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Sample records for chemopreventive agent sulforaphane

  1. Natural sulforaphane as a functional chemopreventive agent: including a review of isolation, purification and analysis methods.

    PubMed

    Liang, Hao; Yuan, Qipeng

    2012-09-01

    Epidemiological data show that a diet rich in fruits and vegetables can reduce the risk from a number of cancers and chronic diseases. Sulforaphane (SF), a phytochemical constituent of cruciferous vegetables, has been widely researched in recent decades as a potential chemopreventive compound. Nonexistent in intact vegetables, natural SF, is formed from glucoraphanin hydrolyzed by myrosinase. This review summarizes and compares different analysis, isolation and purification methods engaged in SF research. Major important chemopreventive properties of SF investigated in existing research are reviewed and discussed, including antioxidant, anticarcinogenic and anti-inflammatory functions. Considering the potential applications of SF in the future, metabolism, stability and formulation developments of SF are also discussed. Research opportunities are identified based on the review of existing studies to facilitate future explorations on SF, a promising natural compound in chemopreventive therapy.

  2. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Frugal Chemoprevention: Targeting Nrf2 with Foods Rich in Sulforaphane

    PubMed Central

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

    2015-01-01

    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 variety of cancers such as breast, prostate, colon, skin, lung, stomach or bladder carcinogenesis, but also cardiovascular disease, neurodegenerative diseases, and diabetes. For reasons of experimental exigency, pre-clinical 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

  4. Role of 4-hydroxynonenal in chemopreventive activities of sulforaphane

    PubMed Central

    Sharma, Rajendra; Sharma, Abha; Chaudhary, Pankaj; Sahu, Mukesh; Jaiswal, Shailesh; Awasthi, Sanjay; Awasthi, Yogesh C.

    2012-01-01

    Chemoprevention of cancer via herbal and dietary supplements is a logical approach to combat cancer and presently it is an attractive area of research investigations. Over the years, the use of isothiocyanates, such as sulforaphane (SFN) found in cruciferous vegetables, has been advocated as chemopreventive agents and their efficacy has been demonstrated in cell lines and animal models. In-vivo studies with SFN suggest that besides protecting normal healthy cells from environmental carcinogens it also exhibits cytotoxicity and apoptotic effects against various cancer cell types. Among several mechanisms for the chemopreventive activity of SFN against chemical carcinogenesis, its effect on drug metabolizing enzymes that causes activation/ neutralization of carcinogenic metabolites is well established. Recent studies suggest that SFN exerts its selective cytotoxicity to cancer cells via reactive oxygen species (ROS)-mediated generation of lipid peroxidation (LPO) products particularly 4-hydroxynonenal (HNE). Against the background of the known biochemical effects of SFN on normal and cancer cells, in this article we have reviewed the underlying molecular mechanisms responsible for the overall chemopreventive effects of SFN focusing on the role of HNE in these mechanisms that may also contribute to its selective cytotoxicity to cancer cells. PMID:22579574

  5. 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.

  6. Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention.

    PubMed

    Cheung, Ka Lung; Kong, Ah-Ng

    2010-03-01

    Development of cancer is a long-term and multistep process which comprises initiation, progression, and promotion stages of carcinogenesis. Conceivably, it can be targeted and interrupted along these different stages. In this context, many naturally occurring dietary compounds from our daily consumption of fruits and vegetables have been shown to possess cancer preventive effects. Phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) are two of the most widely investigated isothiocyanates from the crucifers. Both have been found to be very potent chemopreventive agents in numerous animal carcinogenesis models as well as cell culture models. They exert their chemopreventive effects through regulation of diverse molecular mechanisms. In this review, we will discuss the molecular targets of PEITC and SFN potentially involved in cancer chemoprevention. These include the regulation of drug-metabolizing enzymes phase I cytochrome P450s and phase II metabolizing enzymes. In addition, the signaling pathways including Nrf2-Keap 1, anti-inflammatory NFkappaB, apoptosis, and cell cycle arrest as well as some receptors will also be discussed. Furthermore, we will also discuss the similarities and their potential differences in the regulation of these molecular targets by PEITC and SFN.

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

    PubMed

    Tortorella, Stephanie M; Royce, Simon G; Licciardi, Paul V; Karagiannis, Tom C

    2015-06-01

    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. 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. 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.

  8. 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

  9. From the Table to the Bedside: Can Food-Derived Sulforaphane be used as a Novel Agent to Treat Leukemia?

    PubMed

    Suppipat, Koramit; Lacorazza, H Daniel

    2014-01-01

    The extensive use of the same chemotherapeutics over several decades has resulted in a growing incidence of chemoresistant cancer cells and secondary malignancies. Therefore, there is an increasing need for new drugs to treat high-risk cancer patients with a higher selectivity for cancer cells and lower toxicity to normal cells. Sulforaphane is released upon hydrolysis of glucoraphanin, a constituent of cruciferous vegetables, by myrosinases that are present in the plant or intestinal microbes. Despite a large number of studies describing the chemopreventive and chemotherapeutic properties of sulforaphane in solid tumors, there is little information on the properties of sulforaphane in hematological malignancies. In this review, we discuss the anti-carcinogenic properties of sulforaphane, the need of higher doses than dietary intake, and the challenges related to testing sulforaphane as an adjunctive agent in combination with the current standard of care for frontline blood cancer.

  10. Sulforaphane bioavailability and chemopreventive activity in women scheduled for breast biopsy

    PubMed Central

    Mori, Motomi; Farris, Paige; Vetto, John T.; Naik, Arpana M.; Oh, Karen Y.; Thuillier, Philippe; Ho, Emily; Shannon, Jackilen

    2015-01-01

    Epidemiological 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 2-8-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 (DCIS), or invasive ductal carcinoma (IDC) breast tissues. Within the supplement group, Ki-67 (p = 0.003) and HDAC3 (p = 0.044) levels significantly decreased in benign tissue. Pre-to-post-intervention 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

  11. Polyphenols as cancer chemopreventive agents.

    PubMed

    Stoner, G D; Mukhtar, H

    1995-01-01

    This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (-)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation- and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication. Curcumin is the yellow coloring agent in the spice tumeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition

  12. Chemopreventive Agent Development | Division of Cancer Prevention

    Cancer.gov

    [[{"fid":"174","view_mode":"default","fields":{"format":"default","field_file_image_alt_text[und][0][value]":"Chemoprevenentive Agent Development Research Group Homepage Logo","field_file_image_title_text[und][0][value]":"Chemoprevenentive Agent Development Research Group Homepage Logo","field_folder[und]":"15"},"type":"media","attributes":{"alt":"Chemoprevenentive Agent Development Research Group Homepage Logo","title":"Chemoprevenentive Agent Development Research Group Homepage Logo","heigh | Research on early chemopreventive agent development, from preclinical studies to phase I clinical trials.

  13. Does molecular docking reveal alternative chemopreventive mechanism of activation of oxidoreductase by sulforaphane isothiocyanates?

    PubMed

    Mazur, Pawel; Magdziarz, Tomasz; Bak, Andrzej; Chilmonczyk, Zdzislaw; Kasprzycka-Guttman, Teresa; Misiewicz-Krzemińska, Irena; Skupińska, Katarzyna; Polanski, Jaroslaw

    2010-07-01

    Isothiocyanates (ITC) are well-known chemopreventive agents extracted from vegetables. This activity results from the activation of human oxidoreductase. In this letter, the uncompetitive activatory mechanism of ITC was investigated using docking and molecular dynamics simulations. This indicates that NAD(P)H:quinone oxidoreductase can efficiently improve enzyme-substrate recognition within the catalytic site if the ITC activator supports the interaction in the uncompetitive binding site.

  14. Thiol-reducing agents prevent sulforaphane-induced growth inhibition in ovarian cancer cells.

    PubMed

    Kim, Seung Cheol; Choi, Boyun; Kwon, Youngjoo

    2017-01-01

    The inhibitory potential of sulforaphane against cancer has been suggested for different types of cancer, including ovarian cancer. We examined whether this effect is mediated by mitogen-activated protein kinase (MAPK) and reactive oxygen species (ROS), important signaling molecules related to cell survival and proliferation, in ovarian cancer cells. Sulforaphane at a concentration of 10 μM effectively inhibited the growth of cancer cells. Use of specific inhibitors revealed that activation of MAPK pathways by sulforaphane is unlikely to mediate sulforaphane-induced growth inhibition. Sulforaphane did not generate significant levels of intracellular ROS. Pretreatment with thiol reducers, but not ROS scavengers, prevented sulforaphane-induced growth inhibition. Furthermore, diamide, a thiol-oxidizing agent, enhanced both growth inhibition and cell death induced by sulforaphane, suggesting that the effect of sulforaphane on cell growth may be related to oxidation of protein thiols or change in cellular redox status. Our data indicate that supplementation with thiol-reducing agents should be avoided when sulforaphane is used to treat cancer.

  15. Modulation of apoptosis by cancer chemopreventive agents.

    PubMed

    D'Agostini, Francesco; Izzotti, Alberto; Balansky, Roumen M; Bennicelli, Carlo; De Flora, Silvio

    2005-12-11

    A review of almost 2000 studies showed that the large majority of 39 putative cancer chemopreventive agents induced "spontaneous" apoptosis. Inhibition of the programmed cell death triggered by a variety of stimuli was consistently reported only with ascorbic acid, alpha-tocopherol, and N-acetylcysteine (NAC). We performed experimental studies in rodents exposed to cigarette smoke, either mainstream (MCS) or environmental (ECS), and UV-A/B-containing light. The nonsteroidal anti-inflammatory drug sulindac did not affect the apoptotic process in the skin of light-exposed mice and in the lungs of ECS-exposed mice. Likewise, 5,6-benzoflavone, indole-3-carbinol, 1,2-dithiole-3-thione and oltipraz failed to modulate apoptosis in the respiratory tract of ECS-exposed rats. Phenethyl isothiocyanate further enhanced the frequency of apoptosis in pulmonary alveolar macrophages and bronchial epithelial cells, and upregulated several genes in the lung of ECS-exposed rats. Both individually and in combination with oltipraz, NAC inhibited apoptosis in the respiratory tract of rats exposed either to MCS or ECS. Moreover, NAC attenuated the ECS-related overexpression of proapoptotic genes and normalized the levels of proapoptotic proteins in rat lung. The transplacental administration of NAC to mice considerably attenuated gene overexpression in the liver of fetuses exposed to ECS throughout pregnancy. Inhibition of apoptosis by chemopreventive agents reflects their ability to counteract certain upstream signals, such as genotoxic damage, redox imbalances, and other forms of cellular stress that trigger apoptosis. On the other hand, enhancement of apoptosis is a double-edged sword, since it represents a protective mechanism in carcinogenesis but may contribute to the pathogenesis of other degenerative diseases. We suggest that stimulation of apoptosis by so many chemopreventive agents, as reported in the literature, may often reflect the occurrence of toxic effects at high doses.

  16. Chemoprevention of oxidative stress-associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety.

    PubMed

    Lan, Aixian; Li, Wenjun; Liu, Yao; Xiong, Zhaohui; Zhang, Xinyan; Zhou, Shanshan; Palko, Olesya; Chen, Hao; Kapita, Mayanga; Prigge, Justin R; Schmidt, Edward E; Chen, Xin; Sun, Zheng; Chen, Xiaoxin Luke

    2016-08-16

    Oxidative stress is known to play an important role in oral cancer development. In this study we aimed to examine whether a chemical activator of NRF2, sulforaphane (SFN), may have chemopreventive effects on oxidative stress-associated oral carcinogenesis. We first showed that Nrf2 activation and oxidative damage were commonly seen in human samples of oral leukoplakia. With gene microarray and immunostaining, we found 4-nitroquinoline 1-oxide (4NQO) in drink activated the Nrf2 pathway and produced oxidative damage in mouse tongue. Meanwhile whole exome sequencing of mouse tongue identified mutations consistent with 4NQO's mutagenic profile. Using cultured human oral keratinocytes and 4NQO-treated mouse tongue, we found that SFN pre-treatment activated the NRF2 pathway and inhibited oxidative damage both in vitro and in vivo. On the contrary, a structural analogue of SFN without the isothiocyanate moiety did not have such effects. In a long-term chemoprevention study using wild-type and Nrf2-/- mice, we showed that topical application of SFN activated the NRF2 pathway, inhibited oxidative damage, and prevented 4NQO-induced oral carcinogenesis in an Nrf2-dependent manner. Our data clearly demonstrate that SFN has chemopreventive effects on oxidative stress-associated oral carcinogenesis, and such effects depend on Nrf2 and the isothiocyanate moiety.

  17. Chemoprevention of oxidative stress-associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety

    PubMed Central

    Liu, Yao; Xiong, Zhaohui; Zhang, Xinyan; Zhou, Shanshan; Palko, Olesya; Chen, Hao; Kapita, Mayanga; Prigge, Justin R.; Schmidt, Edward E.; Chen, Xin; Sun, Zheng; Chen, Xiaoxin Luke

    2016-01-01

    Oxidative stress is known to play an important role in oral cancer development. In this study we aimed to examine whether a chemical activator of NRF2, sulforaphane (SFN), may have chemopreventive effects on oxidative stress-associated oral carcinogenesis. We first showed that Nrf2 activation and oxidative damage were commonly seen in human samples of oral leukoplakia. With gene microarray and immunostaining, we found 4-nitroquinoline 1-oxide (4NQO) in drink activated the Nrf2 pathway and produced oxidative damage in mouse tongue. Meanwhile whole exome sequencing of mouse tongue identified mutations consistent with 4NQO's mutagenic profile. Using cultured human oral keratinocytes and 4NQO-treated mouse tongue, we found that SFN pre-treatment activated the NRF2 pathway and inhibited oxidative damage both in vitro and in vivo. On the contrary, a structural analogue of SFN without the isothiocyanate moiety did not have such effects. In a long-term chemoprevention study using wild-type and Nrf2-/- mice, we showed that topical application of SFN activated the NRF2 pathway, inhibited oxidative damage, and prevented 4NQO-induced oral carcinogenesis in an Nrf2-dependent manner. Our data clearly demonstrate that SFN has chemopreventive effects on oxidative stress-associated oral carcinogenesis, and such effects depend on Nrf2 and the isothiocyanate moiety. PMID:27447968

  18. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. 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. ©2016 American Association for Cancer Research.

  20. Transcriptome analysis reveals a dynamic and differential transcriptional response to sulforaphane in normal and prostate cancer cells and suggests a role for Sp1 in chemoprevention.

    PubMed

    Beaver, Laura M; Buchanan, Alex; Sokolowski, Elizabeth I; Riscoe, Allison N; Wong, Carmen P; Chang, Jeff H; Löhr, Christiane V; Williams, David E; Dashwood, Roderick H; Ho, Emily

    2014-10-01

    Epidemiological studies provide evidence that consumption of cruciferous vegetables, like broccoli, can reduce the risk of cancer development. Sulforaphane (SFN) is a phytochemical derived from cruciferous vegetables that induces anti-proliferative and pro-apoptotic responses in prostate cancer cells, but not in normal prostate cells. The mechanisms responsible for this cancer-specific cytotoxicity remain unclear. We utilized RNA sequencing and determined the transcriptomes of normal prostate epithelial cells, androgen-dependent prostate cancer cells, and androgen-independent prostate cancer cells treated with SFN. SFN treatment dynamically altered gene expression and resulted in distinct transcriptome profiles depending on prostate cell line. SFN also down-regulated the expression of genes that were up-regulated in prostate cancer cells. Network analysis of genes altered by SFN treatment revealed that the transcription factor Specificity protein 1 (Sp1) was present in an average of 90.5% of networks. Sp1 protein was significantly decreased by SFN treatment in prostate cancer cells and Sp1 may be an important mediator of SFN-induced changes in expression. Overall, the data show that SFN alters gene expression differentially in normal and cancer cells with key targets in chemopreventive processes, making it a promising dietary anti-cancer agent. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    PubMed

    Thakkar, Arvind; Sutaria, Dhruvitkumar; Grandhi, B Karthik; Wang, Jeffrey; Prabhu, Sunil

    2013-04-01

    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 inhi-bited 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.

  2. 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.

  3. Mechanisms of action of novel agents for prostate cancer chemoprevention.

    PubMed

    Singh, Rana P; Agarwal, Rajesh

    2006-09-01

    Despite advances in the understanding of prostate cancer (PCa) growth and development, it is still the leading incidence of cases and the second leading cause of mortality due to cancer in men. The problem of early diagnosis compounded with the emergence of androgen independence during commonly used anti-androgen therapy of PCa, have been discouraging for optimal therapeutic response. Recently, many chemopreventive agents, including silibinin, inositol hexaphosphate, decursin, apigenin, acacetin, grape seed extract, curcumin, and epigallocatechin-3 gallate have been identified in laboratory studies, which could be useful in the management of PCa. In vivo pre-clinical studies have indicated chemopreventive effect of many such agents in PCa xenograft and transgenic mouse models. The molecular targets of these agents include cell signaling, cell-cycle regulators, and survival/apoptotic molecules, which are implicated in uncontrolled PCa growth and progression. Furthermore, angiogenic and metastatic targets, including vascular endothelial growth factor, hypoxia-inducing factor-1alpha, matrix metalloproteinase, and urokinase-type plasminogen activator are also modulated by many chemopreventive agents to suppress the growth and invasive potential of PCa. This review focuses on novel PCa chemopreventive observations in laboratory studies, which could provide the rationale for the prospective use of chemopreventive agents in translational studies.

  4. Molecular medicine and the development of cancer chemopreventive agents.

    PubMed

    Izzotti, Alberto

    2012-07-01

    Chemoprevention is effective in inhibiting the onset of cancer in experimental animal models, but the transferability of similar results to humans is questionable. Therefore, reliable intermediate molecular biomarkers are needed to evaluate the efficacy of chemopreventive agents before the onset of cancer. The use of genomic biomarkers is limited by their poor predictive value. Although post-genomic biomarkers (i.e., gene-expression analyses) are useful for evaluating the safety, efficacy, and mechanistic basis of chemopreventive agents, the biomarkers are often poorly related to the phenotype, due to posttranscriptional regulation. Proteome analyses can evaluate preclinical phenotype alterations, but only at low protein counts. MicroRNA alterations, which are essential for the development of cancer, may be modulated by chemopreventive agents. Furthermore, microRNA delivery may be used to counteract carcinogenesis. Exposure to cigarette smoke induces microRNA let-7 downregulation and cell proliferation that can be converted to cell growth arrest and apoptosis upon let-7a transfection. Therefore, microRNAs are reliable biomarkers for evaluating chemoprevention efficacy and may be used to counteract carcinogenesis. © 2012 New York Academy of Sciences.

  5. Metabolism and tissue distribution of sulforaphane in Nrf2 knockout and wild-type mice.

    PubMed

    Clarke, John D; Hsu, Anna; Williams, David E; Dashwood, Roderick H; Stevens, Jan F; Yamamoto, Masayuki; Ho, Emily

    2011-12-01

    To determine the metabolism and tissue distribution of the dietary chemoprotective agent sulforaphane following oral administration to wild-type and Nrf2 knockout (Nrf2(-/-)) mice. Male and female wild-type and Nrf2(-/-) mice were given sulforaphane (5 or 20 μmoles) by oral gavage; plasma, liver, kidney, small intestine, colon, lung, brain and prostate were collected at 2, 6 and 24 h (h). The five major metabolites of sulforaphane were measured in tissues by high performance liquid chromatography coupled with tandem mass spectrometry. Sulforaphane metabolites were detected in all tissues at 2 and 6 h post gavage, with the highest concentrations in the small intestine, prostate, kidney and lung. A dose-dependent increase in sulforaphane concentrations was observed in all tissues except prostate. At 5 μmole, Nrf2(-/-) genotype had no effect on sulforaphane metabolism. Only Nrf2(-/-) females given 20 μmoles sulforaphane for 6 h exhibited a marked increase in tissue sulforaphane metabolite concentrations. The relative abundance of each metabolite was not strikingly different between genders and genotypes. Sulforaphane is metabolized and reaches target tissues in wild-type and Nrf2(-/-) mice. These data provide further evidence that sulforaphane is bioavailable and may be an effective dietary chemoprevention agent for several tissue sites.

