess the quality of included studies. The primary outcomes are the incidence of CRC, the incidence/recurrence of any adenoma or change in polyp burden (number or size). Quantitative synthesis or meta-analysis will be considered. We will also construct a network meta-analysis (NMA) to improve precision of the comparisons among chemo-preventive interventions by combining direct and indirect evidence. The probability of each treatment being the best and/or safest, the number-needed-to-treat [NNT; 95% credible interval (CrIs)], and the number-needed-to-harm (NNH; 95% CrIs) will be calculated to provide measures of treatment efficacy. The GRADE approach will be used to rate the quality of evidence of estimates derived from NMA. Results This protocol has been registered (registration number: CRD42015025849) with the PROSPERO (International Prospective Register of Systematic Reviews). The procedures of this systematic review and NMA will be conducted in accordance with the PRISMA-compliant guideline. The results of this systematic review and

  2. Chemoprevention of intestinal tumorigenesis by nabumetone: induction of apoptosis and Bcl-2 downregulation.

    PubMed

    Roy, H K; Karoski, W J; Ratashak, A; Smyrk, T C

    2001-05-18

    Treatment of MIN mice with the nonsteroidal anti-inflammatory drug, nabumetone, resulted in a dose-dependent suppression of intestinal tumorigenesis. In both the uninvolved MIN mouse colonic epithelium and HT-29 colon cancer cells, nabumetone downregulated the anti-apoptotic protein, Bcl-2, with concomitant induction of apoptosis, suggesting a potential mechanism for colon cancer chemoprevention. PMID:11355956

  3. Disruption of androgen and estrogen receptor activity in prostate cancer by a novel dietary diterpene carnosol: implications for chemoprevention

    PubMed Central

    Johnson, Jeremy J.; Syed, Deeba N.; Suh, Yewseok; Heren, Chenelle R.; Saleem, Mohammad; Siddiqui, Imtiaz A.; Mukhtar, Hasan

    2010-01-01

    Emerging data is suggesting that estrogens, in addition to androgens, may also be contributing to the development of prostate cancer (PCa). In view of this notion agents that target estrogens, in addition to androgens, may be a novel approach for PCa chemoprevention and treatment. Thus, the identification and development of non-toxic dietary agents capable of disrupting androgen receptor (AR) in addition to estrogen receptor (ER) could be extremely useful in the management of PCa. Through molecular modeling we found carnosol, a dietary diterpene fits within the ligand binding domain of both AR and ER-α. Using a TR-FRET assay we found that carnosol interacts with both AR and ER-α and additional experiments confirmed that it functions as a receptor antagonist with no agonist effects. LNCaP, 22Rv1, and MCF7 cells treated with carnosol (20–40 µM) showed decreased protein expression of AR and ER-α. Oral administration of carnosol at 30 mg/kg five days weekly for 28 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 36% (p = 0.028) and was associated with a decrease in serum PSA by 26% (p=0.0042). These properties make carnosol unique to any known anti-androgen or anti-estrogen investigated so far for the simultaneous disruption of AR and ER-α. We suggest that carnosol may be developed or chemically modified through more rigorous structure activity relationship studies for a new class of investigational agents - a dual AR/ER modulator. PMID:20736335

  4. Sulforaphane mitigates muscle fibrosis in mdx mice via Nrf2-mediated inhibition of TGF-β/Smad signaling.

    PubMed

    Sun, Chengcao; Li, Shujun; Li, Dejia

    2016-02-15

    Sulforaphane (SFN), an activator of NF-E2-related factor 2 (Nrf2), has been found to have an antifibrotic effect on liver and lung. However, its effects on dystrophic muscle fibrosis remain unknown. This work was undertaken to evaluate the effects of SFN-mediated activation of Nrf2 on dystrophic muscle fibrosis. Male mdx mice (age 3 mo) were treated with SFN by gavage (2 mg/kg body wt per day) for 3 mo. Experimental results demonstrated that SFN remarkably attenuated skeletal and cardiac muscle fibrosis as indicated by reduced Sirius Red staining and immunostaining of the extracellular matrix. Moreover, SFN significantly inhibited the transforming growth factor-β (TGF-β)/Smad signaling pathway and suppressed profibrogenic gene and protein expressions such as those of α-smooth muscle actin (α-SMA), fibronectin, collagen I, plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor metalloproteinase-1 (TIMP-1) in an Nrf2-dependent manner. Furthermore, SFN significantly decreased the expression of inflammatory cytokines CD45, TNF-α, and IL-6 in mdx mice. In conclusion, these results show that SFN can attenuate dystrophic muscle fibrosis by Nrf2-mediated inhibition of the TGF-β/Smad signaling pathway, which indicates that Nrf2 may represent a new target for dystrophic muscle fibrosis. PMID:26494449

  5. Modulation of Arachidonic Acid Metabolism in the Rat Kidney by Sulforaphane: Implications for Regulation of Blood Pressure

    PubMed Central

    2014-01-01

    Background. We investigated the effects of sulforaphane (SF), the main active isothiocyanate in cruciferous vegetables, on arachidonic acid (AA) metabolism in the kidney and its effect on arterial blood pressure, using spontaneously hypertensive rats (SHR) as models. Methods. Rats were treated for 8 weeks with either drinking water alone (control) or SF (20 or 40 mg/kg) added to drinking water. Mean arterial pressure (MAP) was measured at 7-day intervals throughout the study. At the end of treatment rats were euthanized, and kidneys were harvested to prepare microsomes and measure enzymes involved in regulation of vasoactive metabolites: CYP4A, the key enzyme in the formation of 20-hydroxyeicosatetraenoic acid, and the soluble epoxide hydrolase, which is responsible for the degradation of the vasodilator metabolites such as epoxyeicosatetraenoic acids. Effect of SF on kidney expression of CYP4A was investigated by immunoblotting. Results. We found that treatment with SF leads to significant reductions in both, the expression and activity of renal CYP4A isozymes, as well as the activity of soluble epoxide hydrolase (sEH). Consistent with these data, we have found that treatment with SF resisted the progressive rise in MAP in the developing SHR in a dose-dependent manner. Conclusion. This is the first demonstration that SF modulates the metabolism of AA by both P450 enzymes and sEH in SHR rats. This may represent a novel mechanism by which SF protects SHR rats against the progressive rise in blood pressure. PMID:24734194

  6. Modulation of arachidonic Acid metabolism in the rat kidney by sulforaphane: implications for regulation of blood pressure.

    PubMed

    Elbarbry, Fawzy; Vermehren-Schmaedick, Anke; Balkowiec, Agnieszka

    2014-01-01

    Background. We investigated the effects of sulforaphane (SF), the main active isothiocyanate in cruciferous vegetables, on arachidonic acid (AA) metabolism in the kidney and its effect on arterial blood pressure, using spontaneously hypertensive rats (SHR) as models. Methods. Rats were treated for 8 weeks with either drinking water alone (control) or SF (20 or 40 mg/kg) added to drinking water. Mean arterial pressure (MAP) was measured at 7-day intervals throughout the study. At the end of treatment rats were euthanized, and kidneys were harvested to prepare microsomes and measure enzymes involved in regulation of vasoactive metabolites: CYP4A, the key enzyme in the formation of 20-hydroxyeicosatetraenoic acid, and the soluble epoxide hydrolase, which is responsible for the degradation of the vasodilator metabolites such as epoxyeicosatetraenoic acids. Effect of SF on kidney expression of CYP4A was investigated by immunoblotting. Results. We found that treatment with SF leads to significant reductions in both, the expression and activity of renal CYP4A isozymes, as well as the activity of soluble epoxide hydrolase (sEH). Consistent with these data, we have found that treatment with SF resisted the progressive rise in MAP in the developing SHR in a dose-dependent manner. Conclusion. This is the first demonstration that SF modulates the metabolism of AA by both P450 enzymes and sEH in SHR rats. This may represent a novel mechanism by which SF protects SHR rats against the progressive rise in blood pressure. PMID:24734194

  7. Sulforaphane induces DNA damage and mitotic abnormalities in human osteosarcoma MG-63 cells: correlation with cell cycle arrest and apoptosis.