  6. Induction of medulloblastoma cell apoptosis by sulforaphane, a dietary anticarcinogen from Brassica vegetables.

    PubMed

    Gingras, Denis; Gendron, Martin; Boivin, Dominique; Moghrabi, Albert; Théorêt, Yves; Béliveau, Richard

    2004-01-08

    There is increasing evidence that a variety of natural substances derived from the diet may act as potent chemopreventive agents. In this work, we show that DAOY cells, a widely used model of metastatic medulloblastoma (MBL), are highly sensitive to sulforaphane, a naturally occurring isothiocyanate from Brassica vegetables. Sulforaphane induced DAOY cell death by apoptosis, as determined by DNA fragmentation and chromatin condensation. DAOY apoptosis correlates with the induction of caspase-3 and -9 activities, resulting in the cleavage of PARP and vimentin. Both the cytotoxic effect and apoptotic characteristics induced by sulforaphane were reversed by zVAD-fmk, a broad spectrum caspase inhibitor, demonstrating the important role of caspases in its cytotoxic effect. These results identify sulforaphane as a novel inducer of MBL cell apoptosis, supporting the potential clinical usefulness of diet-derived substances as chemopreventive agents.

  7. 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. © 2015 S. Karger AG, Basel.

  8. Sulforaphane inhibits restenosis by suppressing inflammation and the proliferation of vascular smooth muscle cells.

    PubMed

    Kwon, Jin-Sook; Joung, Hosouk; Kim, Yong Sook; Shim, Young-Sun; Ahn, Youngkeun; Jeong, Myung Ho; Kee, Hae Jin

    2012-11-01

    Sulforaphane, a naturally occurring organosulfur compound in broccoli, has chemopreventive properties in cancer. However, the effects of sulforaphane in vascular diseases have not been examined. We therefore aimed to investigate the effects of sulforaphane on vascular smooth muscle cell (VSMC) proliferation and neointimal formation and the related mechanisms. The expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) was examined in VSMCs. The nuclear translocation of nuclear factor-κB (NF-κB) and GATA6 expression was examined in VSMCs and in a carotid artery injury model by Western blot and immunohistochemistry. We also investigated whether local delivery of sulforaphane affected neointimal formation. Sulforaphane inhibited the mRNA and protein expression of VCAM-1 induced by tumor necrosis factor (TNF)-α in VSMCs. Treatment of VSMCs with sulforaphane blocked TNF-α-induced IκBα degradation and NF-κB p65 and GATA6 expression. Furthermore, NF-κB p65 and GATA6 expression were reduced in sulforaphane-treated carotid injury sections. Notably, binding of GATA6 to the VCAM-1 promoter was dramatically reduced by sulforaphane. The MTT, BrdU incorporation, and in vitro scratch assays revealed that the proliferation and migration of VSMCs were reduced by sulforaphane. Furthermore, local administration of sulforaphane significantly reduced neointima formation 14 days after vascular injury in rats. Our results indicate that sulforaphane inhibits neointima formation via targeting of adhesion molecules through the suppression of NF-κB/GATA6. Furthermore, sulforaphane regulates migration and proliferation in VSMCs. Sulforaphane may be a potential therapeutic agent for preventing restenosis after vascular injury. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  9. 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.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  11. 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

  12. 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. |

  13. Targeting HER2 Positive Breast Cancer with Chemopreventive Agents

    PubMed Central

    Wahler, Joseph; Suh, Nanjoo

    2015-01-01

    Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is a subtype of breast cancer that is exhibited in approximately 20-30% of breast cancer cases. The overexpression of HER2 is typically associated with a more aggressive disease and poor prognosis. Currently, the therapeutic drugs trastuzumab and lapatinib are the most commonly used to combat HER2+ breast cancer. However, tumors can develop resistance to these drugs. A better understanding of the mechanism of how HER2+ breast cancer works will help aid the development for new therapeutic approaches which more closely target the source of the signaling dysfunction. This review summarizes four major points in the context of HER2 over-expressing breast cancer (i) HER2 as a molecular target in breast cancer therapy, (ii) current treatment options as well as ongoing clinical studies, (iii) animal and cellular models for the study of HER2 over-expressing breast cancer, and (iv) future therapies and chemopreventive agents used to target HER2+ breast cancer. PMID:26442201

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

    USDA-ARS?s Scientific Manuscript database

    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...

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

    USDA-ARS?s Scientific Manuscript database

    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...

  16. 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.

  17. Kinetics of Sulforaphane in Mice after Consumption of Sulforaphane-Enriched Broccoli Sprout Preparation

    PubMed Central

    Li, Yanyan; Zhang, Tao; Li, Xiaoqin; Zou, Peng; Schwartz, Steven J.; Sun, Duxin

    2013-01-01

    Scope Sulforaphane is a natural isothiocyanate in broccoli sprouts with cancer chemopreventive activity. This study is aimed to to use different methods to develop broccoli sprout preparations to compare their ability to deliver sulforaphane to the mice and to evaluate the kinetics and biodistribution of sulforaphane. Methods and Results The sulforaphane-enriched sprout preparation generated by two-step procedure (quick-steaming followed by myrosinase treatment) contained the highest level of sulforaphane, which was 11 and 5 times higher than the freeze-dried fresh broccoli sprouts and the quick-steamed, freeze-dried broccoli sprouts, respectively. After oral administration of 2.5 mg/g body weight of the broccoli sprout preparations, sulforaphane was quickly absorbed and distributed throughout the tissues. The sulforaphane-rich preparation resulted in the highest exposure, with peak plasma sulforaphane concentration of 337 ng/ml, which is 6.0 times and 2.6 times higher compared to the other two preparations. A whole body physiologically-based pharmacokinetic model (developed with ADAPT 5 software) suggests that distribution of sulforaphane is perfusion-limited in all organs. Conclusion This study provides a broccoli sprout preparation that can serve as a good source of sulforaphane, and the model can be utilized to guide the dose design for the use of broccoli sprout preparation in chemoprevention. PMID:23929742

  18. Neoflavonoids and tetrahydroquinolones as possible cancer chemopreventive agents

    PubMed Central

    Luqman, Suaib; Meena, Abha; Singh, Pragya; Kondratyuk, Tamara P.; Marler, Laura E.; Pezzuto, John M.; Negi, Arvind Singh

    2012-01-01

    Several lactone and lactam based neoflavonoids and tetrahydroquinolones were synthesized and evaluated for cancer chemopreventive studies using cell and molecular target based in vitro bioassays, namely NFκB, aromatase, and quinone reductase 1 (QR1). These analogues blocked TNF-α-induced NFκB activation in a dose-dependent manner with IC50 values in the range of 0.11–3.2 μM. In addition, compound 8 inhibited aromatase activity with an IC50 value of 12.12 μM and compound 10 affected QR1 induction (IR: 3.6, CD: 19.57 μM). Neoflavonoids 8 and 10 exhibiting good results, can further be optimized for improved therapeutic profiles. However, investigations into the actions of neoflavonoids and tetrahydroquinolones, especially those related to the NFκB signaling pathway, aromatase inhibition, induction of QR1 expression and in vivo studies could provide new insights into the cancer chemopreventive ability of these molecules. PMID:22726671

  19. Pharmacokinetics and Pharmacodynamics of Phase II Drug Metabolizing/Antioxidant Enzymes Gene Response by Anti-cancer Agent Sulforaphane in Rat Lymphocytes

    PubMed Central

    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

    2012-01-01

    PURPOSE This study assesses the pharmacokinetics (PK) and pharmacodynamics (PD) of Nrf2-mediated increased expression of Phase II drug metabolizing enzyme (DME) and antioxidant enzymes which represents an important component of cancer chemoprevention in rat lymphocytes following intravenous (i.v.) administration of an anti-cancer phytochemical sulforaphane (SFN) METHODS 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 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, converted to cDNA, and 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. RESULTS 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 folds) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increase (> 5 folds) for GSTT1, GPx1, and Maf. PK-PD analyses using GastroPlus™ and Bootstrap method provided reasonable fitting for the PK and PD profiles and parameter estimates. CONCLUSION 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 i.v. 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

  20. 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

  1. Plant Polyphenols as Chemopreventive Agents for Lung Cancer.

    PubMed

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

    2016-08-19

    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.

  2. Anti-carcinogenic effects of sulforaphane in association with its apoptosis-inducing and anti-inflammatory properties in human cervical cancer cells.

    PubMed

    Sharma, Chhavi; Sadrieh, Lida; Priyani, Anita; Ahmed, Musthaq; Hassan, Ahmad H; Hussain, Arif

    2011-06-01

    The multistep process of carcinogenesis is characterized by progressive disorganization and occurrence of initiation, promotion, and progression events. Several new strategies such as chemoprevention are being developed for treatment and prevention at various stages of carcinogenesis. Sulforaphane, a potential chemopreventive agent, possesses anti-proliferative, anti-inflammatory, anti-oxidant and anti-cancer activities and has attracted extensive interest for better cancer management. We evaluated the effect of sulforaphane alone or in combination with gemcitabine on HeLa cells by cell viability assay and confirmed the results by apoptosis assay. Further we analyzed the effect of sulforaphane on the expression of Bcl-2, COX-2 and IL-1β by RT-PCR on HeLa cells. In the present study, sulforaphane was found to induce dose-dependent selective cytotoxicity in HeLa cells in comparison to normal cells pointing to its safe cytotoxicity profile. Additionally, a combination of sulforaphane and gemcitabine was found to increase the growth inhibition in a synergistic manner in HeLa cells compared to the individual drugs. Also, the expression analysis of genes involved in apoptosis and inflammation revealed significant downregulation of Bcl-2, COX-2 and IL-1β upon treatment with sulforaphane. Our results suggest that sulforaphane exerts its anticancer activities via apoptosis induction and anti-inflammatory properties and provides the first evidence demonstrating synergism between sulforaphane and gemcitabine which may enhance the therapeutic index of prevention and/or treatment of cervical cancer. Copyright © 2010 Elsevier Ltd. All rights reserved.

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

    PubMed

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

    2016-05-01

    The fruits of some varieties of genus Physalis have been used as delicious fruits and functional food in the Northeast of China. To reveal the functional material basis, we performed bioactivity-guided phytochemical research and chemopreventive effect assay of the constituents from Physalis minima. 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. 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.

  4. 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

  5. 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.

  6. In Vivo Testing of Chemopreventive Agents Using the Dog Model of Spontaneous Prostate Carcinogenesis

    DTIC Science & Technology

    2001-03-01

    FUNDING NUMBERS In Vivo Testing of Chemopreventive Agents Using the Dog Model of Spontaneous DAMD1 7-98-1-8550 Prostate Carcinogenesis 6. AUTHOR( S ... castration (n= 9 dogs ). Interventions were well tolerated by all dogs . Although the final data analysis is not yet completed, our project has generated...Waters DJ, Shen S , Glickman LT. Life expectancy, antagonistic pleiotropy, and the testis of dogs and men. Prostate 2000;43:272-277. DNA damage-sparing

  7. 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

  8. Design, synthesis and experimental validation of novel potential chemopreventive agents using random forest and support vector machine binary classifiers

    PubMed Central

    Sprague, Brienne; Kim, Marlene T.; Zhang, Liying; Sedykh, Alexander; Ichiishi, Eiichiro; Tokuda, Harukuni; Lee, Kuo-Hsiung

    2017-01-01

    Compared to the current knowledge on cancer chemotherapeutic agents, only limited information is available on the ability of organic compounds, such as drugs and/or natural products, to prevent or delay the onset of cancer. In order to evaluate chemical chemopreventive potentials and design novel chemopreventive agents with low to no toxicity, we developed predictive computational models for chemopreventive agents in this study. First, we curated a database containing over 400 organic compounds with known chemoprevention activities. Based on this database, various random forest and support vector machine binary classifiers were developed. All of the resulting models were validated by cross validation procedures. Then, the validated models were applied to virtually screen a chemical library containing around 23,000 natural products and derivatives. We selected a list of 148 novel chemopreventive compounds based on the consensus prediction of all validated models. We further analyzed the predicted active compounds by their ease of organic synthesis. Finally, 18 compounds were synthesized and experimentally validated for their chemopreventive activity. The experimental validation results paralleled the cross validation results, demonstrating the utility of the developed models. The predictive models developed in this study can be applied to virtually screen other chemical libraries to identify novel lead compounds for the chemo-prevention of cancers. PMID:24840854

  9. Design, synthesis and experimental validation of novel potential chemopreventive agents using random forest and support vector machine binary classifiers

    NASA Astrophysics Data System (ADS)

    Sprague, Brienne; Shi, Qian; Kim, Marlene T.; Zhang, Liying; Sedykh, Alexander; Ichiishi, Eiichiro; Tokuda, Harukuni; Lee, Kuo-Hsiung; Zhu, Hao

    2014-06-01

    Compared to the current knowledge on cancer chemotherapeutic agents, only limited information is available on the ability of organic compounds, such as drugs and/or natural products, to prevent or delay the onset of cancer. In order to evaluate chemical chemopreventive potentials and design novel chemopreventive agents with low to no toxicity, we developed predictive computational models for chemopreventive agents in this study. First, we curated a database containing over 400 organic compounds with known chemoprevention activities. Based on this database, various random forest and support vector machine binary classifiers were developed. All of the resulting models were validated by cross validation procedures. Then, the validated models were applied to virtually screen a chemical library containing around 23,000 natural products and derivatives. We selected a list of 148 novel chemopreventive compounds based on the consensus prediction of all validated models. We further analyzed the predicted active compounds by their ease of organic synthesis. Finally, 18 compounds were synthesized and experimentally validated for their chemopreventive activity. The experimental validation results paralleled the cross validation results, demonstrating the utility of the developed models. The predictive models developed in this study can be applied to virtually screen other chemical libraries to identify novel lead compounds for the chemoprevention of cancers.

  10. Design, synthesis and experimental validation of novel potential chemopreventive agents using random forest and support vector machine binary classifiers.

    PubMed

    Sprague, Brienne; Shi, Qian; Kim, Marlene T; Zhang, Liying; Sedykh, Alexander; Ichiishi, Eiichiro; Tokuda, Harukuni; Lee, Kuo-Hsiung; Zhu, Hao

    2014-06-01

    Compared to the current knowledge on cancer chemotherapeutic agents, only limited information is available on the ability of organic compounds, such as drugs and/or natural products, to prevent or delay the onset of cancer. In order to evaluate chemical chemopreventive potentials and design novel chemopreventive agents with low to no toxicity, we developed predictive computational models for chemopreventive agents in this study. First, we curated a database containing over 400 organic compounds with known chemoprevention activities. Based on this database, various random forest and support vector machine binary classifiers were developed. All of the resulting models were validated by cross validation procedures. Then, the validated models were applied to virtually screen a chemical library containing around 23,000 natural products and derivatives. We selected a list of 148 novel chemopreventive compounds based on the consensus prediction of all validated models. We further analyzed the predicted active compounds by their ease of organic synthesis. Finally, 18 compounds were synthesized and experimentally validated for their chemopreventive activity. The experimental validation results paralleled the cross validation results, demonstrating the utility of the developed models. The predictive models developed in this study can be applied to virtually screen other chemical libraries to identify novel lead compounds for the chemoprevention of cancers.

  11. Progress in Nanotechnology Based Approaches to Enhance the Potential of Chemopreventive Agents

    PubMed Central

    Muqbil, Irfana; Masood, Ashiq; Sarkar, Fazlul H.; Mohammad, Ramzi M.; Azmi, Asfar S.

    2011-01-01

    Cancer chemoprevention is defined as the use of natural agents to suppress, reverse or prevent the carcinogenic process from turning into aggressive cancer. Over the last two decades, multiple natural dietary compounds with diverse chemical structures such flavonoids, tannins, curcumins and polyphenols have been proposed as chemopreventive agents. These agents have proven excellent anticancer potential in the laboratory setting, however, the observed effects in vitro do not translate in clinic where they fail to live up to their expectations. Among the various reasons for this discrepancy include inefficient systemic delivery and robust bioavailability. To overcome this barrier, researchers have focused towards coupling these agents with nano based encapsulation technology that in principle will enhance bioavailability and ultimately benefit clinical outcome. The last decade has witnessed rapid advancement in the development of nanochemopreventive technology with emergence of many nano encapsulated formulations of different dietary anticancer agents. This review summarizes the most up-to-date knowledge on the studies performed in nanochemoprevention, their proposed use in the clinic and future directions in which this field is heading. As the knowledge of the dynamics of nano encapsulation evolves, it is expected that researchers will bring forward newer and far more superior nanochemopreventive agents that may become standard drugs for different cancers. PMID:24212623

  12. Synergy between sulforaphane and selenium in the up-regulation of thioredoxin reductase and protection against hydrogen peroxide-induced cell death in human hepatocytes.

    PubMed

    Li, Dan; Wang, Wei; Shan, Yujuan; Barrera, Lawrence N; Howie, Alexander F; Beckett, Geoffrey J; Wu, Kun; Bao, Yongping

    2012-07-15

    Dietary isothiocyanates and selenium are chemopreventive agents and potent inducers of antioxidant enzymes. It has been previously shown that sulforaphane and selenium have a synergistic effect on the upregulation of thioredoxin reductase-1 (TrxR-1) in human hepatoma HepG2 cells. In this paper, further evidence is presented to show that sulforaphane and selenium synergistically induce TrxR-1 expression in immortalised human hepatocytes. Sulforaphane was found to be more toxic toward hepatocytes than HepG2 cells with IC50=25.1 and 56.4 μM, respectively. Sulforaphane can protect against hydrogen peroxide-induced cell death and this protection was enhanced by co-treatment with selenium. Using siRNA to knock down TrxR-1 or Nrf2, sulforaphane (5 μM)-protected cell viability was reduced from 73% to 46% and 34%, respectively, suggesting that TrxR-1 is an important enzyme in protection against hydrogen peroxide-induced cell death. Sulforaphane-induced TrxR-1 expression was positively associated with significant levels of Nrf2 translocation into the nucleus, but co-treatment with selenium showed no significant increase in Nrf2 translocation. Moreover, MAPK (ERK, JNK and p38) and PI3K/Akt signalling pathways were found to play no significant role in sulforaphane-induced Nrf2 translocation into the nucleus. However, blocking ERK and JNK signalling pathways decreased sulforaphane-induced TrxR-1 mRNA by about 20%; whereas blocking p38 and PI3K/AKT increased TrxR-1 transcription. In summary, a combination of sulforaphane and selenium resulted in a synergistic upregulation of TrxR-1 that contributed to the enhanced protection against free radical-mediated oxidative damage in human hepatocytes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Null activity of selenium and vitamin e as cancer chemopreventive agents in the rat prostate.