    PubMed

    Ferreira de Oliveira, José Miguel P; Remédios, Catarina; Oliveira, Helena; Pinto, Pedro; Pinho, Francisco; Pinho, Sónia; Costa, Maria; Santos, Conceição

    2014-01-01

    Osteosarcoma is a recalcitrant bone malignancy with poor responsiveness to treatments; therefore, new chemotherapeutic compounds are needed. Sulforaphane (SFN) has been considered a promising chemotherapeutic compound for several types of tumors by inducing apoptosis and cytostasis, but its effects (e.g., genotoxicity) in osteosarcoma cells remains exploratory. In this work, the MG-63 osteosarcoma cell line was exposed to SFN up to 20 μM for 24 and 48 h. SFN induced G2/M phase arrest and decreased nuclear division index, associated with disruption of cytoskeletal organization. Noteworthy, SFN induced a transcriptome response supportive of G2/M phase arrest, namely a decrease in Chk1- and Cdc25C-encoding transcripts, and an increase in Cdk1-encoding transcripts. After 48-h exposure, SFN at a dietary concentration (5 μM) contributed to genomic instability in the MG-63 cells as confirmed by increased number of DNA breaks, clastogenicity, and nuclear and mitotic abnormalities. The increased formation of nucleoplasmic bridges, micronuclei, and apoptotic cells positively correlated with loss of viability. These results suggest that genotoxic damage is an important step for SFN-induced cytotoxicity in MG-63 cells. In conclusion, SFN shows potential to induce genotoxic damage at low concentrations and such potential deserves further investigation in other tumor cell types. PMID:24405297

  8. Sulforaphane ameliorates the insulin responsiveness and the lipid profile but does not alter the antioxidant response in diabetic rats.

    PubMed

    de Souza, Carolina Guerini; da Motta, Leonardo Lisbôa; de Assis, Adriano Martimbianco; Rech, Anderson; Bruch, Ricardo; Klamt, Fábio; Souza, Diogo Onofre

    2016-04-20

    Diabetes is one of the most prevalent chronic non-communicable diseases and is characterized by hyperglycemia and increased oxidative stress. These two alterations are also responsible for the main diabetic complications: cardiovascular disease, retinopathy, nephropathy and peripheral neuropathy. Diabetes progression is governed by pancreatic β-cell failure, and recent studies showed that sulforaphane (SFN) might be able to prevent this change, preserving insulin production. Consequently, our goal was to test the effects of SFN on metabolic parameters related to diabetic complications and antioxidant defenses (superoxide dismutase, catalase and sulfhydryl groups) in the pancreas, liver and kidney of non-diabetic and diabetic rats. Male Wistar rats were treated with water or 0.5 mg kg(-1) SFN i.p. for 21 days after diabetes induction. In diabetic animals treated with SFN, the serum levels of total cholesterol, non-HDL cholesterol and triacylglycerols were similar to those of non-diabetic animals, and the insulin responsiveness was higher than that of the diabetic animals that did not receive the compound. No effect of SFN on the superoxide dismutase and catalase activity or sulfhydryl groups was observed in the pancreas, liver or kidney of the treated animals. We conclude that SFN ameliorates some features of clinical diabetic complications particularly the lipid profile and insulin responsiveness, but it does not modulate the antioxidant response induced by superoxide dismutase, catalase and sulfhydryl groups in the evaluated organs. PMID:27025193

  9. Sulforaphane protects against cytokine- and streptozotocin-induced {beta}-cell damage by suppressing the NF-{kappa}B pathway

    SciTech Connect

    Song, Mi-Young; Kim, Eun-Kyung; Moon, Woo-Sung; Park, Jin-Woo; Kim, Hyung-Jin; So, Hong-Seob; Park, Raekil; Kwon, Kang-Beom Park, Byung-Hyun

    2009-02-15

    Sulforaphane (SFN) is an indirect antioxidant that protects animal tissues from chemical or biological insults by stimulating the expression of several NF-E2-related factor-2 (Nrf2)-regulated phase 2 enzymes. Treatment of RINm5F insulinoma cells with SFN increases Nrf2 nuclear translocation and expression of phase 2 enzymes. In this study, we investigated whether the activation of Nrf2 by SFN treatment or ectopic overexpression of Nrf2 inhibited cytokine-induced {beta}-cell damage. Treatment of RIN cells with IL-1{beta} and IFN-{gamma} induced {beta}-cell damage through a NF-{kappa}B-dependent signaling pathway. Activation of Nrf2 by treatment with SFN and induction of Nrf2 overexpression by transfection with Nrf2 prevented cytokine toxicity. The mechanism by which Nrf2 activation inhibited NF-{kappa}B-dependent cell death signals appeared to involve the reduction of oxidative stress, as demonstrated by the inhibition of cytokine-induced H{sub 2}O{sub 2} production. The protective effect of SFN was further demonstrated by the restoration of normal insulin secreting responses to glucose in cytokine-treated rat pancreatic islets. Furthermore, pretreatment with SFN blocked the development of type 1 diabetes in streptozotocin-treated mice.

  10. Sulforaphane induces CYP1A1 mRNA, protein, and catalytic activity levels via an AhR-dependent pathway in murine hepatoma Hepa 1c1c7 and human HepG2 cells.

    PubMed

    Anwar-Mohamed, Anwar; El-Kadi, Ayman O S

    2009-03-01

    Recent reports have proposed that some naturally occurring phytochemicals can function as anticancer agents mainly through inducing phase II drug detoxification enzymes. Of these phytochemicals, isothiocyanates sulforaphane (SUL), present in broccoli, is by far the most extensively studied. In spite of its positive effect on phase II drug metabolizing enzymes, its effect on the phase I bioactivating enzyme cytochrome P450 1a1 (Cyp1a1) is still a matter of debate. As a first step to investigate this effect, Hepa 1c1c7 and HepG2 cells were treated with various concentration of SUL. Our results showed that SUL-induced CYP1A1 mRNA in a dose- and time-dependent manner. Furthermore, this induction was further reflected on the protein and catalytic activity levels. Investigating the effect of SUL at the transcriptional level revealed that SUL increases the Cyp1a1 mRNA as early as 1h. The RNA polymerase inhibitor actinomycin D (Act-D) completely abolished the SUL-induced Cyp1a1 mRNA. Furthermore, SUL successfully activated AhR transformation and its subsequent binding to the XRE. At the post-transcriptional level, SUL did not affect the levels of existing Cyp1a1 mRNA transcripts. This is the first demonstration that the broccoli-derived SUL can directly induce Cyp1a1 gene expression in an AhR-dependent manner and represents a novel mechanism by which SUL induces this enzyme. PMID:19013013

  11. The chemopreventive action of equol enantiomers in a chemically induced animal model of breast cancer

    PubMed Central

    Brown, Nadine M.; Belles, Carrie A.; Lindley, Stephanie L.; Zimmer-Nechemias, Linda D.; Zhao, Xueheng; Witte, David P.; Kim, Mi-Ok; Setchell, Kenneth D.R.