    PubMed

    McCormick, David L; Rao, K V N; Johnson, William D; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E

    2010-03-01

    To evaluate the potential efficacy of selenium and vitamin E as inhibitors of prostate carcinogenesis, four chemoprevention studies using a common protocol were done in a rat model of androgen-dependent prostate cancer. After stimulation of prostate epithelial cell proliferation by a sequential regimen of cyproterone acetate followed by testosterone propionate, male Wistar-Unilever rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU) followed by chronic androgen stimulation via subcutaneous implantation of testosterone pellets. At 1 week post-MNU, groups of carcinogen-treated rats (39-44/group) were fed either a basal diet or a basal diet supplemented with l-selenomethionine (3 or 1.5 mg/kg diet; study 1), dl-alpha-tocopherol (vitamin E, 4,000 or 2,000 mg/kg diet; study 2), l-selenomethionine + vitamin E (3 + 2,000 mg/kg diet or 3 + 500 mg/kg diet; study 3), or selenized yeast (target selenium levels of 9 or 3 mg/kg diet; study 4). Each chemoprevention study was terminated at 13 months post-MNU, and prostate cancer incidence was determined by histopathologic evaluation. No statistically significant reductions in prostate cancer incidence were identified in any group receiving dietary supplementation with selenium and/or vitamin E. These data do not support the hypotheses that selenium and vitamin E are potent cancer chemopreventive agents in the prostate, and when considered with the recent clinical data reported in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), show the predictive nature of this animal model for human prostate cancer chemoprevention.

  14. Nutritional agents with anti-inflammatory properties in chemoprevention of colorectal neoplasia.

    PubMed

    Hull, Mark A

    2013-01-01

    The strong link between inflammation and colorectal carcinogenesis provides the rationale for using anti-inflammatory agents for chemoprevention of colorectal cancer (CRC). Several naturally occurring substances with anti-inflammatory properties, used in a purified 'nutraceutical' form, including omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and polyphenols such as curcumin and resveratrol, have been demonstrated to have anti-CRC activity in preclinical models. As expected, these agents have an excellent safety and tolerability profile in Phase II clinical trials. Phase III randomized clinical trials of these naturally occurring substances are now beginning to be reported. The omega-3 polyunsaturated fatty acid EPA, in the free fatty acid (FFA) form, has been demonstrated to reduce adenomatous polyp number and size in patients with familial adenomatous polyposis (FAP), a finding which has prompted evaluation of this formulation of EPA for prevention of 'sporadic' colorectal neoplasia. Anti-inflammatory 'nutraceuticals' require further clinical evaluation in polyp prevention trials as they exhibit many of the characteristics of the ideal cancer chemoprevention agent, including safety, tolerability and patient acceptability.

  15. Feasibility of using lower doses of chemopreventive agents in a combination regimen for cancer protection.

    PubMed

    Ip, C

    1988-04-01

    In experimental cancer chemoprevention studies, the doses of the agent used to produce an inhibitory response are generally very high, sometimes bordering on levels that will result in toxicity to the test animals. The present study was designed to test the hypothesis that low doses of two or more agents may be just as effective as high doses of a single agent. An earlier report from our laboratory showed that vitamin E, although ineffective by itself, potentiates the anti-carcinogenic potency of selenite. Our objective was to complete a comprehensive set of dose titration experiments in the quantitative analysis of the synergism between selenium (Se) and vitamin E. Results indicated that the minimal amount of vitamin E required was around 500 ppm, which when combined with as little as 1 ppm Se, produced a significant protective effect in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumor model. This level of Se is 5 times below the marginal toxicity level of 5 ppm observed in our previous experience. With a 3-agent combination protocol involving Se (1 ppm), vitamin E (500 ppm) and vitamin A (66 ppm), it was found that vitamin A at this particular dose did not contribute any further chemoprevention than that provided by the Se/vitamin E duo. Both Se and vitamin E were present at a concentration 10 times, while vitamin A was present at 30 times their respective nutritional requirement. Our findings thus suggest that the minimum effective dose has to be systematically established for each micronutrient, and that it is feasible to use lower doses of a combination of agents if the threshold level of each agent can be determined under a prescribed set of conditions.

  16. What do we know about sulforaphane protection against photoaging?

    PubMed

    Sikdar, Sohely; Papadopoulou, Maria; Dubois, Jacques

    2016-03-01

    Sulforaphane (SFN), a natural compound occurring in cruciferous vegetables, has been known for years as a chemopreventive agent against many types of cancer. Recently, it has been investigated as an antioxidant and anti-aging agent, and interesting conclusions have been made over the last decade. SFN demonstrated protective effects against ultraviolet (UV)-induced skin damage through several mechanisms of action, for example, decrease of reactive oxygen species production, inhibition of matrix metalloproteinase expression, and induction of phase 2 enzymes. SFN used as a protective agent against UV damage is a whole new matter, and it seems to be a very promising ingredient in upcoming anti-aging drugs and cosmetics. © 2016 Wiley Periodicals, Inc.

  17. Metapristone (RU486 derivative) inhibits cell proliferation and migration as melanoma metastatic chemopreventive agent.

    PubMed

    Zheng, Ning; Chen, Jiahang; Liu, Weiqun; Wang, Jichuang; Liu, Jian; Jia, Lee

    2017-04-01

    Uncontrolled cell proliferation and metastasis are the two well-known manifestations of melanoma. We hypothesized that metapristone, a potential cancer metastatic chemopreventive agent derived from mifepristone (RU486), had a dual function to fight cancer. In the present study, our findings clearly demonstrated that metapristone had modest cytostatic effect in melanoma cells. Metapristone inhibited cell viability and induced both early and late apoptosis in B16F10 and A375 cells in a time- and concentrate-dependent manner. Metapristone-treatment caused the cell arrest at the G0/G1 stage, and the inhibition of colony formation in B16F10 cells. Western blot analysis further revealed that metapristone treatment elicited a decline of Akt and ERK phosphorylation and Bcl-2, and facilitated expression of total P53 and Bax in A375 cells. In addition, cell migration and invasion were significantly suppressed by metapristone through down-regulating the expression of MMP-2, MMP-9, N-cadherin and vimentin, whereas up-regulating E-cadherin expression. Notably, metapristone exhibited anti-metastatic activity in melanoma B16F10 cells in vivo. Our results reveal metapristone, having the dual function of anti-proliferation and anti-migration for melanoma cell lines, may be a useful chemopreventive agent to reduce the risk of melanoma cancer metastasis.

  18. 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.

  19. Prevalence of chemopreventive agent use among hospitalised women at high risk for breast cancer: a cross-sectional study

    PubMed Central

    Khaliq, Waseem; Jelovac, Danijela; Wright, Scott M

    2016-01-01

    Objective To characterise the current usage of chemoprevention agents among hospitalised women who are at higher risk for breast cancer. Study design A cross-sectional study. Setting Academic hospital at Baltimore. Participants A bedside survey of 250 women aged 50–75 years was conducted who were cancer-free at the time of study enrolment and hospitalised to a general medicine service. Reproductive history, family history for breast cancer, chemopreventive agents use and medical comorbidities data was collected for all patients. χ2 and t-tests were used to analyse population characteristics. Primary outcome measures Prevalence of women at high risk for developing breast cancer (5-year Gail risk score ≥1.7) and their chemopreventive agent use. Results Mean age for the study population was 61.5 years (SD 7.5), and mean 5-year Gail risk score was 1.67 (SD 0.88). A third of study population was at high risk for breast cancer. None of the high-risk women (0%) were taking chemoprevention for breast cancer risk reduction, and 23% were at very high risk with 5-year Gail score ≥3%. These women were not recognised as being high risk by their hospital providers and none were referred to the high-risk breast cancer clinics following discharge. Conclusions Many hospitalised women are at high risk for breast cancer and we could not identify even a single woman who was using chemoprevention for risk reduction. Current chemoprevention guidelines may be falling short in their dissemination and implementation. Since women at high risk for breast cancer may only interface with the healthcare system at select points, all healthcare providers must be willing and able to do risk assessment. For those identified to be at high risk, providers must then either engage in chemopreventive counselling or refer patients to providers who are more comfortable working with patients on this critical decision. PMID:27852714

  20. Bioavailability of sulforaphane from two broccoli sprout beverages: Results of a short term, cross-over clinical trial in Qidong, China

    PubMed Central

    Egner, Patricia A.; Chen, Jian Guo; Wang, Jin Bing; Wu, Yan; Sun, Yan; Lu, Jian Hua; Zhu, Jian; Zhang, Yong Hui; Chen, Yong Sheng; Friesen, Marlin D.; Jacobson, Lisa P.; Muñoz, Alvaro; Ng, Derek; Qian, Geng Sun; Zhu, Yuan Rong; Chen, Tao Yang; Botting, Nigel P.; Zhang, Qingzhi; Fahey, Jed W.; Talalay, Paul; Groopman, John D; Kensler, Thomas W.

    2011-01-01

    One of several challenges in design of clinical chemoprevention trials is the selection of the dose, formulation and dose schedule of the intervention agent. Therefore, a cross-over clinical trial was undertaken to compare the bioavailability and tolerability of sulforaphane from two of broccoli sprout-derived beverages: one glucoraphanin-rich (GRR) and the other sulforaphane-rich (SFR). Sulforaphane was generated from glucoraphanin contained in GRR by gut microflora or formed by treatment of GRR with myrosinase from daikon (Raphanus sativus) sprouts to provide SFR. Fifty healthy, eligible participants were requested to refrain from crucifer consumption and randomized into two treatment arms. The study design was as follows: 5-day run-in period, 7-day administration of beverages, 5-day washout period, and 7-day administration of the opposite intervention. Isotope dilution mass spectrometry was used to measure levels of glucoraphanin, sulforaphane and sulforaphane thiol conjugates in urine samples collected daily throughout the study. Bioavailability, as measured by urinary excretion of sulforaphane and its metabolites (in approximately 12 hour collections after dosing), was substantially greater with the SFR (mean = 70%) than with GRR (mean = 5%) beverages. Interindividual variability in excretion was considerably lower with SFR than GRR beverage. Elimination rates were considerably slower with GRR allowing for achievement of steady state dosing as opposed to bolus dosing with SFR. Optimal dosing formulations in future studies should consider blends of sulforaphane and glucoraphanin as SFR and GRR mixtures to achieve peak concentrations for activation of some targets and prolonged inhibition of others implicated in the protective actions of sulforaphane. PMID:21372038

  1. 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

  2. Chemopreventive agents attenuate rapid inhibition of gap junctional intercellular communication induced by environmental toxicants

    PubMed Central

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

    2016-01-01

    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, lindane, fluoranthene, DDT, perfluorooctanoic acid 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

  3. 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.

  4. 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

  5. UV-induced immune suppression and photocarcinogenesis: Chemoprevention by dietary botanical agents

    PubMed Central

    Katiyar, Santosh K.

    2007-01-01

    Studies of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that ultraviolet (UV) radiation-induced immune suppression is a risk factor for the development of skin cancer in humans. UV radiation suppresses the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage that is a molecular trigger of UV-mediated immunosuppression. It is therefore important to elucidate the mechanisms underlying UV-induced immunosuppression as a basis for developing strategies to protect individuals from this effect and subsequent development of skin cancer. Dietary botanicals are of particular interest as they have been shown to inhibit UV-induced immune suppression and photocarcinogenesis. In this review, we summarize the most recent investigations and mechanistic studies regarding the photoprotective efficacy of selected dietary agents, including, green tea polyphenols, grape seed proanthocyanidins and silymarin. We present evidence that these chemopreventive agents prevent UVB-induced immunosuppression and photocarcinogenesis through: (i) The induction of immunoregulatory cytokine interleukin (IL)-12; (ii) IL-12-dependent DNA repair; and (iii) Stimulation of cytotoxic T cells in the tumor microenvironment. The new information regarding the mechanisms of action of these agents supports their potential use as adjuncts in the prevention of photocarcinogenesis. PMID:17382466

  6. UV-induced immune suppression and photocarcinogenesis: chemoprevention by dietary botanical agents.

    PubMed

    Katiyar, Santosh K

    2007-09-18

    Studies of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that ultraviolet (UV) radiation-induced immune suppression is a risk factor for the development of skin cancer in humans. UV radiation suppresses the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage that is a molecular trigger of UV-mediated immunosuppression. It is therefore important to elucidate the mechanisms underlying UV-induced immunosuppression as a basis for developing strategies to protect individuals from this effect and subsequent development of skin cancer. Dietary botanicals are of particular interest as they have been shown to inhibit UV-induced immune suppression and photocarcinogenesis. In this review, we summarize the most recent investigations and mechanistic studies regarding the photoprotective efficacy of selected dietary agents, including, green tea polyphenols, grape seed proanthocyanidins and silymarin. We present evidence that these chemopreventive agents prevent UVB-induced immunosuppression and photocarcinogenesis through: (i) the induction of immunoregulatory cytokine interleukin (IL)-12; (ii) IL-12-dependent DNA repair; and (iii) stimulation of cytotoxic T cells in the tumor microenvironment. The new information regarding the mechanisms of action of these agents supports their potential use as adjuncts in the prevention of photocarcinogenesis.

  7. Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent Curcumin*

    PubMed Central

    Griesser, Markus; Pistis, Valentina; Suzuki, Takashi; Tejera, Noemi; Pratt, Derek A.; Schneider, Claus

    2011-01-01

    The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chemical and metabolic instability. Non-enzymatic degradation has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degradation. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 μm/min) and associated with stoichiometric uptake of O2. Oxidation was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nm; 7.5 μm/min), and the rate was increased ≈10-fold by the addition of 300 μm H2O2. The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymatic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H218O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidation to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity. PMID:21071447

  8. Sulforaphane Inhibits Mammary Adipogenesis by Targeting Adipose Mesenchymal Stem Cells

    PubMed Central

    Li, Qinglin; Xia, Jixiang; Yao, Yuan; Gong, Da-wei; Shi, Hongfei; Zhou, Qun

    2013-01-01

    It is now well accepted that tumor cells actively communicate with the tumor microenvironment (e.g., adipocytes) leading to the progression of breast cancer and other malignancies. It is also known that adipose mesenchymal stem cells (MSCs) have the ability to differentiate into mature adipocytes and initiate cytokine signaling within the tumor microenvironment. Here, we examine the role of MSC-differentiated adipocytes on breast cancer cell migration, and test the effects of sulforaphane (SFN, a dietary chemoprevention agent) on adipocyte-breast cancer cell interaction. Our results demonstrate that SFN promotes MSC self-renewal and inhibits adipogenic differentiation. Subsequently, SFN-treatment of adipocytes considerably hinders cytokine communication with breast cancer cells, thereby decreasing breast cancer cell migration and tumor formation. PMID:24002734

  9. Sulforaphane inhibits mammary adipogenesis by targeting adipose mesenchymal stem cells.

    PubMed

    Li, Qinglin; Xia, Jixiang; Yao, Yuan; Gong, Da-Wei; Shi, Hongfei; Zhou, Qun

    2013-09-01

    It is now well accepted that tumor cells actively communicate with the tumor microenvironment (e.g., adipocytes) leading to the progression of breast cancer and other malignancies. It is also known that adipose mesenchymal stem cells (MSCs) have the ability to differentiate into mature adipocytes and initiate cytokine signaling within the tumor microenvironment. Here, we examine the role of MSC-differentiated adipocytes on breast cancer cell migration, and test the effects of sulforaphane (SFN, a dietary chemoprevention agent) on adipocyte-breast cancer cell interaction. Our results demonstrate that SFN promotes MSC self-renewal and inhibits adipogenic differentiation. Subsequently, SFN treatment of adipocytes considerably hinders cytokine communication with breast cancer cells, thereby decreasing breast cancer cell migration and tumor formation.

  10. Dietary Supplement 4-Methylumbelliferone: An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer

    PubMed Central

    Yates, Travis J.; Lopez, Luis E.; Lokeshwar, Soum D.; Ortiz, Nicolas; Kallifatidis, Georgios; Jordan, Andre; Hoye, Kelly; Altman, Norman

    2015-01-01

    Background: Prevention and treatment of advanced prostate cancer (PCa) by a nontoxic agent can improve outcome, while maintaining quality of life. 4-methylumbelliferone (4-MU) is a dietary supplement that inhibits hyaluronic acid (HA) synthesis. We evaluated the chemopreventive and therapeutic efficacy and mechanism of action of 4-MU. Methods: TRAMP mice (7–28 per group) were gavaged with 4-MU (450mg/kg/day) in a stage-specific treatment design (8–28, 12–28, 22–28 weeks). Efficacy of 4-MU (200–450mg/kg/day) was also evaluated in the PC3-ML/Luc+ intracardiac injection and DU145 subcutaneous models. PCa cells and tissues were analyzed for HA and Phosphoinositide 3-kinase (PI-3K)/Akt signaling and apoptosis effectors. HA add-back and myristoylated Akt (mAkt) overexpression studies evaluated the mechanism of action of 4-MU. Data were analyzed with one-way analysis of variance and unpaired t test or Tukey’s multiple comparison test. All statistical tests were two-sided. Results: While vehicle-treated transgenic adenocarcinoma of the prostate (TRAMP) mice developed prostate tumors and metastases at 28 weeks, both were abrogated in treatment groups, without serum/organ toxicity or weight loss; no tumors developed at one year, even after stopping the treatment at 28 weeks. 4-MU did not alter the transgene or neuroendocrine marker expression but downregulated HA levels. However, 4-MU decreased microvessel density and proliferative index (P < .0001,). 4-MU completely prevented/inhibited skeletal metastasis in the PC3-ML/Luc+ model and DU145-tumor growth (85–90% inhibition, P = .002). 4-MU also statistically significantly downregulated HA receptors, PI-3K/CD44 complex and activity, Akt signaling, and β-catenin levels/activation, but upregulated GSK-3 function, E-cadherin, and apoptosis effectors (P < .001); HA addition or mAkt overexpression rescued these effects. Conclusion: 4-MU is an effective nontoxic, oral chemopreventive, and therapeutic agent that

  11. Nanoemulsions of cancer chemopreventive agent benzyl isothiocyanate display enhanced solubility, dissolution, and permeability.

    PubMed

    Qhattal, Hussaini Syed Sha; Wang, Shu; Salihima, Tri; Srivastava, Sanjay K; Liu, Xinli

    2011-12-14

    Benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables, is an effective chemopreventive agent. The objective of this study was to develop nanoemulsion formulations for the oral delivery of BITC. Optimized oil-in-water BITC nanoemulsions were prepared by a spontaneous self-nanoemulsification method and a homogenization-sonication method. Both nanoemulsions entrapped high amounts of BITC (15-17 mg/mL), with low polydispersity and good colloidal stability. The BITC nanoemulsions showed enhanced solubility and dissolution compared to pure BITC. These formulations markedly increased the apical to basolateral transport of BITC in Caco-2 cell monolayers. The apparent permeability values were 3.6 × 10(-6) cm/s for pure BITC and (1.1-1.3) × 10(-5) cm/s for BITC nanoemulsions. The nanoemulsions were easily taken up by human cancer cells A549 and SKOV-3 and inhibited tumor growth in vitro. This work shows for the first time that BITC can be formulated into nanoemulsions and may show promise in enhancing absorption and bioavailability.