    2010-01-01

    We describe for the first time the chemopreventive effects of S-(−)equol and R-(+)equol, diastereoisomers with contrasting affinities for estrogen receptors (ERs). S-(−)equol, a ligand for ERβ, is an intestinally derived metabolite formed by many humans and by rodents consuming diets containing soy isoflavones. Whether the well-documented chemopreventive effect of a soy diet could be explained by equol's action was unclear because neither diastereoisomers had been tested in animal models of chemoprevention. Sprague–Dawley rats (n = 40–41 per group) were fed a soy-free AIN-93G diet or an AIN-93G diet supplemented with 250 mg/kg of S-(−)equol or R-(+)equol beginning day 35. On day 50, mammary tumors were induced by dimethylbenz[a]anthracene and thereafter, animals were palpated for number and location of tumors. On day 190, animals were killed and mammary tumors were removed and verified by histology, and the degree of invasiveness and differentiation was determined. S-(−)equol and R-(+)equol plasma concentrations measured on days 35, 100 and 190 by tandem mass spectrometry confirmed diet compliance and no biotransformation of either diastereoisomer. In this model, S-(−)equol had no chemopreventive action, nor was it stimulatory. In contrast, R-(+)equol compared with Controls reduced palpable tumors (P = 0.002), resulted in 43% fewer tumors (P = 0.004), increased tumor latency (88.5 versus 66 days, P = 0.003), and tumors were less invasive but showed no difference in pattern grade or mitosis. Both enantiomers had no effect on absolute uterine weight but caused a significant reduction in body weight gain. In conclusion, the novel finding that the unnatural enantiomer, R-(+)equol, was potently chemopreventive warrants investigation of its potential for breast cancer prevention and treatment. PMID:20110282

  12. Familial adenomatous polyposis in pediatrics: natural history, emerging surveillance and management protocols, chemopreventive strategies, and areas of ongoing debate.

    PubMed

    Septer, Seth; Lawson, Caitlin E; Anant, Shrikant; Attard, Thomas

    2016-07-01

    Familial adenomatous polyposis (FAP) is a hereditary condition with a near 100 % lifetime risk of colorectal cancer without prophylactic colectomy. Most patients with FAP have a mutation in the adenomatous polyposis coli gene on chromosome 5q22. This condition frequently presents in children with polyps developing most frequently in the second decade of life and surveillance colonoscopy is required starting at age ten. Polyps are found not only in the colon, but in the stomach and duodenum. Knowledge of the natural history of FAP is important as there are several extra-colonic sequelae which also require surveillance. In infants and toddlers, there is an increased risk of hepatoblastoma, while in teenagers and adults duodenal carcinomas, desmoid tumors, thyroid cancer and medulloblastoma are more common in FAP than in the general population. Current chemopreventive strategies include several medications and natural products, although to this point there is no consensus on the most efficacious and safe agent. Genetic counseling is an important part of the diagnostic process for FAP. Appropriate use and interpretation of genetic testing is best accomplished with genetic counselor involvement as many families also have concerns regarding future insurability or discrimination when faced with genetic testing. PMID:27056662

  13. Chemopreventive action of non-steroidal anti-inflammatory drugs on the inflammatory pathways in colon cancer.

    PubMed

    Ghanghas, Preety; Jain, Shelly; Rana, Chandan; Sanyal, S N

    2016-03-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development by cellular proliferation and by promoting apoptosis. Inflammation is principal cause of colon carcinogenesis. A missing link between inflammation and cancer could be the activation of NF-κB, which is a hallmark of inflammatory response, and is commonly detected in malignant tumors. Therefore, targeting pro-inflammatory cyclooxygenase enzymes and transcription factors will be profitable as a mechanism to inhibit tumor growth. In the present study, we have studied the role of various pro-inflammatory enzymes and transcription factors in the development of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer and also observed the role of three NSAIDs, viz., Celecoxib, Etoricoxib and Diclofenac. Carcinogenic changes were observed in morphological and histopathological studies, whereas protein regulations of various biomolecules were identified by immunofluorescence analysis. Apoptotic studies was done by TUNEL assay and Hoechst/PI co-staining of the isolated colonocytes. It was found that DMH-treated animals were having an over-expression of pro-inflammatory enzymes, aberrant nuclear localization of activated cell survival transcription factor, NF-κB and suppression of anti-inflammatory transcription factor PPAR-γ, thereby suggesting a marked role of inflammation in the tumor progression. However, co-administration of NSAIDs has significantly reduced the inflammatory potential of the growing neoplasm. PMID:26898448

  14. Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605)

    PubMed Central

    Pietrofesa, Ralph A.; Velalopoulou, Anastasia; Albelda, Steven M.; Christofidou-Solomidou, Melpo

    2016-01-01

    The interaction of asbestos fibers with macrophages generates harmful reactive oxygen species (ROS) and subsequent oxidative cell damage that are key processes linked to malignancy. Secoisolariciresinol diglucoside (SDG) is a non-toxic, flaxseed-derived pluripotent compound that has antioxidant properties and may thus function as a chemopreventive agent for asbestos-induced mesothelioma. We thus evaluated synthetic SDG (LGM2605) in asbestos-exposed, elicited murine peritoneal macrophages as an in vitro model of tissue phagocytic response to the presence of asbestos in the pleural space. Murine peritoneal macrophages (MFs) were exposed to crocidolite asbestos fibers (20 µg/cm2) and evaluated at various times post exposure for cytotoxicity, ROS generation, malondialdehyde (MDA), and levels of 8-iso Prostaglandin F2α (8-isoP). We then evaluated the ability of LGM2605 to mitigate asbestos-induced oxidative stress by administering LGM2605 (50 µM) 4-h prior to asbestos exposure. We observed a significant (p < 0.0001), time-dependent increase in asbestos-induced cytotoxicity, ROS generation, and the release of MDA and 8-iso Prostaglandin F2α, markers of lipid peroxidation, which increased linearly over time. LGM2605 treatment significantly (p < 0.0001) reduced asbestos-induced cytotoxicity and ROS generation, while decreasing levels of MDA and 8-isoP by 71%–88% and 41%–73%, respectively. Importantly, exposure to asbestos fibers induced cell protective defenses, such as cellular Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1 that were further enhanced by LGM2605 treatment. LGM2605 boosted antioxidant defenses, as well as reduced asbestos-induced ROS generation and markers of oxidative stress in murine peritoneal macrophages, supporting its possible use as a chemoprevention agent in the development of asbestos-induced malignant mesothelioma. PMID:26938529

  15. Agent Orange

    MedlinePlus

    ... Index Agent Orange Agent Orange Home Facts about Herbicides Veterans' Diseases Birth Defects Benefits Exposure Locations Provider ... millions of gallons of Agent Orange and other herbicides on trees and vegetation during the Vietnam War. ...