  12. 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

  13. Salvianolic Acid B, a Potential Chemopreventive Agent, for Head and Neck Squamous Cell Cancer

    PubMed Central

    Zhao, Yuan; Guo, Yinhan; Gu, Xinbin

    2011-01-01

    Head and neck squamous cell cancer (HNSCC) is one of the top ten cancers in the United States. The survival rate of HNSCC has only marginally improved over the last two decades. In addition, African-American men bear a disproportionate burden of this preventable disease. Therefore, a critical challenge of preventive health approaches is warranted. Salvianolic acid B (Sal-B) isolated from Salvia miltiorrhiza Bge, which is a well-know Chinese medicines has been safely used to treat and prevent aging diseases for thousand of years. Recently, the anticancer properties of Sal-B have received more attention. Sal-B significantly inhibits or delays the growth of HNSCC in both cultured HNSCC cells and HNSCC xenograft animal models. The following anticancer mechanisms have been proposed: the inhibition of COX-2/PGE-2 pathway, the promotion of apoptosis, and the modulation of angiogenesis. In conclusion, Sal-B is a potential HNSCC chemopreventive agent working through antioxidation and anti-inflammation mechanisms. PMID:21209716

  14. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis.

    PubMed

    Pardi, Darrell S; Loftus, Edward V; Kremers, Walter K; Keach, Jill; Lindor, Keith D

    2003-04-01

    Ursodeoxycholic acid (UDCA) has shown effectiveness as a colon cancer chemopreventive agent in preclinical studies. In addition, a recent report suggests that it also may decrease the risk for developing colorectal dysplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We sought to evaluate the effect of UDCA on colorectal neoplasia in a group of patients with UC and PSC enrolled in a randomized, placebo-controlled trial. From a prior, randomized, placebo-controlled trial of UDCA therapy in PSC at our center, we followed-up patients with concomitant UC to assess the effect of UDCA on the development of colorectal dysplasia and cancer as compared with placebo. Fifty-two subjects were followed-up for a total of 355 person-years. Those originally assigned to receive UDCA had a relative risk of 0.26 for developing colorectal dysplasia or cancer (95% confidence interval, 0.06-0.92; P = 0.034). Many of the patients originally assigned to the placebo group eventually received open-label UDCA. Assigning these patients to the UDCA group from the time they began active therapy did not change the magnitude of the protective effect (relative risk, 0.26; 95% confidence interval, 0.07-0.99; P = 0.049). UDCA significantly decreases the risk for developing colorectal dysplasia or cancer in patients with UC and PSC.

  15. 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

  16. The Effect of Cancer Chemopreventive Agents on DNA Adduct Formation by the Dietary Prostate Carcinogen PhIP

    DTIC Science & Technology

    2001-04-01

    8217,5,7-pentahyroxyflavone/kg (quercetin), 906mg 1-isothiocyanato- (4R,S)-(methylsulfinyl) butane/kg ( sulforaphane ), or the de-alcoholized-dehydrated...and sulforaphane altered the concentrations of PhIP or its metabolites in some of the tissues, suggesting that these diet supplements significantly...fed for one week prior to the diet fortified with sulforaphane , phenethylisothiocyanate (PEITC), catechin, quercetin, wine ,drogen and NMU (50 mg/kg

  17. Cancer preventive agents 9. Betulinic acid derivatives as potent cancer chemopreventive agents.

    PubMed

    Nakagawa-Goto, Kyoko; Yamada, Koji; Taniguchi, Masahiko; Tokuda, Harukuni; Lee, Kuo-Hsiung

    2009-07-01

    C-3 esterifications of betulinic acid (BA, 1) and its A-ring homolog, ceanothic acid (CA, 2), were carried out to provide sixteen terpenoids, 4-19, including nine new compounds (4-12). All synthesized compounds were evaluated in an in vitro antitumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Among them, compounds 4-6, 11-14, 16, and 17 displayed remarkable inhibitory effects of EBV-EA activation. BA analog 6, which contains a prenyl-like group, showed the most potent inhibitory effect (100%, 76%, 37%, and 11% inhibition of EBA activation at 1000, 500, 100, and 10mol ratio/TPA, respectively, with IC(50) value of 285mol ratio/32pmol TPA). Compound 6 merits further development as a cancer preventive agent.

  18. RNA-Sequencing studies identify genes differentially regulated during inflammation-driven lung tumorigenesis and targeted by chemopreventive agents

    PubMed Central

    Qian, Xuemin; Khammanivong, Ali; Song, Jung Min; Teferi, Fitsum; Upadhyaya, Pramod; Dickerson, Erin; Kassie, Fekadu

    2016-01-01

    Chronic pulmonary inflammation has been consistently shown to increase the risk of lung cancer. Therefore, assessing the molecular links between the two diseases and identification of chemopreventive agents that inhibit inflammation-driven lung tumorigenesis is indispensable. Recently, we found that 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung tumorigenesis was significantly enhanced by chronic treatment with the inflammatory agents lipopolysaccharide (LPS) and combinatory treatment with the chemoprevenitve agents silibinin (Sil) and indole-3-carbinol (I3C) significantly inhibited the burden of inflammation-driven lung tumors. In this report, we described gene expression profiling of lung tissues derived from these studies to determine the gene expression signature in inflammation-driven lung tumors and modulation of this signature by the chemopreventive agents Sil and I3C. We found that 330, 2,957, and 1,143 genes were differentially regulated in mice treated with NNK, LPS, and NNK + LPS, respectively. The inflammatory response of lung tumors to LPS, as determined by the number of proinflammatory genes with altered gene expression or the level of alteration, was markedly less than that of normal lungs. Among 1,143 genes differentially regulated in the NNK + LPS group, the expression of 162 genes and associated signaling pathways were significantly modulated by I3C and/or Sil + I3C. These genes include cytokines, chemokines, putative oncogenes and tumor suppressor genes and Ros1, AREG, EREG, Cyp1a1, Arntl, and Npas2. To our knowledge, this is the first report that provides insight into genes that are differentially expressed during inflammation-driven lung tumorigenesis and the modulation of these genes by chemopreventive agents. PMID:25795230

  19. In vitro and in vivo efficacy and safety evaluation of metapristone and mifepristone as cancer metastatic chemopreventive agents.

    PubMed

    Wang, Jichuang; Chen, Jianzhong; Zhu, Yewei; Zheng, Ning; Liu, Jian; Xiao, Yingying; Lu, Yusheng; Dong, Haiyan; Xie, Jingjing; Yu, Suhong; Shao, Jingwei; Jia, Lee

    2016-03-01

    Malignant melanoma, the most deadly form of skin cancer, has a high propensity for metastatic spread and is notoriously chemotherapy-resistant. Metapristone is the primary metabolite of mifepristone (RU486) and shows biological activities similar to RU486. In the present study, we comprehensively investigated the efficacy of metapristone as a metastatic chemopreventive against melanoma B16F10 cells in vitro and in vivo, and evaluated the safety profile of both drugs in mice. Metapristone showed less cytostatic effect in vitro and in vivo in comparison with mifepristone. However, metapristone interfered the adhesion of B16F10 cells to fibronectin by down-regulating cellular expression of integrin α4. Chemopreventive pretreatment followed by oral administration of metapristone and mifepristone (2.5, 10, 50 mg/kg/day for 35 days) to melanoma C57BL/6 mouse model showed significant attenuation of pulmonary metastatic development. Oral administration of high doses of metapristone and mifepristone to normal mice for 35 days (25, 100, 250 mg/kg/day) resulted in a dose-dependent increase in mouse liver weight that was more severe with mifepristone than metapristone. The long-term toxicity study revealed more changes by mifepristone in counts of erythrocytes, leukocytes and platelets than by metapristone. In conclusion, metapristone may fit into a new class of cancer metastatic chemopreventive agents. It showed a safety and efficacy profile better than mifepristone. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

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

    USDA-ARS?s Scientific Manuscript database

    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. 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

  2. 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

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

    2015-05-01

    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.

  3. Efficacy of the potential chemopreventive agent, hesperetin (citrus flavanone), on 1,2-dimethylhydrazine induced colon carcinogenesis.

    PubMed

    Aranganathan, S; Nalini, N

    2009-10-01

    Our current study is an effort to identify a potent chemopreventive agent against colon cancer. Here we have investigated the efficacy of hesperetin on tissue lipid peroxidation, antioxidant defense system and colonic histoarchitecture in male Wistar rats in colon carcinogenesis. Rats in groups 3, 4, 5 and 6 were treated with DMH (20 mg kg body weight s.c.) once a week for 15 weeks. Group 1 rats received modified pellet diet and served as control; group 2 received modified pellet diet along with hesperetin (20mg/kg body weight, p.o., every day); and hesperetin was given to the rats as in-group 2 during the initiation, post-initiation and entire period stages of colon carcinogenesis. Lipid peroxidation was studied by measuring the formation of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dienes (CD), and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), reduced glutathione (GSH), in the liver and colonic tissues of DMH administered rats. (1) Decreased levels of lipid peroxidation in the colonic tissues; (2) decreased activities of antioxidant enzymes SOD, CAT, GPX, GR and GSH levels in the tissues on DMH treatment. Hesperetin supplementation during the initiation, post-initiation and entire period stages of carcinogenesis significantly reversed these activities. These results indicate that hesperetin may be a potential chemopreventive agent against DMH-induced colon cancer.

  4. Clove (Syzygium aromaticum L.), a potential chemopreventive agent for lung cancer.

    PubMed

    Banerjee, Sarmistha; Panda, Chinmay Kr; Das, Sukta

    2006-08-01

    Spices and flavoring plants part rich in supposedly health-promoting phytochemicals are currently receiving much attention as a possible source of cancer chemopreventive compounds. Clove, the sun-dried unopened flower bud from the plant Syzygium aromaticum L. is a commonly used spice and food flavor. In the present work we assess the chemopreventive potential of aqueous infusion of clove during benzo[a]pyrene (BP)-induced lung carcinogenesis in strain A mice. Incidence of hyperplasia, dysplasia and carcinoma in situ evident in the carcinogen control group on the 8th, 17th and 26th weeks, respectively, were effectively reduced after treatment with clove infusion. Significant reduction in the number of proliferating cells and an increased number of apoptotic cells was also noted in these BP-induced lung lesions following clove treatment. Western blotting analysis revealed that clove infusion upregulates the expression of pro-apoptotic proteins p53 and Bax, and downregulates the expression of anti-apoptotic protein Bcl-2 in the precancerous stages. Expression of caspase 3 and its activation by clove infusion were evident from a very early stage of carcinogenesis (eighth week). Clove infusion was also found to downregulate the expression of some growth-promoting proteins, viz, COX-2, cMyc, Hras. The observations signify the chemopreventive potential of clove in view of its apoptogenic and anti-proliferative properties.

  5. 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

  6. Antioxidant, Anti-inflammatory, and Genomic Stability Enhancement Effects of Zinc l-carnosine: A Potential Cancer Chemopreventive Agent?

    PubMed

    Ooi, Theng Choon; Chan, Kok Meng; Sharif, Razinah

    2017-01-01

    Cancer is one of the major causes of death worldwide, and the incidence and mortality rates of cancer are expected to rise tremendously in the near future. Despite a better understanding of cancer biology and advancement in cancer management, current strategies in cancer treatment remain costly and ineffective. Hence, instead of putting more efforts to search for new cancer cures, attention has now been shifted to the development of cancer chemopreventive agents as a preventive measure for cancer formation. It is well known that neoplastic transformation of cells is multifactorial, and the occurrence of oxidative stress, chronic inflammation, and genomic instability events has been implicated in the carcinogenesis of cells. Zinc l-carnosine (ZnC), which is clinically used as gastric ulcer treatment in Japan, has been suggested to have the potential in preventing cancer development. Multiple studies have revealed that ZnC possesses potent antioxidant, anti-inflammatory, and genomic stability enhancement effects. Thus, this review provides some mechanistic insight into the antioxidant, anti-inflammatory, and genomic stability enhancement effects of ZnC in relevance to its chemopreventive potential.

  7. 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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Anti-genotoxicity of galangin as a cancer chemopreventive agent candidate.

    PubMed

    Heo, M Y; Sohn, S J; Au, W W

    2001-05-01

    Flavonoids are polyphenolic compounds that are present in plants. They have been shown to possess a variety of biological activities at non-toxic concentrations in organisms. Galangin, a member of the flavonol class of flavonoid, is present in high concentrations in medicinal plants (e.g. Alpinia officinarum) and propolis, a natural beehive product. Results from in vitro and in vivo studies indicate that galangin with anti-oxidative and free radical scavenging activities is capable of modulating enzyme activities and suppressing the genotoxicity of chemicals. These activities will be discussed in this review. Based on our review, galangin may be a promising candidate for cancer chemoprevention.

  9. Elemental selenium at nano size (Nano-Se) as a potential chemopreventive agent with reduced risk of selenium toxicity: comparison with se-methylselenocysteine in mice.

    PubMed

    Zhang, Jinsong; Wang, Xufang; Xu, Tongwen

    2008-01-01

    Selenium (Se) is an essential trace element with a narrow margin between beneficial and toxic effects. As a promising chemopreventive agent, its use requires consumption over the long term, so the toxicity of Se is always a crucial concern. Based on clinical findings and recent studies in selenoprotein gene-modified mice, it is likely that the antioxidant function of one or more selenoproteins is responsible for the chemopreventive effect of Se. Furthermore, upregulation of phase 2 enzymes by Se has been implicated as a possible chemopreventive mechanism at supranutritional dietary levels. Se-methylselenocysteine (SeMSC), a naturally occurring organic Se product, is considered as one of the most effective chemopreventive selenocompounds. The present study revealed that, as compared with SeMSC, elemental Se at nano size (Nano-Se) possessed equal efficacy in increasing the activities of glutathione peroxidase, thioredoxin reductase, and glutathione S-transferase, but had much lower toxicity as indicated by median lethal dose, acute liver injury, survival rate, and short-term toxicity. Our results suggest that Nano-Se can serve as a potential chemopreventive agent with reduced risk of Se toxicity.

  10. Sulforaphane down-regulates SKP2 to stabilize p27(KIP1) for inducing antiproliferation in human colon adenocarcinoma cells.

    PubMed

    Chung, Yuan-Kai; Chi-Hung Or, Richard; Lu, Chien-Hsing; Ouyang, Wei-Ting; Yang, Shu-Yi; Chang, Chia-Che

    2015-01-01

    Sulforaphane is a cruciferous vegetable-derived isothiocyanate with promising chemopreventive and therapeutic activities. Induction of proliferation arrest and apoptosis principally contribute to sulforaphane's anticancer activity, but the precise molecular mechanisms remain elusive. The oncoprotein SKP2 is a key component of the SKP1-CULLIN1-F-box (SCF) E3 ligase complex and is responsible for directing SCF-mediated degradation of cyclin-dependent kinase inhibitor p27(KIP1) to promote cell proliferation. We herein provide the first evidence supporting the critical involvement of the SKP2-p27(KIP1) axis in sulforaphane-induced antiproliferation in various human colon adenocarcinoma cell lines. Specifically, sulforaphane markedly suppressed the levels of bromodeoxyuridine (BrdU) incorporation and clonogenicity in all tested cell lines, illustrating the antiproliferative effect of sulforaphane. Of note, sulforaphane-induced antiproliferation was accompanied with down-regulation of SKP2, leading to the stabilization and thus up-regulation of p27(KIP1). Additionally, sulforaphane was found to down-regulate SKP2 mainly through transcriptional repression, as sulforaphane lowered SKP2 mRNA expression and the SKP2 promoter activity. Furthermore, sulforaphane treatment led to the activation of both AKT and ERK, thus ruling out the possibility that sulforaphane down-regulates SKP2 by inhibiting AKT or ERK. Notably, sulforaphane-elicited suppression of BrdU incorporation and clonogenicity were significantly rescued in the context of SKP2 overexpression or p27(KIP1) depletion, therefore highlighting the important role of SKP2 down-regulation and the ensuing stabilization of p27(KIP1) in sulforaphane-induced antiproliferation. Collectively, these data expand our molecular understanding about how sulforaphane elicits proliferation arrest, but also implicate the application of sulforaphane in therapeutic modalities targeting SKP2. Copyright © 2014 The Society for Biotechnology

  11. Deguelin, a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention

    PubMed Central

    WANG, YING; MA, WENLI; ZHENG, WENLING

    2013-01-01

    Deguelin is a natural compound of the flavonoid family products isolated from Derris trifoliata Lour. or Mundulea sericea (Leguminosae). It exhibited significant anti-tumorigenesis and anti-proliferative activity in various types of cancer both in vitro and in vivo. Deguelin induced cell apoptosis by blocking anti-apoptotic pathways, such as PI3K-Akt, IKK-IκBα-NF-κB and AMPK-mTOR-survivin, while inhibiting tumor cell propagation and malignant transformation through p27-cyclinE-pRb-E2F1 cell cycle control and HIF-1α-VEGF anti-angiogenic pathways. In pre-clinical trials, deguelin markedly decreased the tumor incidence. These biological findings identified deguelin as a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention and chemotherapy. PMID:24649149

  12. Quercetin potentiates UVB-induced c-Fos expression: Implications for its use as a chemopreventive agent

    PubMed Central

    Olson, Erik R.; Melton, Tania; Dickinson, Sally E.; Dong, Zigang; Alberts, David S.; Bowden, G. Tim

    2010-01-01

    Quercetin (Qu) is currently being investigated as a chemopreventive agent for a number of cancers including non-melanoma skin cancer induced by ultraviolet (UV) light. We previously reported that Qu degradation has important consequences on signaling and cell biology. In the current study, we report that Qu induces c-Fos mRNA and protein expression through activation of p38 and CREB, and Qu potentiates UVB-induced c-Fos expression. Inclusion of ascorbic acid (AA) in cell culture medium stabilizes Qu and completely prevents both Qu- and UVB- induced p38 and CREB activation, leading to a blockade of c-fos gene expression through reduced CREB/CRE binding. AA stabilizes c-Fos mRNA, increasing steady state levels even when c-fos gene expression is suppressed, but this has no effect on c-Fos protein levels in either mock- or UVB-irradiated cells. We report that Qu blocks mTOR signaling and inhibits c-Fos protein expression directly through this mechanism, since co-treatment with Qu and AA resulted in complete suppression of UVB-induced c-Fos protein expression even in the presence of significantly increased mRNA levels. We further confirmed that this was not due to increased protein turnover since inhibition of proteasome activity with MG-132 did not raise c-Fos protein levels in Qu+AA treated cells. Together, these data indicate that while Qu has been reported to have some beneficial properties as a chemopreventive agent, it is also capable of inducing c-fos expression, a cellular event important for the promotion phase of tumor development, if it is not stabilized. PMID:20551291

  13. Kaiware Daikon (Raphanus sativus L.) extract: a naturally multipotent chemopreventive agent.

    PubMed

    Barillari, Jessica; Iori, Renato; Papi, Alessio; Orlandi, Marina; Bartolini, Giovanna; Gabbanini, Simone; Pedulli, Gian Franco; Valgimigli, Luca

    2008-09-10

    Brassica vegetables are attracting major attention as healthy foods because of their content of glucosinolates (GLs) that release the corresponding isothiocyanates (ITCs) upon myrosinase hydrolysis. A number of studies have so far documented the chemopreventive properties of some ITCs. On the other hand, single nutrients detached from the food itself risk being somewhat "reductive", since plants contain several classes of compounds endowed with a polyhedral mechanism of action. Our recent finding that 4-methylthio-3-butenyl isothiocyanate (GRH-ITC) and 4-methylsulfinyl-3-butenyl isothiocyanate (GRE-ITC), released by the GLs purified from Japanese (Kaiware) Daikon (Raphanus sativus L.) seeds and sprouts, had selective cytotoxic/apoptotic activity on three human colon carcinoma cell lines prompted further research on the potential chemopreventive role of a standardized Kaiware Daikon extract (KDE), containing 10.5% w/w GRH and 3.8% w/w GRE, compared to its isolated components. KDE administered in combination with myrosinase at doses corresponding to 50 microM GRH-ITC plus 15 microM GRE-ITC (50 microM KDE-ITC) to three human cancer cell lines (LoVo, HCT-116 and HT-29) significantly reduced cell growth by 94-96% of control in six days (p < 0.05), outperforming pure GRH-ITC or GRE-ITC at the same dose. On the other hand, the same treatment had no significant toxicity on normal human T-lymphocytes. A 50 microM concentration of KDE-ITC had relevant apoptosis induction in all tested cancer cell lines, as confirmed by annexin V assay (e.g., 33% induction in LoVo compared to control, p < 0.05), Bax protein induction (e.g., +20% in HT-29, p < 0.05), and Bcl2 downregulation (e.g.-20% in HT-29, p < 0.05), and induced caspase-1 and PARP-1 activation in all cancer cells as shown by Western blot analysis. Unlike pure GRH or GRH-ITC, KDE also had significant chain-breaking antioxidant activity, retarding the AAPH-initiated autoxidation of methyl linoleate in SDS micelles at

  14. When Anti-Aging Studies Meet Cancer Chemoprevention: Can Anti-Aging Agent Kill Two Birds with One Blow?

    PubMed

    Yokoyama, Noriko N; Denmon, Andria; Uchio, Edward M; Jordan, Mark; Mercola, Dan; Zi, Xiaolin

    2015-12-01

    Recent evidence has strongly supported that the rate of aging is controlled, at least to some extent, by evolutionarily conserved nutrient sensing pathways (e.g. the insulin/IGF-1-signaling, mTOR, AMPK, and sirtuins) from worms to humans. These pathways are also commonly involved in carcinogenesis and cancer metabolism. Agents (e.g. metformin, resveratrol, and Rhodiola) that target these nutrient sensing pathways often have both anti-aging and anti-cancer efficacy. These agents not only reprogram energy metabolism of malignant cells, but also target normal postmitotic cells by suppressing their conversion into senescent cells, which confers systematic metabolism benefits. These agents are fundamentally different from chemotherapy (e.g. paclitaxel and doxorubicin) or radiation therapy that causes molecular damage (e.g. DNA and protein damages) and thereby no selection resistance may be expected. By reviewing molecular mechanisms of action, epidemiological evidence, experimental data in tumor models, and early clinical study results, this review provides information supporting the promising use of agents with both anti-aging and anti-cancer efficacy for cancer chemoprevention.