  16. Pancreatic Cancer Chemoprevention Translational Workshop | Division of Cancer Prevention

    Cancer.gov

    Thursday, September 10th (6:00 to 9:30 PM) Welcome Barnett Kramer, MD, MPH (6:00 to 6:10 PM) Director of the Division of Cancer Prevention, NCI Introduction – Goals of the Workshop: ABCs of Cancer Prevention (Agents, Biomarkers, Cohorts) Mark Miller, PhD (6:10 to 6:25 PM) Program Director Division of Cancer Prevention, NCI |

  17. Correction: Chemopreventive activity of ellagitannins and their derivatives from black raspberry seeds on HT-29 colon cancer cells.

    PubMed

    Cho, Hyunnho; Jung, Hana; Lee, Heejae; Yi, Hae Chang; Kwak, Ho-Kyung; Hwang, Keum Taek

    2015-08-01

    Correction for 'Chemopreventive activity of ellagitannins and their derivatives from black raspberry seeds on HT-29 colon cancer cells' by Hyunnho Cho et al., Food Funct., 2015, 6, 1675-1683. PMID:26211477

  18. Suppression of protein kinase C and nuclear oncogene expression as possible action mechanisms of cancer chemoprevention by Curcumin.

    PubMed

    Lin, Jen-Kun

    2004-07-01

    Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)kappaB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans. PMID:15356994

  19. Sulforaphane inhibits de novo synthesis of IL-8 and MCP-1 in human epithelial cells generated by cigarette smoke extract.

    PubMed

    Starrett, Warren; Blake, David J

    2011-06-01

    Chronic obstructive pulmonary disease (COPD) is currently the fifth leading cause of death worldwide. Exposure to cigarette smoke (CS) is the primary factor associated with the COPD development. CS activates epithelial cells to secrete chemokines such as interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) that recruit neutrophils and macrophages to the lung. These inflammatory cells then release additional chemokines and cytokines leading to chronic inflammation that initiates apoptosis in epithelial and endothelial cells and destruction of alveolar structure. Pulmonary epithelium responds to oxidative stress mediated by CS through activating NRF2-dependent pathways, leading to an increased expression of antioxidant and cytoprotective enzymes thereby providing a protective response against CS-induced lung injury. We hypothesized that activating NRF2-dependent cytoprotective gene expression with sulforaphane (SFN) affords protection against CS-induced lung damage by inhibiting chemokine production. Results indicate that in the human BEAS-2B epithelial cell line, 5 μM SFN activated NRF2-dependent gene expression by triggering the translocation of NRF2 to the nucleus and significantly increased the expression of NRF2-dependent genes such as NADPH quinone oxidoreductase-1, heme oxygenase-1, and glutamate cysteine ligase modulatory subunit. Cigarette smoke extract (CSE) exposure of BEAS-2B cells significantly increased production of both IL-8 and MCP-1. Production of both chemokines was significantly reduced with SFN given prior to CSE; SFN inhibited IL-8 and MCP-1 gene expression at the transcription level. Our results indicate that activating NRF2 pathways with SFN inhibits CSE-induced chemokine production in human epithelial cells. However, the mechanism by which the production of chemokines is inhibited through SFN still remains to be elucidated. SFN may enhance NRF2 transcriptional activity resulting in the inhibition of proinflammatory pathways such

  20. Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane.

    PubMed

    Saw, Constance L; Huang, Mou-Tuan; Liu, Yue; Khor, Tin Oo; Conney, Allan H; Kong, Ah-Ng

    2011-06-01

    Ultraviolet (UV) of sunlight is a complete carcinogen that can burn skin, enhance inflammation, and drive skin carcinogenesis. Previously, we have shown that sulforaphane (SFN) inhibited chemically induced skin carcinogenesis via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and others have shown that broccoli sprout extracts containing high SFN protected against UV-induced skin carcinogenesis in SKH-1 hairless mice. A recent study showed that there was no difference between Nrf2 knockout (Nrf2 KO) and Nrf2 wild-type (WT) BALB/C mice after exposing to high dose of UVB. Since Nrf2 plays critical roles in the anti-oxidative stress/anti-inflammatory responses, it is relevant to assess the role of Nrf2 for photoprotection against UV. In this context, the role of Nrf2 in UVB-induced skin inflammation in Nrf2 WT and Nrf2 KO C57BL/6 mice was studied. A single dose of UVB (300 mJ/cm(2)) resulted in skin inflammation in both WT and Nrf2 KO (-/-) mice (KO mice) at 8 h and 8 d following UVB irradiation. In the WT mice inflammation returned to the basal level to a greater extent when compared to the KO mice. SFN treatment of Nrf2 WT but not Nrf2 KO mice restored the number of sunburn cells back to their basal level by 8 d after UVB irradiation. Additionally, UVB-induced short-term inflammatory biomarkers (interleukin-1β and interleukin-6) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT. Taken together, our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation, sunburn reaction, and SFN-mediated photoprotective effects in the skin. PMID:21557329

  1. Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression.

    PubMed

    Lan, Fengming; Yang, Yang; Han, Jing; Wu, Qiaoli; Yu, Huiming; Yue, Xiao

    2016-02-01

    The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN. PMID:26648123

  2. Bioavailability and biotransformation of sulforaphane and erucin metabolites in different biological matrices determined by LC-MS-MS.

    PubMed

    Platz, Stefanie; Piberger, Ann Liza; Budnowski, Julia; Herz, Corinna; Schreiner, Monika; Blaut, Michael; Hartwig, Andrea; Lamy, Evelyn; Hanske, Laura; Rohn, Sascha

    2015-03-01

    The food-related isothiocyanate sulforaphane (SFN), a hydrolysis product of the secondary plant metabolite glucoraphanin, has been revealed to have cancer-preventive activity in experimental animals. However, these studies have often provided inconsistent results with regard to bioavailability, bioaccessibility, and outcome. This might be because the endogenous biotransformation of SFN metabolites to the structurally related erucin (ERN) metabolites has often not been taken into account. In this work, a fully validated liquid chromatography tandem mass spectrometry (LC-MS-MS) method was developed for the simultaneous determination of SFN and ERN metabolites in a variety of biological matrices. To reveal the importance of the biotransformation pathway, matrices including plasma, urine, liver, and kidney samples from mice and cell lysates derived from colon-cancer cell lines were included in this study. The LC-MS-MS method provides limits of detection from 1 nmol L(-1) to 25 nmol L(-1) and a mean recovery of 99 %. The intra and interday imprecision values are in the range 1-10 % and 2-13 %, respectively. Using LC-MS-MS, SFN and ERN metabolites were quantified in different matrices. The assay was successfully used to determine the biotransformation in all biological samples mentioned above. For a comprehensive analysis and evaluation of the potential health effects of SFN, it is necessary to consider all metabolites, including those formed by biotransformation of SFN to ERN and vice versa. Therefore, a sensitive and robust LC-MS-MS method was validated for the simultaneous quantification of mercapturic-acid-pathway metabolites of SFN and ERN. PMID:25650001

  3. Differential modulation of dibenzo[def,p]chrysene transplacental carcinogenesis: Maternal diets rich in indole-3-carbinol versus sulforaphane

    SciTech Connect

    Shorey, Lyndsey E.; Madeen, Erin P.; Atwell, Lauren L.; Ho, Emily; Löhr, Christiane V.; Pereira, Clifford B.; Dashwood, Roderick H.; Williams, David E.

    2013-07-01

    Cruciferous vegetable components have been documented to exhibit anticancer properties. Targets of action span multiple mechanisms deregulated during cancer progression, ranging from altered carcinogen metabolism to the restoration of epigenetic machinery. Furthermore, the developing fetus is highly susceptible to changes in nutritional status and to environmental toxicants. Thus, we have exploited a mouse model of transplacental carcinogenesis to assess the impact of maternal dietary supplementation on cancer risk in offspring. In this study, transplacental and lactational exposure to a maternal dose of 15 mg/Kg B.W. of dibenzo[def,p]chrysene (DBC) resulted in significant morbidity of offspring due to an aggressive T-cell lymphoblastic lymphoma. As in previous studies, indole-3-carbinol (I3C, feed to the dam at 100, 500 or 1000 ppm), derived from cruciferous vegetables, dose-dependently reduced lung tumor multiplicity and also increased offspring survival. Brussels sprout and broccoli sprout powders, selected for their relative abundance of I3C and the bioactive component sulforaphane (SFN), respectively, surprisingly enhanced DBC-induced morbidity and tumorigenesis when incorporated into the maternal diet at 10% wt/wt. Purified SFN, incorporated in the maternal diet at 400 ppm, also decreased the latency of DBC-dependent morbidity. Interestingly, I3C abrogated the effect of SFN when the two purified compounds were administered in equimolar combination (500 ppm I3C and 600 ppm SFN). SFN metabolites measured in the plasma of neonates positively correlated with exposure levels via the maternal diet but not with offspring mortality. These findings provide justification for further study of the safety and bioactivity of cruciferous vegetable phytochemicals at supplemental concentrations during the perinatal period. - Highlights: • Dietary supplementation may modulate cancer risk in a mouse model of lymphoma. • Cruciferous vegetables may not contain sufficient I3C

  4. Sulforaphane Ameliorates Bladder Dysfunction through Activation of the Nrf2-ARE Pathway in a Rat Model of Partial Bladder Outlet Obstruction

    PubMed Central

    Liu, Chong; Xu, Huan; Fu, Shi; Chen, Yanbo; Chen, Qi; Cai, Zhikang; Zhou, Juan; Wang, Zhong

    2016-01-01

    Purpose. We evaluated the effect of sulforaphane (SFN) treatment on the function and changes of expression of Nrf2-ARE pathway in the bladder of rats with bladder outlet obstruction (BOO). Materials and Methods. A total of 18 male Sprague-Dawley rats at age of 8 weeks were divided into 3 groups (6 of each): the sham operated group, the BOO group, and the BOO+SFN group. We examined histological alterations and the changes of oxidative stress markers and the protein expression of the Nrf2-ARE pathway. Results. We found that SFN treatment could prolong micturition interval and increase bladder capacity and bladder compliance. However, the peak voiding pressure was lower than BOO group. SFN treatment can ameliorate the increase of collagen fibers induced by obstruction. SFN treatment also increased the activity of SOD, GSH-Px, and CAT compared to the other groups. The level of bladder cell apoptosis was decreased in BOO rats with SFN treatment. Moreover, SFN could reduce the ratio of Bax/Bcl-2 expression. Furthermore, SFN could activate the Nrf2 expression with elevation of its target antioxidant proteins. Conclusions. The sulforaphane-mediated decrease of oxidative stress and activation of the Nrf2-ARE pathway may ameliorate bladder dysfunction caused by bladder outlet obstruction. PMID:27433291

  5. Sulforaphane Ameliorates Bladder Dysfunction through Activation of the Nrf2-ARE Pathway in a Rat Model of Partial Bladder Outlet Obstruction.

    PubMed

    Liu, Chong; Xu, Huan; Fu, Shi; Chen, Yanbo; Chen, Qi; Cai, Zhikang; Zhou, Juan; Wang, Zhong

    2016-01-01

    Purpose. We evaluated the effect of sulforaphane (SFN) treatment on the function and changes of expression of Nrf2-ARE pathway in the bladder of rats with bladder outlet obstruction (BOO). Materials and Methods. A total of 18 male Sprague-Dawley rats at age of 8 weeks were divided into 3 groups (6 of each): the sham operated group, the BOO group, and the BOO+SFN group. We examined histological alterations and the changes of oxidative stress markers and the protein expression of the Nrf2-ARE pathway. Results. We found that SFN treatment could prolong micturition interval and increase bladder capacity and bladder compliance. However, the peak voiding pressure was lower than BOO group. SFN treatment can ameliorate the increase of collagen fibers induced by obstruction. SFN treatment also increased the activity of SOD, GSH-Px, and CAT compared to the other groups. The level of bladder cell apoptosis was decreased in BOO rats with SFN treatment. Moreover, SFN could reduce the ratio of Bax/Bcl-2 expression. Furthermore, SFN could activate the Nrf2 expression with elevation of its target antioxidant proteins. Conclusions. The sulforaphane-mediated decrease of oxidative stress and activation of the Nrf2-ARE pathway may ameliorate bladder dysfunction caused by bladder outlet obstruction. PMID:27433291

  6. Molecular mechanisms underlying chemopreventive potential of curcumin: Current challenges and future perspectives.

    PubMed

    Kumar, Gaurav; Mittal, Sonam; Sak, Katrin; Tuli, Hardeep Singh

    2016-03-01

    In recent years, natural compounds have received considerable attention in preventing and curing most dreadful diseases including cancer. The reason behind the use of natural compounds in chemoprevention is associated with fewer numbers of side effects than conventional chemotherapeutics. Curcumin (diferuloylmethane, PubMed CID: 969516), a naturally occurring polyphenol, is derived from turmeric, which is used as a common Indian spice. It governs numerous intracellular targets, including proteins involved in antioxidant response, immune response, apoptosis, cell cycle regulation and tumor progression. A huge mass of available studies strongly supports the use of Curcumin as a chemopreventive drug. However, the main challenge encountered is the low bioavailability of Curcumin. This extensive review covers various therapeutic interactions of Curcumin with its recognized cellular targets involved in cancer treatment, strategies to overcome the bioavailability issue and adverse effects associated with Curcumin consumption. PMID:26876915

  7. Chemopreventive properties of 3,3'-diindolylmethane in breast cancer: evidence from experimental and human studies.

    PubMed

    Thomson, Cynthia A; Ho, Emily; Strom, Meghan B

    2016-07-01

    Diet is a modifiable factor associated with the risk of several cancers, with convincing evidence showing a link between diet and breast cancer. The role of bioactive compounds of food origin, including those found in cruciferous vegetables, is an active area of research in cancer chemoprevention. This review focuses on 3,3'-diindolylmethane (DIM), the major bioactive indole in crucifers. Research of the cancer-preventive activity of DIM has yielded basic mechanistic, animal, and human trial data. Further, this body of evidence is largely supported by observational studies. Bioactive DIM has demonstrated chemopreventive activity in all stages of breast cancer carcinogenesis. This review describes current evidence related to the metabolism and mechanisms of DIM involved in the prevention of breast cancer. Importantly, this review also focuses on current evidence from human observational and intervention trials that have contributed to a greater understanding of exposure estimates that will inform recommendations for DIM intake. PMID:27261275

  8. Combination chemoprevention of hamster buccal pouch carcinogenesis by bovine milk lactoferrin and black tea polyphenols.