  15. When Anti-Aging Studies Meet Cancer Chemoprevention: Can Anti-Aging Agent Kill Two Birds with One Blow?

    PubMed Central

    Yokoyama, Noriko N.; Denmon, Andria; Uchio, Edward M.; Jordan, Mark; Mercola, Dan; Zi, Xiaolin

    2015-01-01

    Recent evidence has strongly supported that the rate of aging is controlled, at least to some extent, by evolutionarily conserved nutrient sensing pathways (e.g. the insulin/IGF-1-signaling, mTOR, AMPK, and sirtuins) from worms to humans. These pathways are also commonly involved in carcinogenesis and cancer metabolism. Agents (e.g. metformin, resveratrol, and Rhodiola) that target these nutrient sensing pathways often have both anti-aging and anti-cancer efficacy. These agents not only reprogram energy metabolism of malignant cells, but also target normal postmitotic cells by suppressing their conversion into senescent cells, which confers systematic metabolism benefits. These agents are fundamentally different from chemotherapy (e.g. paclitaxel and doxorubicin) or radiation therapy that causes molecular damage (e.g. DNA and protein damages) and thereby no selection resistance may be expected. By reviewing molecular mechanisms of action, epidemiological evidence, experimental data in tumor models, and early clinical study results, this review provides information supporting the promising use of agents with both anti-aging and anti-cancer efficacy for cancer chemoprevention. PMID:26756023

  16. Dietary chemoprevention strategies for induction of phase II xenobiotic-metabolizing enzymes in lung carcinogenesis: A review

    PubMed Central

    Tan, Xiang-Lin; Spivack, Simon D.

    2013-01-01

    Lung cancer is the leading cause of cancer mortality for men and women in the United States and is a growing worldwide problem. Protection against lung cancer is associated with higher dietary intake of fruits and vegetables, according to recent large epidemiologic studies. One strategy for lung cancer chemoprevention focuses on the use of agents to modulate the metabolism and disposition of tobacco, environmental and endogenous carcinogens through upregulation of detoxifying phase II enzymes. We summarize the substantial evidence that suggests that induction of phase II enzymes, particularly the glutathione S-transferases, plays a direct role in chemoprotection against lung carcinogenesis. The engagement of the Keap1–Nrf2 complex regulating the antioxidant response element (ARE) signaling pathway has been identified as a key molecular target of chemopreventive phase II inducers in several systems. Monitoring of phase II enzyme induction has led to identification of novel chemopreventive agents such as the isothiocyanate sulforaphane, and the 1,2-dithiole-3-thiones. However, no agents have yet demonstrated clear benefit in human cell systems, or in clinical trials. Alternative strategies include: (a) using intermediate cancer biomarkers for the endpoint in human trials; (b) high-throughput small molecule discovery approaches for induced expression of human phase II genes; and (c) integrative approaches that consider pharmacogenetics, along with pharmacokinetics and pharmacodynamics in target lung tissue. These approaches may lead to a more effective strategy of tailored chemoprevention efforts using compounds with proven human activity. PMID:19185948

  17. Dietary chemoprevention strategies for induction of phase II xenobiotic-metabolizing enzymes in lung carcinogenesis: A review.

    PubMed

    Tan, Xiang-Lin; Spivack, Simon D

    2009-08-01

    Lung cancer is the leading cause of cancer mortality for men and women in the United States and is a growing worldwide problem. Protection against lung cancer is associated with higher dietary intake of fruits and vegetables, according to recent large epidemiologic studies. One strategy for lung cancer chemoprevention focuses on the use of agents to modulate the metabolism and disposition of tobacco, environmental and endogenous carcinogens through upregulation of detoxifying phase II enzymes. We summarize the substantial evidence that suggests that induction of phase II enzymes, particularly the glutathione S-transferases, plays a direct role in chemoprotection against lung carcinogenesis. The engagement of the Keap1-Nrf2 complex regulating the antioxidant response element (ARE) signaling pathway has been identified as a key molecular target of chemopreventive phase II inducers in several systems. Monitoring of phase II enzyme induction has led to identification of novel chemopreventive agents such as the isothiocyanate sulforaphane, and the 1,2-dithiole-3-thiones. However, no agents have yet demonstrated clear benefit in human cell systems, or in clinical trials. Alternative strategies include: (a) using intermediate cancer biomarkers for the endpoint in human trials; (b) high-throughput small molecule discovery approaches for induced expression of human phase II genes; and (c) integrative approaches that consider pharmacogenetics, along with pharmacokinetics and pharmacodynamics in target lung tissue. These approaches may lead to a more effective strategy of tailored chemoprevention efforts using compounds with proven human activity.

  18. 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.

  19. Erucin, a new promising cancer chemopreventive agent from rocket salads, shows anti-proliferative activity on human lung carcinoma A549 cells.

    PubMed

    Melchini, A; Costa, C; Traka, M; Miceli, N; Mithen, R; De Pasquale, R; Trovato, A

    2009-07-01

    Erucin (ER) is a dietary isothiocyanate present in cruciferous vegetables, such as rocket salads (Erucasativa Mill., Diplotaxis sp.), that has been recently considered a promising cancer chemopreventive phytochemical. Biological activity of ER was investigated on human lung adenocarcinoma A549 cells, analyzing its effects on molecular pathways involved in apoptosis and cell cycle arrest, such as PARP-1 cleavage, p53 and p21 protein expression. Our results show that ER affects the A549 cell proliferation, enhancing significantly p53 and p21 protein expression in a dose-dependent manner (p<0.001). PARP-1 cleavage occurs only after exposure to high concentrations of ER (50 microM), in accordance to previous studies showing similar bioactivity of other isothiocyanates (ITCs). Our study reports for the first time that the induction of p53, p21 and PARP-1 cleavage may participate in the anti-proliferative activity of ER in human lung adenocarcinoma A549 cells. Comparison of data with those obtained with the isothiocyanate sulforaphane (SF), structurally related to ER, underlines the strong relationship between structural analogy of ITCs and their biological activity. The ability of dietary compounds to modulate molecular mechanisms that affect cancer cell proliferation is certainly a key point of the cancer prevention potential by functional foods.

  20. 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.

  1. Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50(Cdc37) complex and direct interactions with amino acids residues of Hsp90.

    PubMed

    Li, Yanyan; Karagöz, G Elif; Seo, Young Ho; Zhang, Tao; Jiang, Yiqun; Yu, Yanke; Duarte, Afonso M S; Schwartz, Steven J; Boelens, Rolf; Carroll, Kate; Rüdiger, Stefan G D; Sun, Duxin

    2012-12-01

    Sulforaphane [1-isothiocyanato-4-(methyl-sulfinyl) butane)], an isothiocyanate derived from cruciferous vegetables, has been shown to possess potent chemopreventive activity. We analyzed the effect of sulforaphane on the proliferation of pancreatic cancer cells. Sulforaphane inhibited pancreatic cancer cell growth in vitro with IC(50)s of around 10-15 μM and induced apoptosis. In pancreatic cancer xenograft mouse model, administration of sulforaphane showed remarkable inhibition of tumor growth without apparent toxicity noticed. We found that sulforaphane induced the degradation of heat shock protein 90 (Hsp90) client proteins and blocked the interaction of Hsp90 with its cochaperone p50(Cdc37) in pancreatic cancer cells. Using nuclear magnetic resonance spectroscopy (NMR) with an isoleucine-specific labeling strategy, we overcame the protein size limit of conventional NMR and studied the interaction of sulforaphane with full-length Hsp90 dimer (170 kDa) in solution. NMR revealed multiple chemical shifts in sheet 2 and the adjacent loop in Hsp90 N-terminal domain after incubation of Hsp90 with sulforaphane. Liquid chromatography coupled to mass spectrometry further mapped a short peptide in this region that was tagged with sulforaphane. These data suggest a new mechanism of sulforaphane that disrupts protein-protein interaction in Hsp90 complex for its chemopreventive activity. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50Cdc37 complex and direct interactions with amino acids residues of Hsp90

    PubMed Central

    Li, Yanyan; Karagöz, G. Elif; Seo, Young Ho; Zhang, Tao; Jiang, Yiqun; Yu, Yanke; Duarte, Afonso M.S.; Schwartz, Steven J.; Boelens, Rolf; Carroll, Kate; Rüdiger, Stefan G. D.; Sun, Duxin

    2011-01-01

    Sulforaphane [1-isothiocyanato-4-(methyl-sulfinyl) butane)], an isothiocyanate derived from cruciferous vegetables, has been shown to possess potent chemopreventive activity. We analyzed the effect of sulforaphane on the proliferation of pancreatic cancer cells. Sulforaphane inhibited pancreatic cancer cell growth in vitro with the IC50's around 10-15 μM and induced apoptosis. In pancreatic cancer xenograft mouse model, administration of sulforaphane showed remarkable inhibition of tumor growth without apparent toxicity noticed. We found that sulforaphane induced the degradation of heat shock protein 90 (Hsp90) client proteins and blocked the interaction of Hsp90 with its cochaperone p50Cdc37 in pancreatic cancer cells. Using Nuclear Magnetic Resonance Spectroscopy (NMR) with an isoleucine-specific labeling strategy, we overcame the protein size limit of conventional NMR and studied the interaction of sulforaphane with full-length Hsp90 dimer (170 kDa) in solution. NMR revealed multiple chemical shifts in sheet 2 and the adjacent loop in Hsp90 N-terminal domain after incubation of Hsp90 with sulforaphane. Liquid Chromatography coupled to Mass Spectrometry (LC-MS) further mapped a short peptide in this region that was tagged with sulforaphane. These data suggest a new mechanism of sulforaphane that disrupts protein-protein interaction in Hsp90 complex for its chemopreventive activity. PMID:22444872

  3. Sulforaphane inhibits hypoxia-induced HIF-1α and VEGF expression and migration of human colon cancer cells.

    PubMed

    Kim, Dong Hwan; Sung, Bokyung; Kang, Yong Jung; Hwang, Seong Yeon; Kim, Min Jeong; Yoon, Jeong-Hyun; Im, Eunok; Kim, Nam Deuk

    2015-12-01

    The effects of sulforaphane (a natural product commonly found in broccoli) was investigated on hypoxia inducible factor-1α (HIF-1α) expression in HCT116 human colon cancer cells and AGS human gastric cancer cells. We found that hypoxia-induced HIF-1α protein expression in HCT116 and AGS cells, while treatment with sulforaphane markedly and concentration-dependently inhibited HIF-1α expression in both cell lines. Treatment with sulforaphane inhibited hypoxia-induced vascular endothelial growth factor (VEGF) expression in HCT116 cells. Treatment with sulforaphane modulated the effect of hypoxia on HIF-1α stability. However, degradation of HIF-1α by sulforaphane was not mediated through the 26S proteasome pathway. We also found that the inhibition of HIF-1α by sulforaphane was not mediated through AKT and extracellular signal-regulated kinase phosphorylation under hypoxic conditions. Finally, hypoxia-induced HCT116 cell migration was inhibited by sulforaphane. These data suggest that sulforaphane may inhibit human colon cancer progression and cancer cell angiogenesis by inhibiting HIF-1α and VEGF expression. Taken together, these results indicate that sulforaphane is a new and potent chemopreventive drug candidate for treating patients with human colon cancer.

  4. 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

  5. A Novel Derivative of the Natural Agent Deguelin for Cancer Chemoprevention and Therapy

    PubMed Central

    Kim, Woo-Young; Chang, Dong Jo; Hennessy, Bryan; Kang, Hae-Jin; Yoo, Jakyung; Han, Seung-Ho; Kim, Yoo-Shin; Park, Hyun-Ju; Geo, Seung-Yong; Mills, Gordon; Kim, Kyu-Won; Hong, Waun Ki; Suh, Young-Ger; Lee, Ho-Young

    2009-01-01

    The natural compound deguelin has promising preventive and therapeutic activity against diverse cancers by directly binding to heat-shock protein 90 (Hsp90) and thus suppressing its function. Potential side effects of deguelin over a certain dose, however, could be a substantial obstacle to its clinical use. To develop a derivative(s) of deguelin with reduced potential side effects, we synthesized five deguelin analogues (SH-02, SH-03, SH-09, SH-14 and SH-15) and compared them with the parent compound and each other for structural and biochemical features, solubility, and antiproliferative effects on normal, premalignant and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines. Four derivatives destabilized hypoxia-inducible factor-1α as potently as did deguelin. Reverse-phase protein array (RPPA) analysis in H460 NSCLC cells revealed that deguelin and the derivatives suppressed expression of a number of proteins including Hsp90 clients and proteins involved in the phosphoinositide 3 kinase (PI3K)/Akt pathway. One derivative, SH-14, showed several features of potential superiority for clinical use: the highest apoptotic activity; no detectable influence on Src/signal transducer and activator of transcription (STAT) signaling, which can promote cancer progression and is closely related to pathogenesis of Parkinson’s disease (deguelin, SH-02 and SH-03 strongly activated this signaling); better aqueous solubility; and less cytotoxicity to immortalized HBE cells (versus deguelin) at a dose (1 μM) that induced apoptotic activity in most premalignant and malignant HBE and NSCLC cell lines. These collective results suggest that the novel derivative SH-14 has strong potential for cancer chemoprevention and therapy, with equivalent efficacy and lesser toxicity (versus deguelin). PMID:19139008

  6. Chemoprevention of Lung Cancer

    PubMed Central

    Szabo, Eva; Mao, Jenny T.; Lam, Stephen; Reid, Mary E.

    2013-01-01

    Background: Lung cancer is the most common cause of cancer death in men and women in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk of developing lung cancer compared with lifetime never smokers. Chemoprevention refers to the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention. Methods: Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations. Results: None of the phase 3 trials with the agents β-carotene, retinol, 13-cis-retinoic acid, α-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium has demonstrated beneficial and reproducible results. To facilitate the evaluation of promising agents and to lessen the need for a large sample size, extensive time commitment, and expense, surrogate end point biomarker trials are being conducted to assist in identifying the most promising agents for later-stage chemoprevention trials. With the understanding of important cellular signaling pathways and the expansion of potentially important targets, agents (many of which target inflammation and the arachidonic acid pathway) are being developed and tested which may prevent or reverse lung carcinogenesis. Conclusions: By integrating biologic knowledge, additional early-phase trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points. PMID:23649449

  7. Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property.

    PubMed

    Azmi, Asfar S; Sarkar, Fazlul H; Hadi, S M

    2013-01-01

    " Let food be thy medicine and medicine be thy food" was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating) behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

  8. Off-target effects of sulforaphane include the derepression of long terminal repeats through histone acetylation events.

    PubMed

    Baier, Scott R; Zbasnik, Richard; Schlegel, Vicki; Zempleni, Janos

    2014-06-01

    Sulforaphane is a naturally occurring isothiocyanate in cruciferous vegetables. Sulforaphane inhibits histone deacetylases, leading to the transcriptional activation of genes including tumor suppressor genes. The compound has attracted considerable attention in the chemoprevention of prostate cancer. Here we tested the hypothesis that sulforaphane is not specific for tumor suppressor genes but also activates loci such as long terminal repeats (LTRs), which might impair genome stability. Studies were conducted using chemically pure sulforaphane in primary human IMR-90 fibroblasts and in broccoli sprout feeding studies in healthy adults. Sulforaphane (2.0 μM) caused an increase in LTR transcriptional activity in cultured cells. Consumption of broccoli sprouts (34, 68 or 102 g) by human volunteers caused a dose dependent elevation in LTR mRNA in circulating leukocytes, peaking at more than a 10-fold increase. This increase in transcript levels was associated with an increase in histone H3 K9 acetylation marks in LTR 15 in peripheral blood mononuclear cells from subjects consuming sprouts. Collectively, this study suggests that sulforaphane has off-target effects that warrant further investigation when recommending high levels of sulforaphane intake, despite its promising activities in chemoprevention. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. The failure of cancer chemoprevention.

    PubMed

    Potter, John D

    2014-05-01

    Chemoprevention is proposed as a clinical analogue of population prevention, aimed at reducing likelihood of disease progression, not across the population, but in identified high-risk individuals and not by behavioral or lifestyle modification, but by the use of pharmaceutical agents. Cardiovascular chemoprevention is successful via control of hyperlipidemias and hypertension. However, chemoprevention of cancer is an almost universal failure: not only are some results null; even more frequently, there is an excess of disease, including disease that the agents were chosen specifically to reduce. A brief introduction is followed by the evidence for a wide variety of agents and their largely deleterious, sometimes null, and in one case, largely beneficial, consequences as possible chemopreventives. The agents include (i) those that are food derived and their synthetic analogues: β-carotene, folic acid, retinol and retinoids, vitamin E, multivitamin supplements, vitamin C, calcium and selenium and (ii) agents targeted at metabolic and hormonal pathways: statins, estrogen and antagonists, 5α-reductase inhibitors. There are two agents for which there is good evidence of benefit when the strategy is focused on those at defined high risk but where wider application is much more problematic: aspirin and tamoxifen. The major problems with cancer chemoprevention are presented. This is followed by a hypothesis to explain the failure of cancer chemoprevention as an enterprise, arguing that the central tenets that underpin it are flawed and showing why, far from doing good, cancer chemoprevention causes harm.