    PubMed

    Mohan, K V P Chandra; Letchoumy, P Vidjaya; Hara, Y; Nagini, S

    2008-03-01

    Combination chemoprevention is a promising approach for oral cancer prevention. The authors evaluated the combined chemopreventive effects of bovine milk lactoferrin (bLF) and black tea polyphenols (Polyphenon-B) in a clinically relevant in vivo model of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Although dietary administration of bLF and Polyphenon-B alone significantly reduced the tumor incidence, combined administration of bLF and polyphenon-B was more effective in inhibiting DMBA-induced genotoxicity and development of HBP carcinomas by modulation of carcinogen-metabolizing enzymes and cellular redox status. These results suggest that a "designer item" approach will be useful for human oral cancer prevention strategies. PMID:18259952

  9. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer.

    PubMed

    Aviello, Gabriella; Romano, Barbara; Borrelli, Francesca; Capasso, Raffaele; Gallo, Laura; Piscitelli, Fabiana; Di Marzo, Vincenzo; Izzo, Angelo A

    2012-08-01

    Colon cancer affects millions of individuals in Western countries. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. Thus, we investigated its possible chemopreventive effect in the model of colon cancer induced by azoxymethane (AOM) in mice. AOM treatment was associated with aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation, up-regulation of phospho-Akt, iNOS and COX-2 and down-regulation of caspase-3. Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARγ-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms. PMID:22231745

  10. Chronic unpredictable stress deteriorates the chemopreventive efficacy of pomegranate through oxidative stress pathway.

    PubMed

    Hasan, Shirin; Suhail, Nida; Bilal, Nayeem; Ashraf, Ghulam Md; Zaidi, Syed Kashif; AlNohair, Sultan; Banu, Naheed

    2016-05-01

    Chronic unpredictable stress (CUS) can influence the risk and progression of cancer through increased oxidative stress. Pomegranate is known to protect carcinogenesis through its anti-oxidative properties. This study is carried out to examine whether CUS affects the chemopreventive potential of pomegranate through oxidative stress pathway. Role of CUS on early stages of 7, 12 dimethyl benz(a) anthracene (DMBA) induced carcinogenesis, and its pre-exposure effect on chemopreventive efficacy of pomegranate juice (PJ) was examined in terms of in vivo antioxidant and biochemical parameters in Swiss albino rats. Rats were divided in various groups and were subjected to CUS paradigm, DMBA administration (65 mg/kg body weight, single dose), and PJ treatment. Exposure to stress (alone) and DMBA (alone) led to increased oxidative stress by significantly decreasing the antioxidant enzymes activities and altering the glutathione (GSH), malondialdehyde (MDA), glutamate oxaloacetate transaminase (GOT), and glutamate pyruvate transaminase (GPT) levels. A significant increase in DNA damage demonstrated by comet assay was seen in the liver cells. Stress exposure to DMBA-treated rats further increased the oxidative stress and disturbed the biochemical parameters as compared to DMBA (alone)-treated rats. Chemoprevention with PJ in DMBA (alone)-treated rats restored the altered parameters. However, in the pre-stress DMBA-treated rats, the overall antioxidant potential of PJ was significantly diminished. Our results indicate that chronic stress not only increases the severity of carcinogenesis but also diminishes the anti-oxidative efficacy of PJ. In a broader perspective, special emphasis should be given to stress management and healthy diet during cancer chemoprevention. PMID:26596837

  11. Histone deacetylase inhibitor sulforaphane: The phytochemical with vibrant activity against prostate cancer.

    PubMed

    Ganai, Shabir Ahmad

    2016-07-01

    Epigenetic modifications are closely involved in the patho-physiology of prostate cancer. Histone deacetylases (HDACs), the transcriptional corepressors have strong crosstalk with prostate cancer progression as they influence various genes related to tumour suppression. HDACs play a marked role in myriad of human cancers and as such are emerging as striking molecular targets for anticancer drugs and therapy. Histone deacetylase inhibitors (HDACi), the small-molecules interfering HDACs are emerging as promising chemotherapeutic agents. These inhibitors have shown multiple effects including cell growth arrest, differentiation and apoptosis in prostate cancer. The limited efficacy of HDACi as single agents in anticancer therapy has been strongly improved via novel therapeutic strategies like doublet therapy (combined therapy). More than 20HDACi have already entered into the journey of clinical trials and four have been approved by FDA against diverse cancers. This review deals with plant derived HDACi sulphoraphane (SFN; 1-isothiocyanato-4-(methylsulfinyl)-butane) and its potential role in prostate cancer therapy along with the underlying molecular mechanism being involved. The article further highlights the therapeutic strategy that can be utilized for sensitizing conventional therapy resistant cases and for acquiring the maximum therapeutic benefit from this promising inhibitor in the upcoming future. PMID:27261601

  12. Colon Cancer Chemoprevention by Sage Tea Drinking: Decreased DNA Damage and Cell Proliferation.

    PubMed

    Pedro, Dalila F N; Ramos, Alice A; Lima, Cristovao F; Baltazar, Fatima; Pereira-Wilson, Cristina

    2016-02-01

    Salvia officinalis and some of its isolated compounds have been found to be preventive of DNA damage and increased proliferation in vitro in colon cells. In the present study, we used the azoxymethane model to test effects of S. officinalis on colon cancer prevention in vivo. The results showed that sage treatment reduced the number of ACF formed only if administered before azoxymethane injection, demonstrating that sage tea drinking has a chemopreventive effect on colorectal cancer. A decrease in the proliferation marker Ki67 and in H2 O2 -induced and azoxymethane-induced DNA damage to colonocytes and lymphocytes were found with sage treatment. This confirms in vivo the chemopreventive effects of S. officinalis. Taken together, our results show that sage treatment prevented initiation phases of colon carcinogenesis, an effect due, at least in part, to DNA protection, and reduced proliferation rates of colon epithelial cell that prevent mutations and their fixation through cell replication. These chemopreventive effects of S. officinalis on colon cancer add to the many health benefits attributed to sage and encourage its consumption. PMID:26661587

  13. Comprehensive Review on Betulin as a Potent Anticancer Agent

    PubMed Central

    Kiełbus, Michał; Stepulak, Andrzej

    2015-01-01

    Numerous plant-derived substances, and their derivatives, are effective antitumour and chemopreventive agents. Yet, there are also a plethora of tumour types that do not respond, or become resistant, to these natural substances. This requires the discovery of new active compounds. Betulin (BE) is a pentacyclic triterpene and secondary metabolite of plants abundantly found in the outer bark of the birch tree Betulaceae sp. BE displays a broad spectrum of biological and pharmacological properties, among which the anticancer and chemopreventive activity attract most of the attention. In this vein, BE and its natural and synthetic derivatives act specifically on cancer cells with low cytotoxicity towards normal cells. Although the antineoplastic mechanism of action of BE is not well understood yet, several interesting aspects of BE's interactions are coming to light. This review will summarize the anticancer and chemopreventive potential of BE in vitro and in vivo by carefully dissecting and comparing the doses and tumour lines used in previous studies, as well as focusing on mechanisms underlying its activity at cellular and molecular level, and discuss future prospects. PMID:25866796

  14. Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study

    PubMed Central

    Sambol, Nancy C.; Tappero, Jordan W.; Arinaitwe, Emmanuel; Parikh, Sunil

    2016-01-01

    Background The combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children. Methods Based on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1–2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose). Results Once daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention. Conclusions Once weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field

  15. Dietary Agents in Cancer Prevention: An Immunological Perspective †

    PubMed Central

    Zheng, Ya Ying; Viswanathan, Bharathi; Kesarwani, Pravin; Mehrotra, Shikhar

    2013-01-01

    Skin cancer is the most common form of cancer diagnosed in the United States. Exposure to solar ultraviolet (UV) radiations is believed to be the primary cause for skin cancer. Excessive UV radiation can lead to genetic mutations and damage in the skin's cellular DNA that in turn can lead to skin cancer. Lately, chemoprevention by administering naturally occurring non-toxic dietary compounds has proven to be a potential strategy to prevent the occurrence of tumors. Attention has been drawn towards several natural dietary agents such as resveratrol, one of the major components found in grapes, red wines, berries and peanuts, proanthocyanidins from grape seeds, (-)-epigallocatechin-3-gallate (EGCG) from green tea etc. However, the effect these dietary agents have on the immune system and the immunological mechanisms involved there in are still being explored. In this review we shall focus on the role of key chemopreventive agents on various immune cells and discuss their potential as anti-tumor agents with an immunological perspective. PMID:22372381

  16. Nutri-epigenetics and synthetic analogs in cancer chemoprevention.

    PubMed

    Flabouraris, Gerassimos; Karikas, George Albert

    2016-01-01

    Nutri-epigenetics has lately emerged as a new field in cancer epigenetic research. Cancer represents a multistage and heterogeneous disease that is driven by progressive genetic and epigenetic abnormalities. Epigenetic activity is influenced by several exogenous and endogenous factors including, nutrition, environment, disease, ethnicity, life style, medication, toxins, physical activity, age, gender and family genetics. Epigenetic therapy including mainly natural phenolics is a new area for drug development in cancer prevention. The current generation of epigenetic synthetic analogs are primarily target to inhibit the activity and expression of methyltransferases and histone deacetylases. Epigenetic mechanisms underlying nutrition seem very important tools nowadays in further understanding human health in general. New targeted natural and synthetic agents, along with the application of modern genomic methods, could substantially offer more specific armamentarium towards the prevention and therapy of cancer. The present short review demonstrates a selection of natural and recent synthetic chemopreventing compounds, in relation to their epigenetic mechanisms and current/future uses/limitations in therapeutics. PMID:27061524

  17. Effects of chemopreventive natural products on non-homologous end-joining DNA double-strand break repair.

    PubMed

    Charles, Catherine; Nachtergael, Amandine; Ouedraogo, Moustapha; Belayew, Alexandra; Duez, Pierre

    2014-07-01

    Double-strand breaks (DSBs) may result from endogenous (e.g., reactive oxygen species, variable (diversity) joining, meiotic exchanges, collapsed replication forks, nucleases) or exogenous (e.g., ionizing radiation, chemotherapeutic agents, radiomimetic compounds) events. DSBs disrupt the integrity of DNA and failed or improper DSBs repair may lead to genomic instability and, eventually, mutations, cancer, or cell death. Non-homologous end-joining (NHEJ) is the major pathway used by higher eukaryotic cells to repair these lesions. Given the complexity of NHEJ and the number of proteins and cofactors involved, secondary metabolites from medicinal or food plants might interfere with the process, activating or inhibiting repair. Twelve natural products, arbutin, curcumin, indole-3-carbinol, and nine flavonoids (apigenin, baicalein, chalcone, epicatechin, genistein, myricetin, naringenin, quercetin, sakuranetin) were chosen for their postulated roles in cancer chemoprevention and/or treatment. The effects of these compounds on NHEJ were investigated with an in vitro protocol based on plasmid substrates. Plasmids were linearized by a restriction enzyme, generating cohesive ends, or by a combination of enzymes, generating incompatible ends; plasmids were then incubated with a nuclear extract prepared from normal human small-intestinal cells (FHS 74 Int), either treated with these natural products or untreated (controls). The NHEJ repair complex from nuclear extracts ligates linearized plasmids, resulting in plasmid oligomers that can be separated and quantified by on-chip microelectrophoresis. Some compounds (chalcone, epicatechin, myricetin, sakuranetin and arbutin) clearly activated NHEJ, whereas others (apigenin, baicalein and curcumin) significantly reduced the repair rate of both types of plasmid substrates. Although this in vitro protocol is only partly representative of the in vivo situation, the natural products appear to interfere with NHEJ repair and warrant

  18. In vitro chemo-preventive activities of hydroxytyrosol: the main phenolic compound present in extra-virgin olive oil.

    PubMed

    Rosignoli, Patrizia; Fuccelli, Raffaela; Sepporta, Maria Vittoria; Fabiani, Roberto

    2016-01-01

    The co-incubation in the culture medium with hydroxytyrosol [3,4-dihydroxyphenyl ethanol (3,4-DHPEA)], the main phenolic compound present in extra-virgin olive oil, and H2O2 reduces the oxidative DNA damage in peripheral blood mononuclear cells (PBMC). In this study we investigate, by the comet assay, the ability of 3,4-DHPEA to inhibit the H2O2 induced DNA damage when pre-incubated with PBMC and then removed before the exposure of cells to H2O2. Low doses of 3,4-DHPEA (10-100 μM) pre-incubated for 30 min with PBMC reduced the DNA damage induced by the treatment with H2O2 200 μM for 5 min at 4 °C. Prolonging the exposure time up to 6 h completely prevented the DNA damage. Furthermore we extensively analysed, by the MTT assay, the anti-proliferative activities of 3,4-DHPEA on breast (MDA and MCF-7), prostate (LNCap and PC3) and colon (SW480 and HCT116) cancer cell lines and correlated these effects with the H2O2 accumulation. The concentration of H2O2 in the culture medium was measured by the ferrous ion oxidation-xylenol orange method. The proliferation of all the cell lines was inhibited but at different levels: the prostate cancer cells were more resistant to the growth inhibition with respect to breast and colon cancer cells. The ability of the different cell lines to remove H2O2 from the culture medium was inversely correlated with their sensitivity to the anti-proliferative effect of 3,4-DHPEA. Therefore, 3,4-DHPEA may act as a chemopreventive agent acting on both initiation and promotion/progression phases of carcinogenesis. PMID:26469183

  19. Biological Agents

    MedlinePlus

    ... to Z Index Contact Us FAQs What's New Biological Agents This page requires that javascript be enabled ... and Health Topics A-Z Index What's New Biological agents include bacteria, viruses, fungi, other microorganisms and ...

  20. Sulforaphane Protects Rodent Retinas against Ischemia-Reperfusion Injury through the Activation of the Nrf2/HO-1 Antioxidant Pathway

    PubMed Central

    Liu, Ruixing; Brecha, Nicholas C.; Yu, Albert Cheung Hoi; Pu, Mingliang

    2014-01-01

    Retinal ischemia-reperfusion (I/R) injury induces oxidative stress, leukocyte infiltration, and neuronal cell death. Sulforaphane (SF), which can be obtained in cruciferous vegetables such as broccoli, exerts protective effects in response to oxidative stress in various tissues. These effects can be initiated through nuclear factor E2-related factor 2 (Nrf2)-mediated induction of heme oxygenase-1 (HO-1). This investigation was designed to elucidate the neural protective mechanisms of SF in the retinal I/R rat model. Animals were intraperitoneally (i.p.) injected with SF (12.5 mg/kg) or vehicle (corn oil) once a day for 7 consecutive days. Then, retinal I/R was made by elevating the intraocular pressure (IOP) to 130 mmHg for 1 h. To determine if HO-1 was involved in the Nrf2 antioxidant pathway, rats were subjected to protoporphyrin IX zinc (II) (ZnPP, 30 mg/kg, i.p.) treatments at 24 h before retinal ischemia. The neuroprotective effects of SF were assessed by determining the morphology of the retina, counting the infiltrating inflammatory cells and the surviving retinal ganglion cells (RGCs) and amacrine cells, and measuring apoptosis in the retinal layers. The expression of Nrf2 and HO-1 was studied by immunofluorescence analysis and western blotting. I/R induced a marked increase of ROS generation, caused pronounced inflammation, increased the apoptosis of RGCs and amacrine cells and caused the thinning of the inner retinal layer (IRL), and these effects were diminished or abolished by SF pretreatment. Meanwhile, SF pretreatment significantly elevated the nuclear accumulation of Nrf2 and the level of HO-1 expression in the I/R retinas; however, ZnPP reversed the protective effects of SF on I/R retinas. Together, we offer direct evidence that SF had protective effects on I/R retinas, which could be attributed, at least in part, to the activation of the Nrf2/HO-1 antioxidant pathway. PMID:25470382