  10. The cyclooxygenase-2 inhibitor etoricoxib is a potent chemopreventive agent of colon carcinogenesis in the rat model.

    PubMed

    Saini, Manpreet Kaur; Sharma, Pinky; Kaur, Jasmeet; Sanyal, Sankar Nath

    2009-01-01

    Cyclooxygenase-2 (COX-2), an inducible prostaglandin G/H synthase, is overexpressed in several human cancers, including colon cancer, and therefore the potential ability of a selective COX-2 inhibitor, etoricoxib, is considered in the prevention of the 1,2-dimethyl hydrazine (DMH)-induced colon carcinogenesis in the rat model. DMH was injected s.c. for 6 weeks, whereas etoricoxib was fed orally to the rats on a daily basis. The results showed that DMH produced a very high number of multiple plaque lesions (MPLs), putative neoplastic biomarkers, localized throughout the colon, whereas considerable regression was observed with etoricoxib treatment. In addition, the etoricoxib group was the only group that exhibited very few of these lesions. Histopathological analysis revealed extreme dysplasia, a few adenomas, and other carcinogenic changes in the DMH group, which are distinctly absent in the etoricoxib-treated group. COX-2 was also seen to be highly expressed following DMH treatment. The DMH treatment caused very few apoptotic cells, as determined by the TUNEL assay of the colonic mucosa in paraffin sections whose number greatly increased following etoricoxib treatment. Because all these changes were clearly reversed by etoricoxib in DMH-treated animals, and the use of etoricoxib alone did not produce a neoplastic effect per se, it appears that etoricoxib, a selective COX-2 inhibitor, might be a safe and potentially chemopreventive agent in colon cancer.

  11. Chemoprevention: a primary cancer prevention strategy.

    PubMed

    Smith, Judith J; Tully, Patricia; Padberg, Rose Mary

    2005-11-01

    To review cancer chemoprevention clinical trials, and to discuss associated roles, responsibilities, and challenges for nursing. Journal articles, textbooks, and government reports. Chemoprevention offers a promising approach to primary cancer prevention for a variety of organ systems. Candidate agents are rigorously evaluated for safety and efficacy through the chemoprevention clinical trials process. Chemoprevention is an emerging discipline in which complex clinical trials are being conducted. Nurses play key roles in planning, coordinating, and implementing these studies.

  12. 25-Hydroxyvitamin D3 is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture

    PubMed Central

    Peng, Xinjian; Hawthorne, Michael; Vaishnav, Avani; St-Arnaud, René

    2009-01-01

    chemopreventive agent for further development for breast cancer prevention. PMID:18205042

  13. 25-Hydroxyvitamin D3 is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture.

    PubMed

    Peng, Xinjian; Hawthorne, Michael; Vaishnav, Avani; St-Arnaud, René; Mehta, Rajendra G

    2009-01-01

    (OH)D(3) could serve as a non-toxic natural chemopreventive agent for further development for breast cancer prevention.

  14. Chemoprevention of Melanoma

    PubMed Central

    Madhunapantula, SubbaRao V.; Robertson, Gavin P.

    2013-01-01

    Despite advances in drug discovery programs and molecular approaches for identifying the drug targets, incidence and mortality rates due to melanoma continues to rise at an alarming rate. Existing preventive strategies generally involve mole screening followed by surgical removal of the benign nevi and abnormal moles. However, due to lack of effective programs for screening and disease recurrence after surgical resection there is a need for better chemopreventive agents. Although sunscreens have been used extensively for protecting from UV-induced skin cancer, results of correlative population based studies are controversial, requiring further authentication to conclusively confirm the chemoprotective efficacy of sunscreens. Certain studies suggest increased skin-cancer rates in sunscreen users. Therefore, effective chemopreventive agents for preventing melanoma are urgently required. This book-chapter, reviews the current understanding regarding melanoma chemoprevention and the various strategies used to accomplish this objective. PMID:22959032

  15. 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

  16. Relationships between pulmonary micro-RNA and proteome profiles, systemic cytogenetic damage and lung tumors in cigarette smoke-exposed mice treated with chemopreventive agents.

    PubMed

    Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; La Maestra, Sebastiano; Micale, Rosanna T; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

    2013-10-01

    Assessing the correlation between molecular endpoints and cancer induction or prevention aims at validating the use of intermediate biomarkers. We previously developed murine models that are suitable to detect both the carcinogenicity of mainstream cigarette smoke (MCS) and the induction of molecular alterations. In this study, we used 931 Swiss mice in two parallel experiments and in a preliminary toxicity study. The chemopreventive agents included vorinostat, myo-inositol, bexarotene, pioglitazone and a combination of bexarotene and pioglitazone. Pulmonary micro-RNAs and proteins were evaluated by microarray analyses at 10 weeks of age in male and female mice, either unexposed or exposed to MCS since birth, and either untreated or receiving each one of the five chemopreventive regimens with the diet after weaning. At 4 months of age, the frequency of micronucleated normochromatic erythrocytes was evaluated. At 7 months, the lungs were subjected to standard histopathological analysis. The results showed that exposure to MCS significantly downregulated the expression of 79 of 694 lung micro-RNAs (11.4%) and upregulated 66 of 1164 proteins (5.7%). Administration of chemopreventive agents modulated the baseline micro-RNA and proteome profiles and reversed several MCS-induced alterations, with some intergender differences. The stronger protective effects were produced by the combination of bexarotene and pioglitazone, which also inhibited the MCS-induced clastogenic damage and the yield of malignant tumors. Pioglitazone alone increased the yield of lung adenomas. Thus, micro-RNAs, proteins, cytogenetic damage and lung tumors were closely related. The molecular biomarkers contributed to evaluate both protective and adverse effects of chemopreventive agents and highlighted the mechanisms involved.

  17. Mitochondrial structure alteration in human prostate cancer cells upon initial interaction with a chemopreventive agent phenethyl isothiocyanate.

    PubMed

    Xue, Chengsen; Pasolli, Hilda A; Piscopo, Irene; Gros, Daniel J; Liu, Christina; Chen, Yamei; Chiao, Jen Wei

    2014-03-31

    Phenethyl isothiocyanate (PEITC), present naturally in cruciferous vegetables, is a chemopreventive agent. It blocks initiation and post-initiation progression of carcinogenesis. Mechanism study in human prostate cancer cells revealed that PEITC is a dual inhibitor of aberrant DNA hypermethylation and histone deacetylases, reactivating silenced genes and regulating the androgen-mediated growth of tumor cells. The identity of the cellular organelle that initially interacts with PEITC has not been fully described. Human prostate cancer LNCaP cells were exposed to PEITC and the effects on cellular fine structure examined by transmission electron microscopic studies. Alteration of mitochondrial membrane potential and cytochrome c release were evaluated as early events of apoptosis, and the TUNEL method for quantifying apoptotic cells. Mitochondria were isolated for determining their protein expression. Ultrastructural analyses have revealed condensed mitochondria and a perturbed mitochondrial cristae structure, which assumed a rounded and dilated shape within 4-hours of PEITC contact, and became more pronounced with longer PEITC exposure. They presented as the most prominent intracellular alterations in the early hours. Mitochondria structure alterations were demonstrated, for the first time, with the isothiocyanates. An increase in the number of smooth endoplasmic reticulum and vacuoles were also noted that is consistent with the presence of autophagy. Early events of apoptosis were detected, with cytochrome c released along with the appearance of mitochondrial alteration. Mitochondrial membrane potential was disrupted within 18 hours of PEITC exposure, preceding the appearance of apoptotic cells with DNA strand breaks. In parallel, the expression of the mitochondrial class III ß-tubulin in the outer membrane, which associates with the permeability transition pore, was significantly reduced as examined with isolated mitochondria. Mitochondria may represent the

  18. Chemoprevention strategies for pancreatic cancer

    PubMed Central

    Stan, Silvia D.; Singh, Shivendra V.; Brand, Randall E.

    2010-01-01

    Pancreatic cancer has a poor prognosis and it is often diagnosed at advanced stages, which makes it very difficult to treat. The low survival rate of patients with pancreatic cancer points toward an increased need for novel therapeutic and chemopreventive strategies and early detection. Increased consumption of fruits and vegetables has been associated with a reduced risk of pancreatic cancer. Both synthetic as well as natural, diet-derived bioactive compounds have been evaluated as pancreatic cancer chemopreventive agents and have been shown to have various degrees of efficacy in cellular and in vivo animal models. Some chemopreventive agents (for example curcumin, resveratrol, B-DIM) have also been reported to sensitize pancreatic cancer cells to standard chemotherapeutic drugs (for example gemcitabine or erlotinib), which suggests the potential use of chemopreventive agents as potentiators of standard chemotherapy. Very few clinical trials with pancreatic cancer chemopreventive agents have been completed and some are in early phases. Further development of pancreatic cancer chemopreventive agents may prove to be tremendously valuable for individuals at high-risk of developing pancreatic cancer and patients who present with premalignant lesions. This Review discusses the current state of the pancreatic cancer chemoprevention field and highlights the challenges ahead. PMID:20440279

  19. 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

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

    PubMed

    Sakai, Hiroyasu; Shirakami, Yohei; Shimizu, Masahito

    2016-01-07

    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.

  1. Evaluation of skin cancer chemoprevention potential of sunscreen agents using the Epstein-Barr virus early antigen activation in vitro assay.

    PubMed

    Kapadia, G J; Rao, G S; Takayasu, J; Takasaki, M; Iida, A; Suzuki, N; Konoshima, T; Tokuda, H

    2013-04-01

    In our continuing search for novel cancer chemopreventive compounds of natural and synthetic origin, we have evaluated 14 commonly used ultraviolet (UV) sunscreen agents (designated UV-1 to UV-14) for their skin cancer chemoprevention potential. They belong to 8 different chemical categories: aminobenzoate (UV-5, UV-7, UV-8 and UV-14), benzophenone (UV-1, UV-2, UV-3 and UV-13), benzotriazole (UV-10), benzyloxyphenol (UV-9), cinnamate (UV-6), quinolone (UV-4), salicylate (UV-11) and xanthone (UV-12). In the in vitro assay employed, the sunscreens were assessed by their inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in human lymphoblastoid Raji cells. All sunscreens tested were found to exhibit anti-tumour promoting activity: listed in decreasing order, moderate (UV-11, UV-2, UV-7, UV-12, UV-3, UV-9 and UV-14) to weak (UV-1, UV-6, UV-8, UV-16, UV-5, UV-4 and UV-10) with octyl salicylate (UV-11) as the most potent and drometrizole (UV-10) as the least potent among the compounds evaluated. A plausible relationship between the antioxidant property of sunscreens and their ability to promote anti-tumour activity was noted. The results call for a comprehensive analysis of skin cancer chemoprevention potential of currently used UV sunscreen agents around the globe to identify those with the best clinical profile.

  2. Cell cycle control as a basis for cancer chemoprevention through dietary agents

    PubMed Central

    Meeran, Syed Musthapa; Katiyar, Santosh Kumar

    2008-01-01

    The development of cancer is associated with disorders in the regulation of the cell cycle. The purpose of this review is to briefly summarize the known sequence of events that regulate cell cycle progression with an emphasis on the checkpoints and the mechanisms cell employ to insure DNA stability in the face of genotoxic stress. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinases (CDK) molecules. The cyclins are CDK binding partners which are required for kinase activity and their protein levels are intimately linked to the cell cycle stage. CDK activity can be regulated by other mechanisms, such as phosphorylation events, that may contribute to deregulation of cell cycle and the development of cancer. While fruits and vegetables are recommended for prevention of cancer, their active ingredients and mechanisms of action are less well understood. Here, we briefly present evidence that dietary agents identified from fruits and vegetables can act to modulate the effects of deregulated cell cycle checkpoints, and that this may contribute to the prevention of cancer. The agents include apigenin (celery, parsley), curcumin (turmeric), (−)-epigallocatechin-3-gallate (green tea), resveratrol (red grape, peanuts and berries), genistein (soybean), and silymarin (milk thistle). The teachings of Hippocrates are still true “let food be thy medicine and medicine be thy food”. PMID:17981702

  3. 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. © 2013 International Life Sciences Institute.

  4. Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells

    PubMed Central

    Li, Yanyan; Zhang, Tao; Korkaya, Hasan; Liu, Suling; Lee, Hsiu-Fang; Newman, Bryan; Yu, Yanke; Clouthier, Shawn G.; Schwartz, Steven J.; Wicha, Max S.; Sun, Duxin

    2010-01-01

    Purpose The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. In this study, we evaluated sulforaphane, a natural compound derived from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs and its potential mechanism. Experimental Design Aldefluor assay and mammosphere formation assay were used to evaluate the effect of sulforaphane on breast CSCs in vitro. A NOD/SCID xenograft model was employed to determine whether sulforaphane could target breast CSCs in vivo, as assessed by Aldefluor assay and tumor growth upon cell re-implantation in secondary mice. The potential mechanism was investigated utilizing Western blotting analysis and β-catenin reporter assay. Results Sulforaphane (1~5 μM) decreased aldehyde dehydrogenase (ALDH)-positive cell population by 65%~80% in human breast cancer cells (P < 0.01), and reduced the size and number of primary mammospheres by 8~125-fold and 45%~75% (P < 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for two weeks reduced ALDH-positive cells by more than 50% in NOD/SCID xenograft tumors (P = 0.003). Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor growth after re-implantation of primary tumor cells into the secondary mice (P < 0.01). Western blotting analysis and β-catenin reporter assay showed that sulforaphane down-regulated Wnt/β-catenin self-renewal pathway. Conclusions Sulforaphane inhibits breast CSCs and down-regulates Wnt/β-catenin self-renewal pathway. These findings support the use of sulforaphane for chemoprevention of breast cancer stem cells and warrant further clinical evaluation. PMID:20388854

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

    PubMed

    Pastorek, Michal; Simko, Veronika; Takacova, Martina; Barathova, Monika; Bartosova, Maria; Hunakova, Luba; Sedlakova, Olga; Hudecova, Sona; Krizanova, Olga; Dequiedt, Franck; Pastorekova, Silvia; Sedlak, Jan

    2015-07-01

    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.

  6. Chemopreventive Agents and Inhibitors of Cancer Hallmarks: May Citrus Offer New Perspectives?

    PubMed Central

    Cirmi, Santa; Ferlazzo, Nadia; Lombardo, Giovanni E.; Maugeri, Alessandro; Calapai, Gioacchino; Gangemi, Sebastiano; Navarra, Michele

    2016-01-01

    Fruits and vegetables have long been recognized as potentially important in the prevention of cancer risk. Thus, scientific interest in nutrition and cancer has grown over time, as shown by increasing number of experimental studies about the relationship between diet and cancer development. This review attempts to provide an insight into the anti-cancer effects of Citrus fruits, with a focus on their bioactive compounds, elucidating the main cellular and molecular mechanisms through which they may protect against cancer. Scientific literature was selected for this review with the aim of collecting the relevant experimental evidence for the anti-cancer effects of Citrus fruits and their flavonoids. The findings discussed in this review strongly support their potential as anti-cancer agents, and may represent a scientific basis to develop nutraceuticals, food supplements, or complementary and alternative drugs in a context of a multi-target pharmacological strategy in the oncology. PMID:27827912

  7. Isolation and identification of potential cancer chemopreventive agents from methanolic extracts of green onion (Allium cepa).

    PubMed

    Xiao, Hang; Parkin, Kirk L

    2007-04-01

    Phase II xenobiotic metabolizing enzymes confer amelioration of risk arising from potentially carcinogenic chemicals derived both endogenously, and exogenously, from food and the environment. In this study, efforts were made to isolate and identify potentially cancer preventive constituents from methanolic extracts of green onion (Allium cepa) directed by the quinone reductase (QR) induction bioassay using murine hepatoma (Hepa 1c1c7) cells. Crude methanolic extracts of green onion tissue were solvent-partitioned, and subsequently fractionated by flash chromatography, thin layer chromatography and high pressure preparative liquid chromatography to afford pure QR-inducing isolates. Multiple isolates were found active at inducing QR. One newly identified compound, 5-hydroxy-3-methyl-4-propylsulfanyl-5H-furan-2-one (3), and four known compounds: 5-(hydroxymethyl) furfural (1), acetovanillone (2), methyl 4-hydroxyl cinnamate (4) and ferulic acid methyl ester (5), were isolated and identified as active agents.

  8. Chemopreventive Agents and Inhibitors of Cancer Hallmarks: May Citrus Offer New Perspectives?

    PubMed

    Cirmi, Santa; Ferlazzo, Nadia; Lombardo, Giovanni E; Maugeri, Alessandro; Calapai, Gioacchino; Gangemi, Sebastiano; Navarra, Michele

    2016-11-04

    Fruits and vegetables have long been recognized as potentially important in the prevention of cancer risk. Thus, scientific interest in nutrition and cancer has grown over time, as shown by increasing number of experimental studies about the relationship between diet and cancer development. This review attempts to provide an insight into the anti-cancer effects of Citrus fruits, with a focus on their bioactive compounds, elucidating the main cellular and molecular mechanisms through which they may protect against cancer. Scientific literature was selected for this review with the aim of collecting the relevant experimental evidence for the anti-cancer effects of Citrus fruits and their flavonoids. The findings discussed in this review strongly support their potential as anti-cancer agents, and may represent a scientific basis to develop nutraceuticals, food supplements, or complementary and alternative drugs in a context of a multi-target pharmacological strategy in the oncology.

  9. The Inactivation of Human CYP2E1 by Phenethyl Isothiocyanate, a Naturally Occurring Chemopreventive Agent, and Its Oxidative Bioactivation

    PubMed Central

    Yoshigae, Yasushi; Sridar, Chitra; Kent, Ute M.

    2013-01-01

    Phenethylisothiocyanate (PEITC), a naturally occurring isothiocyanate and potent cancer chemopreventive agent, works by multiple mechanisms, including the inhibition of cytochrome P450 (P450) enzymes, such as CYP2E1, that are involved in the bioactivation of carcinogens. PEITC has been reported to be a mechanism-based inactivator of some P450s. We describe here the possible mechanism for the inactivation of human CYP2E1 by PEITC, as well as the putative intermediate that might be involved in the bioactivation of PEITC. PEITC inactivated recombinant CYP2E1 with a partition ratio of 12, and the inactivation was not inhibited in the presence of glutathione (GSH) and not fully recovered by dialysis. The inactivation of CYP2E1 by PEITC is due to both heme destruction and protein modification, with the latter being the major pathway for inactivation. GSH-adducts of phenethyl isocyanate (PIC) and phenethylamine were detected during the metabolism by CYP2E1, indicating formation of PIC as a reactive intermediate following P450-catalyzed desulfurization of PEITC. Surprisingly, PIC bound covalently to CYP2E1 to form protein adducts but did not inactivate the enzyme. Liquid chromatography mass spectroscopy analysis of the inactivated CYP2E1 apo-protein suggests that a reactive sulfur atom generated during desulfurization of PEITC is involved in the inactivation of CYP2E1. Our data suggest that the metabolism of PEITC by CYP2E1 that results in the inactivation of CYP2E1 may occur by a mechanism similar to that observed with other sulfur-containing compounds, such as parathion. Digestion of the inactivated enzyme and analysis by SEQUEST showed that Cys 268 may be the residue modified by PIC. PMID:23371965

  10. 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

  11. 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

  12. Potential Chemopreventive Agents Based on the Structure of the Lead Compound 2-Bromo-1-hydroxyphenazine, Isolated from Streptomyces sp., Strain CNS284

    PubMed Central

    Conda-Sheridan, Martin; Marler, Laura; Park, Eun-Jung; Kondratyuk, Tamara P.; Jermihov, Katherine; Mesecar, Andrew D.; Pezzuto, John M.; Asolkar, Ratnakar N.; Fenical, William; Cushman, Mark

    2010-01-01

    The isolation of 2-bromo-1-hydroxyphenazine from a marine Streptomyces sp., strain CNS284, and its activity against NFκB, suggested that a short and flexible route for the synthesis of this metabolite and a variety of phenazine analogues be developed. Numerous phenazines were subsequently prepared and evaluated as inducers of quinone reductase 1 (QR1) and inhibitors of quinone reductase 2 (QR2), NF-κB, and inducible nitric oxide synthase (iNOS). Several of the active phenazine derivatives displayed IC50 values vs. QR1 induction and QR2 inhibition in the nanomolar range, suggesting they may find utility as cancer chemopreventive agents. PMID:21105712

  13. 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

  14. 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.