  1. NO-NSAIDs and cancer: promising novel agents.

    PubMed

    Rigas, B; Kalofonos, H; Lebovics, E; Vagenakis, A G

    2003-05-01

    Three potential applications of NO-donating NSAIDs in human cancer include their use: as chemopreventive agents; against already developed cancers (chemotherapy); and for the control of cancer symptoms, notably cancer pain. The evidence to date of greater safety and enhanced efficacy of NO-donating NSAIDs underscores their potential to prevent colon cancer and overcome the limitations of traditional NSAIDs. NO-donating NSAIDs affect several pathways critical to colon carcinogenesis and this may explain in part their greater efficacy in colon cancer prevention as assessed in preclinical models. PMID:12846441

  2. Recruitment strategies for a lung cancer chemoprevention trial involving ex-smokers.

    PubMed

    Kye, Steve H; Tashkin, Donald P; Roth, Michael D; Adams, Bradley; Nie, Wen-Xian; Mao, Jenny T

    2009-09-01

    The ability to recruit qualified subjects who are willing to adhere to the study protocol in clinical trials is an essential component of translational research. Such tasks can be particularly challenging for chemoprevention studies when the targeted study population is healthy, at risk individuals who do not have signs or symptoms of the disease, and the study participation involves complex scheduling and invasive procedures such as bronchoscopy. In this report, we describe the recruitment process and evaluated the effectiveness of various recruitment strategies utilized in our National Cancer Institute sponsored lung cancer chemoprevention study with celecoxib. Heavy ex-smokers were recruited into the study through various methods such as radio advertisements, print media, mass mailings, flyers, internet postings and others. The number of inquiries, on-site screenees and randomization generated by each method determined the efficacy of that recruitment strategy. We prescreened 4470 individuals, invited 323 people for on-site screening and randomized 137 subjects. Radio advertisements (ads) generated the most inquiries (71.1%), followed by internet posting (11.8%), print media (6.0%), posted and racked flyers (4.4%), mass mailings (2.7%) and other strategies such as referrals from friends or family members or health care providers (2.3%). Radio ads, although costly, yielded the most subjects for on-site screening and randomization. Moreover, among the various types of radio stations, news radio stations were by far the most successful. Our results suggest that advertising on news radio is a highly effective recruitment method for successful accrual of ex-smokers into lung cancer chemoprevention trials. PMID:19508900

  3. Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats.

    PubMed

    Adeneye, A A; Benebo, A S

    2016-01-01

    Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male Wistar rats were randomly divided into five groups (n = 5 rats per group) and daily pretreated with oral doses of distilled water (10 mLkg-1), ascorbic acid (100 mgkg-1), Tadalafil (2 mgkg-1 and 5 mgkg-1) for 7 days before cisplatin (5 mgkg-1, intraperitoneal) was administered. 72 hours post-cisplatin injections, rats were sacrificed humanely and blood samples for serum electrolytes, urea and creatinine and renal tissues for reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malonialdehyde dehydrogenase (MAD) assays and histopathology were collected. Results showed that cisplatin injection caused significant decreases in the serum sodium (Na+), potassium (K+), bicarbonate (HCO3-), calcium (Ca2+), phosphate (PO42-) and concomitant significant increases in the serum urea and creatinine levels. In addition, there were significant decreases in the renal tissue GSH, SOD, CAT and increased MAD and GSH-Px levels which were corroborated by histopathological features of tubulonephritis. However, these histo-biochemical alterations were significantly attenuated by ascorbic acid and Tadalafil pretreatments. Overall, results of this study showed the chemopreventive potential of Tadalafil against cisplatin-induced nephrotoxicity which was possibly mediated via antioxidant and anti-lipoperoxidation mechanisms. PMID:27574758

  4. Characterization of the threshold for NAD(P)H:quinone oxidoreductase activity in intact sulforaphane-treated pulmonary arterial endothelial cells.

    PubMed

    Bongard, Robert D; Krenz, Gary S; Gastonguay, Adam J; Williams, Carol L; Lindemer, Brian J; Merker, Marilyn P

    2011-04-15

    Treatment of bovine pulmonary arterial endothelial cells in culture with the phase II enzyme inducer sulforaphane (5μM, 24h; sulf-treated) increased cell-lysate NAD(P)H:quinone oxidoreductase (NQO1) activity by 5.7 ± 0.6 (mean ± SEM)-fold, but intact-cell NQO1 activity by only 2.8 ± 0.1-fold compared to control cells. To evaluate the hypothesis that the threshold for sulforaphane-induced intact-cell NQO1 activity reflects a limitation in the capacity to supply NADPH at a sufficient rate to drive all the induced NQO1 to its maximum activity, total KOH-extractable pyridine nucleotides were measured in cells treated with duroquinone to stimulate maximal NQO1 activity. NQO1 activation increased NADP(+) in control and sulf-treated cells, with the effect more pronounced in the sulf-treated cells, in which the NADPH was also decreased. Glucose-6-phosphate dehydrogenase (G-6-PDH) inhibition partially blocked NQO1 activity in control and sulf-treated cells, but G-6-PDH overexpression via transient transfection with the human cDNA alleviated neither the restriction on intact sulf-treated cell NQO1 activity nor the impact on the NADPH/NADP(+) ratios. Intracellular ATP levels were not affected by NQO1 activation in control or sulf-treated cells. An increased dependence on extracellular glucose and a rightward shift in the K(m) for extracellular glucose were observed in NQO1-stimulated sulf-treated vs control cells. The data suggest that glucose transport in the sulf-treated cells may be insufficient to support the increased metabolic demand for pentose phosphate pathway-generated NADPH as an explanation for the NQO1 threshold. PMID:21238579

  5. Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer.

    PubMed

    Abdalla, Mohamed M; Al-Omar, Mohamed A; Bhat, Mashooq A; Amr, Abdel-Galil E; Al-Mohizea, Abdullah M

    2012-05-01

    The aromatase and quinone reductase-2 inhibition of synthesized heterocyclic pyrazole derivatives fused with steroidal structure for chemoprevention of cancer is reported herein. All compounds were interestingly less toxic than the reference drug (Cyproterone(®)). The aromatase inhibitory activities of these compounds were much more potent than the lead compound resveratrol, which has an IC(50) of 80 μM. In addition, all the compounds displayed potent quinone reductase-2 inhibition. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). The aromatase and quinone reductase-2 inhibitors resulting from this study have potential value in the treatment and prevention of cancer. PMID:22361454