  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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Cancer chemoprevention - selected molecular mechanisms.

    PubMed

    Walczak, Katarzyna; Marciniak, Sebastian; Rajtar, Grażyna

    2017-03-02

    The effect of diet on cancer formation and prevention of carcinogenesis has attracted considerable attention for years and is the subject of several studies. Some components of the daily diet, such as resveratrol, curcumin, genistein, gingerol, can significantly reduce the risk of cancer or affect the rate of tumor progression. Cancer chemoprevention assumes the use of natural or synthetic biologically active substances in order to prevent, inhibit or reverse the progression of cancer. There are many biologically active compounds in several natural products, i.e. garlic, ginger, soy, curcuma, tomatoes, cruciferous plants or green tea. Their chemopreventive activity is based on the inhibition of processes underlying carcinogenesis (inflammation, transformation and proliferation), but also affects the final phase of carcinogenesis - angiogenesis and metastasis. Despite the relatively low toxicity of chemopreventive agents, their molecular targets often coincide with the objectives of the currently used cancer therapies. The widespread use of chemopreventive agents may contribute to reduction of the rate of cancer incidence, and increase the effectiveness of conventional cancer therapies. In the present study, selected molecular mechanisms of the chemopreventive activity have been discussed, especially their involvement in the regulation of signal transduction, cell cycle regulation, apoptosis, metastasis and angiogenesis. The role of chemopreventive agents in the inflammatory process, the metabolism of xenobiotics and multidrug resistance has been also characterized.

  17. [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.

  18. The challenges for cancer chemoprevention.

    PubMed

    Penny, Lewis K; Wallace, Heather M

    2015-12-21

    The incidence of cancer is rising in parallel with an ageing populous thus increasing the strain on both treatment options and budgets for healthcare providers worldwide. New cancer therapies are being developed but at what cost? The new treatments are expensive and poor survival rates still exist for some cancers. What is needed now is to prevent or at least limit the disease occurring in the first place. This review evaluates the current situation and the progress in upcoming strategies as well as suggesting some areas for further research within the increasingly important field of cancer chemoprevention. The key principles of cancer chemoprevention are discussed and areas for improvement highlighted. Despite significant progress, chemoprevention has not been widely adopted. Cancer chemoprevention has many challenges to face but this only emphasises the size of the task. These hurdles include a lack of awareness of the benefits, a lack of interest and a lack of investment in taking prevention forward. Despite the huge potential importance of cancer prevention and clinical success stories such as the well-publicised HPV vaccine, the challenges remain significant. With cancer and its treatment being a global issue, the opportunities offered by chemoprevention must be re-evaluated and uptake of chemoprevention actively encouraged. If chemoprevention is to be adopted successfully, a holistic approach is required. This approach will involve multidisciplinary teams of healthcare providers and scientists with the big challenge particularly for medicinal chemists being to design and synthesise the ideal chemopreventative agent.

  19. Synthesis, spectral characterization, and in vitro cellular activities of metapristone, a potential cancer metastatic chemopreventive agent derived from mifepristone (RU486).

    PubMed

    Wang, Jichuang; Chen, Jianzhong; Wan, Liyuan; Shao, Jingwei; Lu, Yusheng; Zhu, Yewei; Ou, Minrui; Yu, Suhong; Chen, Haijun; Jia, Lee

    2014-03-01

    Mifepristone (RU486) is marketed and used widely by women as an abortifacient, and experimentally for psychotic depression and anticancer treatments. After administration, metapristone is found to be the most predominant metabolite of mifepristone. We hypothesized that adhesion of circulating tumor cells (CTCs) to vascular endothelial bed is a crucial starting point in metastatic cascade, and that metapristone can serve as a cancer metastatic chemopreventive agent that can interrupt adhesion and invasion of CTCs to the intima of microvasculature. In the present study, we modified the synthesis procedure to produce grams of metapristone, fully characterized its spectral properties and in vitro cellular activities, including its cytostatic effects, cell cycle arrest, mitochondrial membrane potential, and apoptosis on human colorectal cancer HT-29 cells. Metapristone concentration dependently interrupted adhesion of HT-29 cells to endothelial cells. Metapristone may potentially be a useful agent to interrupt metastatic initiation.

  20. Chemopreventive Effects of the p53-Modulating Agents CP-31398 and Prima-1 in Tobacco Carcinogen-Induced Lung Tumorigenesis in A/J Mice1

    PubMed Central

    Rao, Chinthalapally V; Patlolla, Jagan Mohan R; Qian, Li; Zhang, Yuting; Brewer, Misty; Mohammed, Altaf; Desai, Dhimant; Amin, Shantu; Lightfoot, Stan; Kopelovich, Levy

    2013-01-01

    Lung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 µmol/mouse) by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group) or 34 weeks (15 mice/group) to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001) lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation. PMID:24027427

  1. Effect of Sulforaphane in Men with Biochemical Recurrence after Radical Prostatectomy.

    PubMed

    Cipolla, Bernard G; Mandron, Eric; Lefort, Jean Marc; Coadou, Yves; Della Negra, Emmanuel; Corbel, Luc; Le Scodan, Ronan; Azzouzi, Abdel Rahmene; Mottet, Nicolas

    2015-08-01

    Increases in serum levels of prostate-specific antigen (PSA) occur commonly in prostate cancer after radical prostatectomy and are designated "biochemical recurrence." Because the phytochemical sulforaphane has been studied extensively as an anticancer agent, we performed a double-blinded, randomized, placebo-controlled multicenter trial with sulforaphane in 78 patients (mean age, 69 ± 6 years) with increasing PSA levels after radical prostatectomy. Treatment comprised daily oral administration of 60 mg of a stabilized free sulforaphane for 6 months (M0-M6) followed by 2 months without treatment (M6-M8). The study was designed to detect a 0.012 log (ng/mL)/month decrease in the log PSA slope in the sulforaphane group from M0 to M6. The primary endpoint was not reached. For secondary endpoints, median log PSA slopes were consistently lower in sulforaphane-treated men. Mean changes in PSA levels between M6 and M0 were significantly lower in the sulforaphane group (+0.099 ± 0.341 ng/mL) than in placebo (+0.620 ± 1.417 ng/mL; P = 0.0433). PSA doubling time was 86% longer in the sulforaphane than in the placebo group (28.9 and 15.5 months, respectively). PSA increases >20% at M6 were significantly greater in the placebo group (71.8%) than in the sulforaphane group (44.4%); P = 0.0163. Compliance and tolerance were very good. Sulforaphane effects were prominent after 3 months of intervention (M3-M6). After treatment, PSA slopes from M6 to M8 remained the same in the 2 arms. Daily administration of free sulforaphane shows promise in managing biochemical recurrences in prostate cancer after radical prostatectomy.

  2. Sulforaphane mitigates genotoxicity induced by radiation and anticancer drugs in human lymphocytes.

    PubMed

    Katoch, Omika; Kumar, Arun; Adhikari, Jawahar S; Dwarakanath, Bilikere S; Agrawala, Paban K

    2013-12-12

    Sulforaphane, present in cruciferous vegetables such as broccoli, is a dietary anticancer agent. Sulforaphane, added 2 or 20 h following phytohemaglutinin stimulation to cultured peripheral blood lymphocytes of individuals accidentally exposed to mixed γ and β-radiation, reduced the micronucleus frequency by up to 70%. Studies with whole blood cultures obtained from healthy volunteers confirmed the ability of sulforaphane to ameliorate γ-radiation-induced genotoxicity and to reduce micronucleus induction by other DNA-damaging anticancer agents, such as bleomycin and doxorubicin. This reduction in genotoxicity in lymphocytes treated at the G(0) or G(1) stage suggests a role for sulforaphane in modulating DNA repair. Sulforaphane also countered the radiation-induced increase in lymphocyte HDAC activity, to control levels, when cells were treated 2 h after exposure, and enhanced histone H4 acetylation status. Sulforaphane post-irradiation treatment enhanced the CD 34(+)Lin(-) cell population in culture. Sulforaphane has therapeutic potential for management of the late effects of radiation. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Cancer chemoprevention: a radical perspective.

    PubMed

    Hail, Numsen; Cortes, Marcela; Drake, Edgar N; Spallholz, Julian E

    2008-07-15

    Cancer chemopreventive agents block the transformation of normal cells and/or suppress the promotion of premalignant cells to malignant cells. Certain agents may achieve these objectives by modulating xenobiotic biotransformation, protecting cellular elements from oxidative damage, or promoting a more differentiated phenotype in target cells. Conversely, various cancer chemopreventive agents can encourage apoptosis in premalignant and malignant cells in vivo and/or in vitro, which is conceivably another anticancer mechanism. Furthermore, it is evident that many of these apoptogenic agents function as prooxidants in vitro. The constitutive intracellular redox environment dictates a cell's response to an agent that alters this environment. Thus, it is highly probable that normal cells, through adaption, could acquire resistance to transformation via exposure to a chemopreventive agent that promotes oxidative stress or disrupts the normal redox tone of these cells. In contrast, transformed cells, which typically endure an oxidizing intracellular environment, would ultimately succumb to apoptosis due to an uncontrollable production of reactive oxygen species caused by the same agent. Here, we provide evidence to support the hypothesis that reactive oxygen species and cellular redox tone are exploitable targets in cancer chemoprevention via the stimulation of cytoprotection in normal cells and/or the induction of apoptosis in transformed cells.

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

    PubMed

    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.

  5. 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

  6. 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.

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

    PubMed

    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.

  8. Plant Extracts of the Family Lauraceae: A Potential Resource for Chemopreventive Agents that Activate the Nuclear Factor-Erythroid 2-Related Factor 2/Antioxidant Response Element Pathway

    PubMed Central

    Shen, Tao; Chen, Xue-Mei; Harder, Bryan; Long, Min; Wang, Xiao-Ning; Lou, Hong-Xiang; Wondrak, Georg T.; Ren, Dong-Mei; Zhang, Donna D.

    2015-01-01

    Cells and tissues counteract insults from exogenous or endogenous carcinogens through the expression of genes encoding antioxidants and phase II detoxifying enzymes regulated by antioxidant response element promoter regions. Nuclear factor-erythroid 2-related factor 2 plays a key role in regulating the antioxidant response elements-target gene expression. Hence, the Nrf2/ARE pathway represents a vital cellular defense mechanism against damage caused by oxidative stress and xenobiotics, and is recognized as a potential molecular target for discovering chemo-preventive agents. Using a stable antioxidant response element luciferase reporter cell line derived from human breast cancer MDA-MB-231 cells combined with a 96-well high-throughput screening system, we have identified a series of plant extracts from the family Lauraceae that harbor Nrf2-inducing effects. These extracts, including Litsea garrettii (ZK-08), Cinnamomum chartophyllum (ZK-02), C. mollifolium (ZK-04), C. camphora var. linaloolifera (ZK-05), and C. burmannii (ZK-10), promoted nuclear translocation of Nrf2, enhanced protein expression of Nrf2 and its target genes, and augmented intracellular glutathione levels. Cytoprotective activity of these extracts against two electrophilic toxicants, sodium arsenite and H2O2, was investigated. Treatment of human bronchial epithelial cells with extracts of ZK-02, ZK-05, and ZK-10 significantly improved cell survival in response to sodium arsenite and H2O2, while ZK-08 showed a protective effect against only H2O2. Importantly, their protective effects against insults from both sodium arsenite and H2O2 were Nrf2-dependent. Therefore, our data provide evidence that the selected plants from the family Lauraceae are potential sources for chemopreventive agents targeting the Nrf2/ARE pathway. PMID:24585092

  9. Plant extracts of the family Lauraceae: a potential resource for chemopreventive agents that activate the nuclear factor-erythroid 2-related factor 2/antioxidant response element pathway.

    PubMed

    Shen, Tao; Chen, Xue-Mei; Harder, Bryan; Long, Min; Wang, Xiao-Ning; Lou, Hong-Xiang; Wondrak, Georg T; Ren, Dong-Mei; Zhang, Donna D

    2014-03-01

    Cells and tissues counteract insults from exogenous or endogenous carcinogens through the expression of genes encoding antioxidants and phase II detoxifying enzymes regulated by antioxidant response element promoter regions. Nuclear factor-erythroid 2-related factor 2 plays a key role in regulating the antioxidant response elements-target gene expression. Hence, the Nrf2/ARE pathway represents a vital cellular defense mechanism against damage caused by oxidative stress and xenobiotics, and is recognized as a potential molecular target for discovering chemopreventive agents. Using a stable antioxidant response element luciferase reporter cell line derived from human breast cancer MDA-MB-231 cells combined with a 96-well high-throughput screening system, we have identified a series of plant extracts from the family Lauraceae that harbor Nrf2-inducing effects. These extracts, including Litsea garrettii (ZK-08), Cinnamomum chartophyllum (ZK-02), C. mollifolium (ZK-04), C. camphora var. linaloolifera (ZK-05), and C. burmannii (ZK-10), promoted nuclear translocation of Nrf2, enhanced protein expression of Nrf2 and its target genes, and augmented intracellular glutathione levels. Cytoprotective activity of these extracts against two electrophilic toxicants, sodium arsenite and H2O2, was investigated. Treatment of human bronchial epithelial cells with extracts of ZK-02, ZK-05, and ZK-10 significantly improved cell survival in response to sodium arsenite and H2O2, while ZK-08 showed a protective effect against only H2O2. Importantly, their protective effects against insults from both sodium arsenite and H2O2 were Nrf2-dependent. Therefore, our data provide evidence that the selected plants from the family Lauraceae are potential sources for chemopreventive agents targeting the Nrf2/ARE pathway. Georg Thieme Verlag KG Stuttgart · New York.

  10. Kinetics of sulforaphane in mice after consumption of sulforaphane-enriched broccoli sprout preparation.

    PubMed

    Li, Yanyan; Zhang, Tao; Li, Xiaoqin; Zou, Peng; Schwartz, Steven J; Sun, Duxin

    2013-12-01

    Sulforaphane (SF) is a natural isothiocyanate in broccoli sprouts with cancer chemopreventive activity. This study is aimed to use different methods to develop broccoli sprout preparations to compare their ability to deliver SF to the mice and to evaluate the kinetics and biodistribution of SF. The SF-enriched sprout preparation generated by two-step procedure (quick-steaming followed by myrosinase treatment) contained the highest level of SF, which was 11 and 5 times higher than the freeze-dried fresh broccoli sprouts and the quick-steamed, freeze-dried broccoli sprouts, respectively. After oral administration of 2.5 mg/g body weight of the broccoli sprout preparations, SF was quickly absorbed and distributed throughout the tissues. The SF-rich preparation resulted in the highest exposure, with peak plasma SF concentration of 337 ng/mL, which is 6.0 times and 2.6 times higher compared to the other two preparations. A whole body physiologically based pharmacokinetic model (developed with ADAPT 5 software) suggests that distribution of SF is perfusion-limited in all organs. This study provides a broccoli sprout preparation that can serve as a good source of SF, and the model can be utilized to guide the dose designed for the use of broccoli sprout preparation in chemoprevention. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. 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.

  12. 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.

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

    PubMed

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

    2014-07-01

    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, delay mammary gland tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model. In dose de-escalation studies, mice were fed with 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 with 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 and 6.5 weeks, respectively, compared with 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. ©2014 American Association for Cancer Research.

  14. 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

  15. [Chemoprevention of colorectal cancer].

    PubMed

    Herszényi, László; Juhász, Márk; Prónai, László; Tulassay, Zsolt

    2004-03-21

    Although colorectal cancer is one of the most preventable forms of cancer, it remains the second leading cause of cancer death worldwide. Primary prevention involves the identification and elimination of factors, which cause or promote colorectal cancer. The goal of screening is to prevent colorectal cancer mortality through the detection and treatment of premalignant adenomas and curable-stage cancer. Most colorectal cancers are believed to arise from adenomatous polyps. Early identification and removal of adenomas can prevent the development of colorectal cancer. Chemoprevention is the use of specific chemical compounds to prevent, inhibit, or reverse carcinogenesis. Several chemoprevention options have been investigated and confirmed as effective. Aspirin and other nonsteroidal anti-inflammatory drugs are the most widely studied agents, their use has been consistently associated with reduction in the risk of mortality and the incidence of colorectal adenomas and cancers. The selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been demonstrated to decrease the number and the size of polyps in patients with familial adenomatous polyposis syndrome. Because the gastrointestinal toxicity of coxibs is lower, it might be safer than aspirin or other non-selective nonsteroidal anti-inflammatory drugs for long-term use. This review aims to summarize the recent theoretical and practical advances in the chemoprevention of colorectal cancer.

  16. 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.

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

    PubMed

    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.

  18. 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

  19. Linking genomic responses of gonads with reproductive impairment in marine medaka (Oryzias melastigma) exposed chronically to the chemopreventive and antifouling agent, 3,3'-diindolylmethane (DIM).

    PubMed

    Chen, Lianguo; Au, Doris W T; Hu, Chenyan; Zhang, Weipeng; Zhou, Bingsheng; Cai, Lin; Giesy, John P; Qian, Pei-Yuan

    2017-02-01

    3,3'-Diindolylmethane (DIM) has been promoted as an effective chemopreventive and antifouling additive. However, the concurrent risks or side effects of DIM are not fully understood, especially on tissues responsive to estrogen. Therefore, this study employed marine medaka (Oryzias melastigma) as a test model to evaluate relative safety and explore mechanisms of toxic action of DIM on development and function of gonad after chronic (28days) aqueous exposure to relatively low doses (0μg/L or 8.5μg/L). Integration of comprehensive toxicogenomic analysis at the transcriptome and proteome levels with apical endpoints, such as production of eggs and swimming performance of larvae, elucidated the molecular linkage in gonad from bottom up along the reproductive adverse outcome pathway. A series of sequential changes at the transcript and protein levels were linked to lesser fecundity and viability of larvae exposed to DIM. Anomalous production of vitellogenin (VTG) and eggshell proteins in testis confirmed the estrogenic potency of DIM. In the ovary, although storage of VTG was greater, lesser expressions of cathepsin enzymes blocked cleavage and incorporation of VTG into oocytes as yolk, which acted together with lower eggshell proteins to inhibit maturation of primary oocyte and thus contributed to impairment of fecundity. Overall, this study demonstrated that exposure to DIM impaired reproductive fitness. Diverse molecular initiating changes in gonads were linked to apical endpoints that could be used in assessment of risks posed by DIM on gametogenesis. In combination with chemical stability and potent endocrine disruption, the results of this study can inform decisions about the use of DIM either as chemopreventive or antifouling agent.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Sulforaphane suppresses LPS-induced or TPA-induced downregulation of PDCD4 in RAW 264.7 cells.

    PubMed

    Cho, Jong-Ho; Kim, Young-Woo; Keum, Young-Sam

    2014-11-01

    Sulforaphane is a natural chemopreventive isothiocyanate and abundantly found in various cruciferous vegetables. Although chemopreventive activity of sulforaphane is well documented, the detailed biochemical mechanism(s), underlying how it regulates the protein translation process to antagonize pro-inflammatory responses are largely unclear. In the present study, we show that lipopolysaccharide (LPS) or 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment reduces cellular levels of PDCD4, and this event is mediated by affecting both transcription and proteolysis in RAW 264.7 cells. We show that LPS-mediated or TPA-mediated PDCD4 downregulation is catalyzed by the activation of intracellular Akt1 or S6K1 kinases and that sulforaphane suppresses LPS-induced or TPA-induced Akt1 or S6K1 activation, thereby resulting in the attenuation of PDCD4 downregulation in RAW 264.7 cells. We propose that sulforaphane suppression of PDCD4 downregulation serves as a novel molecular mechanism to control proliferation in response to pro-inflammatory signals. Copyright © 2014 John Wiley & Sons, Ltd.

  6. Chemoprevention of premalignant and malignant lesions of oral cavity: Recent trends

    PubMed Central

    Bodhade, Ashish S.; Dive, Alka M.

    2013-01-01

    The word chemoprevention includes prevention of initiation, promotion, and progression of carcinogenesis to cancer. This article is an attempt to review the dietary chemopreventive agents and their mode of action in chemoprevention of oral premalignant lesions and oral cancer using a systematic approach. Selected chemoprevention trials are discussed with a focus on strategies of trial design and clinical outcome. Future in the field of chemoprevention will be more promising than the recently available therapeutic alternatives. PMID:24883036

  7. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.

    PubMed

    Cheng, A L; Hsu, C H; Lin, J K; Hsu, M M; Ho, Y F; Shen, T S; Ko, J Y; Lin, J T; Lin, B R; Ming-Shiang, W; Yu, H S; Jee, S H; Chen, G S; Chen, T M; Chen, C A; Lai, M K; Pu, Y S; Pan, M H; Wang, Y J; Tsai, C C; Hsieh, C Y

    2001-01-01

    of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.

  8. 2-(Allylthio)pyrazine, a cancer chemopreventive agent, inhibits liver fibrosis induced by dimethylnitrosamine in rats: role of inhibition of transforming growth factor-beta1 expression.

    PubMed

    Kang, K W; Ha, J R; Kim, C W; Kim, N D; Kim, S G

    2001-07-01

    Exposure to nitrosamines may be the occupational risk factor for liver cirrhosis. 2-(Allylthio)pyrazine, a chemopreventive agent, inhibits CYP2E1 and induces phase II enzymes. We examined the effects of 2-(allylthio)pyrazine on hepatic fibrosis, a prepathologic state of cirrhosis, and on the expression of transforming growth factor-beta1 induced by dimethylnitrosamine. Treatment of rats with dimethylnitrosamine for 4 weeks increased plasma alanine/aspartate amino-transferase and y-glutamyl transpeptidase activities, and bilirubin content, whereas the total plasma protein and albumin levels were decreased. 2-(Allylthio)pyrazine inhibited dimethylnitrosamine-induced increases in the enzyme activities and bilirubin, and restored the plasma protein and albumin contents. Masson's trichrome staining showed that dimethylnitrosamine induced liver fibrosis, the extent of which was reduced by 2-(allylthio)pyrazine treatments. Reverse transcription-polymerase chain reaction analysis revealed that 2-(allylthio)pyrazine inhibited production of transforming growth factor-beta1 mRNA by dimethylnitrosamine. These results demonstrated that 2-(allylthio)pyrazine might inhibit dimethylnitrosamine-induced liver fibrosis due to suppression of CYP2E1 expression and transforming growth factor-beta1 production.

  9. Study on the interaction of sulforaphane with human and bovine serum albumins.

    PubMed

    Abassi, Parvane; Abassi, Farzane; Yari, Faramarz; Hashemi, Mehrdad; Nafisi, Shohreh

    2013-05-05

    Sulforaphane; [1-isothiocyanato-4-(methylsulfinyl) butane], (SFN) is an isothiocyanate derived from glucoraphanin present in cruciferous vegetables and has a variety of potential chemopreventive actions. This study was designed to examine the interaction of sulforaphane with HSA and BSA. FTIR, UV-Vis spectroscopic methods as well as molecular modeling were used to determine the drug binding mode, binding constant and the effect of drug complexation on serum albumins stability and conformation. Structural analysis showed that SFN bind HSA and BSA via polypeptide polar groups with overall binding constants of KSFN-HSA=6.54×10(4) and KSFN-BSA=8.55×10(4) M(-1). HSA and BSA conformations were altered by a major reduction of α-helix upon SFN interaction. These results suggest that serum albumins might act as carrier proteins for SFN in delivering them to target tissues.

  10. Chemoprevention of nonmelanoma skin cancer.

    PubMed

    Wright, Tina I; Spencer, James M; Flowers, Franklin P

    2006-06-01

    Skin cancer is the most common cancer in human beings. The increased incidence of skin cancer has brought much attention to the process by which these tumors develop and how they can be prevented. Efforts have been made to educate the public about the importance of protecting skin from excessive ultraviolet light. Despite this work, the incidence of skin cancer continues to increase. Available compounds may be useful in the chemoprevention of skin cancer. Chemoprevention is defined as oral or topical use of dietary or pharmacologic agents to inhibit or reverse the development of cancer. Potential agents included are the retinoids; difluoromethylornithine; T4 endonuclease V; polyphenolic antioxidants, such as (-)-epigallocatechin gallate, found in green tea and grape seed extract; silymarin; isoflavone genestein; nonsteroidal anti-inflammatory drugs; curcumin; lycopene; vitamin E; beta-carotene; and selenium. Many of these agents are available over the counter as topical or oral preparations. At the conclusion of this activity, participants should be familiar with the chemopreventive agents and their efficacy, as well as any significant side effects associated with them.

  11. Nutritional aspects regarding lung cancer chemoprevention.

    PubMed

    Thanopoulou, E; Baltayiannis, N; Lykogianni, V

    2006-01-01

    Lung cancer is still one of the major causes of cancer-related deaths and its mortality figures argue powerfully for new approaches to control this leading cancer threat. Chemoprevention can be defined as the use of specific agents to reverse, or prevent premalignancy from progressing to invasive cancer. The use of foods and dietary supplements present a safe chemopreventive strategy. Data for this review were identified by searches of PubMed and references from relevant articles. Articles were identified by use of the search terms "lung cancer", "chemoprevention", "carcinogenesis", and "retinoids". Only papers published in English were included. Trials in lung cancer chemoprevention have so far produced either neutral or harmful primary endpoint results, whether in the primary, secondary, or tertiary settings. Lung cancer was not prevented by beta-carotene, alpha-tocopherol, retinol, retinyl palmitate, N-acetylcysteine, or isotretinoin in smokers. Ongoing trials may help define new avenues for chemoprevention. The concept of chemoprevention in lung cancer is still in its infancy, but in the future it may have a significant impact on the incidence and mortality of lung cancer. In addition to epidemiologic studies, basic science research to detect mechanisms and evaluate the chemopreventive potential of food components is necessary. The overwhelming evidence of a major role of nutrition in carcinogenesis, the many leads that nutritional intervention may reduce cancer incidence, and the growth and increasing sophistication of clinical trials networks point to a very promising future for nutritional intervention trials leading to substantial public benefit.

  12. d,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway

    PubMed Central

    Miao, Ziwei; Yu, Fei; Ren, Yahao; Yang, Jun

    2017-01-01

    d,l-Sulforaphane (SFN), a synthetic analogue of broccoli-derived isomer l-SFN, exerts cytotoxic effects on multiple tumor cell types through different mechanisms and is more potent than the l-isomer at inhibiting cancer growth. However, the means by which SFN impairs glioblastoma (GBM) cells remains poorly understood. In this study, we investigated the anti-cancer effect of SFN in GBM cells and determined the underlying molecular mechanisms. Cell viability assays, flow cytometry, immunofluorescence, and Western blot results revealed that SFN could induced apoptosis of GBM cells in a dose- and time-dependent manner, via up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2. Mechanistically, SFN treatment led to increase the intracellular reactive oxygen species (ROS) level in GBM cells. Meanwhile, SFN also suppressed both constitutive and IL-6-induced phosphorylation of STAT3, and the activation of upstream JAK2 and Src tyrosine kinases, dose- and time-dependently. Moreover, blockage of ROS production by using the ROS inhibitor N-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis by blocking the induction of apoptosis-related genes in GBM cells. Taken together, our data suggests that SFN induces apoptosis in GBM cells via ROS-dependent inactivation of STAT3 phosphorylation. These findings motivate further evaluation of SFN as a cancer chemopreventive agent in GBM treatment. PMID:28054986

  13. Bioactivation of the Cancer Chemopreventive Agent Tamoxifen to Quinone Methides by Cytochrome P4502B6 and Identification of the Modified Residue on the Apoprotein

    PubMed Central

    Sridar, Chitra; D'Agostino, Jaime

    2012-01-01

    The nonsteroidal antiestrogen tamoxifen was introduced as a treatment for breast cancer 3 decades ago. It has also been approved as a chemopreventive agent and is prescribed to women at high risk for this disease. However, several studies have shown that use of tamoxifen leads to increased risk of endometrial cancer in humans. One potential pathway of tamoxifen toxicity could involve metabolism via hydroxylation to give 4-hydroxytamoxifen (4OHtam), which may be further oxidized to form a quinone methide. CYP2B6 is a highly polymorphic drug-metabolizing enzyme, and it metabolizes a number of clinically important drugs. Earlier studies from our laboratory have shown that tamoxifen is a mechanism-based inactivator of CYP2B6. The aim of the current study was to investigate the possible formation of reactive intermediates through detection of protein covalent binding and glutathione ethyl ester adduct (GSHEE) formation. The incubation of tamoxifen with 2B6 gave rise to an adduct of 4OHtam with glutathione, which was characterized as the 4OHtam quinone methide + GSHEE with an m/z value of 719, and the structure was characterized by liquid chromatography-tandem mass spectrometry. The metabolic activation of tamoxifen in the CYP2B6 reconstituted system also resulted in the formation of an adduct to the P4502B6 apoprotein, which was identified using liquid chromatography mass spectrometry. The site responsible for the inactivation of CYP2B6 was determined by proteolytic digestion and identification of the labeled peptide. This revealed a tryptic peptide 188FHYQDQE194 with the site of adduct formation localized to Gln193 as the site modified by the reactive metabolite formed during tamoxifen metabolism. PMID:22942317

  14. A novel UPLC/MS/MS method for rapid determination of metapristone in rat plasma, a new cancer metastasis chemopreventive agent derived from mifepristone (RU486).

    PubMed

    Chen, Jian-Zhong; Wang, Ji-Chuang; Gao, Yu; Zeng, Rong-Jie; Jiang, Zhou; Zhu, Ye-Wei; Shao, Jing-Wei; Jia, Lee

    2014-07-01

    Mifepristone (RU486) is a chemical abortifacient used by hundreds of millions of women world-wide. It has recently been used in clinical trials for psychotic depression and cancer chemotherapy. Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent based on its unique pharmacological properties. In this study, a novel rapid and sensitive method using UPLC/MS/MS was developed and validated for quantitative analysis of metapristone in plasma, which used less plasma volume and was demonstrated to be more simple and low-cost than the published methods. Metapristone in plasma was recovered by liquid-liquid extraction using 1 mL of ethyl acetate and chromatographic separation was carried on a C₁₈ column at 35 °C, with a gradient mobile phase consisting of methanol and water containing 0.1% (v/v) formic acid at a flow rate of 0.3 mL/min. The mass spectrometric detection was carried out using a triple-quadrupole system via positive electrospray ionization. Multiple reaction monitoring was used for quantitation of m/z transitions from 416.3 to 119.9 for metapristone and from 313.1 to 109 for levonorgestrel (internal standard). Good linearity (r²> 0.9926) was achieved over a concentration range from 7.1 to 2840 ng/mL with a lower limit of quantification of 7.1 ng/mL for metapristone. The intra- and inter-day variations of the assay were 2.4-10.0% relative standard deviation with an accuracy of -5.6 to 8.6% relative error. This newly developed method was successfully applied to a pharmacokinetic study that revealed, for the first time, that there was a significant difference in pharmacokinetic profile between genders. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. 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

  16. Effects of chemopreventive agents on the incidence of recurrent colorectal adenomas: a systematic review with network meta-analysis of randomized controlled trials

    PubMed Central

    Veettil, Sajesh K; Teerawattanapong, Nattawat; Ching, Siew Mooi; Lim, Kean Ghee; Saokaew, Surasak; Phisalprapa, Pochamana; Chaiyakunapruk, Nathorn

    2017-01-01

    Background Protective effects of several chemopreventive agents (CPAs) against colorectal adenomas have been well documented in randomized controlled trials (RCTs); however, there is uncertainty regarding which agents are the most effective. Methods We searched for RCTs published up until September 2016. Retrieved trials were evaluated using risk of bias. We performed both pairwise analysis and network meta-analysis (NMA) of RCTs to compare the effects of CPAs on the recurrence of colorectal adenomas (primary outcome). Using NMA, we ranked CPAs based on efficacy. Results We identified 20 eligible RCTs enrolling 12,625 participants with a history of colorectal cancer or adenomas who were randomly assigned to receive either a placebo or one of 12 interventions. NMA using all trials demonstrated that celecoxib 800 mg/day (relative risk [RR] 0.61, 95% confidence interval [CI] 0.45–0.83), celecoxib 400 mg/day (RR 0.70, 95% CI 0.55–0.87), low-dose aspirin (RR 0.75, 95% CI 0.59–0.96) and calcium (RR 0.81, 95% CI 0.69–0.96) were significantly associated with a reduction in the recurrence of any adenomas. NMA results were consistent with those from pairwise meta-analysis. The evidence indicated a high (celecoxib), moderate (low-dose aspirin) and low (calcium) Grading of Recommendations, Assessment, Development and Evaluation (GRADE) quality. NMA ranking showed that celecoxib 800 mg/day and celecoxib 400 mg/day were the best CPAs, followed by low-dose aspirin and calcium. Considering advanced adenoma recurrence, only celecoxib 800 mg/day and celecoxib 400 mg/day were demonstrated to have a protective effect (RR 0.37, 95% CI 0.27–0.52 vs RR 0.48, 95% CI 0.38–0.60, respectively). Conclusion The available evidence from NMA suggests that celecoxib is more effective in reducing the risk of recurrence of colorectal adenomas, followed by low-dose aspirin and calcium. Since cyclooxygenase-2 (COX-2) inhibitors (eg, celecoxib) are associated with important cardiovascular

  17. 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

  18. Cognition Enhancing Activity of Sulforaphane Against Scopolamine Induced Cognitive Impairment in Zebra Fish (Danio rerio).

    PubMed

    Rajesh, Venugopalan; Ilanthalir, Sakthivel

    2016-10-01

    Several epidemiological studies have shown that consumption of large quantities of vegetables especially cruciferous vegetables (Broccoli and Brussels sprouts) can protect against chronic diseases. Sulforaphane, an isothiocynate found in cruciferous vegetables has been demonstrated to have neuroprotective effects in several experimental paradigms. This study was undertaken to examine the effect of sulforaphane on cognitive impairment in zebra fish model using a novel method of fear conditioning. Initially, the normal behaviour of zebra fishes was studied in light-dark tank for 10 min daily for 10 days. Fishes were then divided into seven groups of twelve in each. Group I served as normal, group II served as fear conditioned control, group III and group IV were sulforaphane (25 µM/L) and piracetam (200 mg/L) treated respectively. Group V served as scopolamine (400 µM/L) induced memory impairment fishes. Group VI and VII were sulforaphane (25 µM/L) and piracetam (200 mg/L) treated scopolamine induced memory impairment groups respectively. In normal behavioural analysis, fishes preferred to stay in dark compartment. The average number of entries into the dark and time spent in dark were significantly more. Fishes in group II to VII were individually subjected to fear conditioning passive avoidance task and evaluated for learned task memory. It was observed that the average number of entries into dark and time spent in dark were significantly decreased. After exposure to respective treatment fishes in group III to VII were subjected to cognitive evaluation. There was no significant difference in cognition of group III and IV fishes exposed to sulforaphane and piracetam alone respectively. Fishes exposed to scopolamine showed a significant cognitive impairment. Sulforaphane exposure prior to scopolamine significantly retained the memory of learned task. These findings suggest that sulforaphane might be a promising therapeutic agent for cognitive enhancement in

  19. Combination Chemoprevention with Grape Antioxidants

    PubMed Central

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

    2016-01-01

    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

  20. Recent advances in cancer chemoprevention.

    PubMed

    Lippman, S M; Hittelman, W N; Lotan, R; Pastorino, U; Hong, W K

    1991-02-01

    The CCPC 90 conference and workshop included presentations by basic scientists describing the key in vitro and in vivo model systems used to study epithelial carcinogenesis and its associated biochemical and molecular alterations. A major conference theme was the identification of markers identifying specific carcinogenic stages. Current work focuses on defining the biology of preneoplasia, the critical specific molecular events in multistep carcinogenesis, and the dynamic interplay between viral, behavioral, dietary, and genetic factors in human carcinogenesis. Studies of molecular epidemiology and genetic susceptibility are identifying new risk groups and contributing to preventive strategies. Another major theme of the conference was the concept of field carcinogenesis and the study of carcinogen-exposed tissue "at risk" for the development of cancer. A specific example discussed by several investigators was the issue of SPT development in head and neck and lung cancers. Novel studies of biologic markers for use in early detection and as intermediate end points were described. The latter application, if validated in human trials, may allow short-term screening of chemopreventive agents and determinations of optimal doses/schedules for phase III chemoprevention trials. These biomarker trials may serve as a bridge between preclinical work and full-scale randomized trials. The status of the major phase III clinical trials was presented. Major problems in chemoprevention trials include (1) selection of agents, doses, and schedules, (2) lack of pharmacologic and pharma quality control, (5) adherence (drop-out and drop-in), and (6) trial-specific feasibility/recruitment, issues.

  1. 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. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Sulforaphane enhances temozolomide-induced apoptosis because of down-regulation of miR-21 via Wnt/β-catenin signaling in glioblastoma.

    PubMed

    Lan, FengMing; Pan, Qiang; Yu, Huiming; Yue, Xiao

    2015-09-01

    Temozolomide (TMZ) has been widely used in the treatment of glioblastoma (GBM), although inherent or acquired resistance restricts the application. This study was aimed to evaluate the efficacy of sulforaphane (SFN) to TMZ-induced apoptosis in GBM cells and the potential mechanism. Biochemical assays and subcutaneous tumor establishment were used to characterize the function of SFN in TMZ-induced apoptosis. Our results revealed that β-catenin and miR-21 were concordantly expressed in GBM cell lines, and SFN significantly reduced miR-21 expression through inhibiting the Wnt/β-catenin/TCF4 pathway. Furthermore, down-regulation of miR-21 enhanced the pro-apoptotic efficacy of TMZ in GBM cells. Finally, we observed that SFN strengthened TMZ-mediated apoptosis in a miR-21-dependent manner. In conclusion, SFN effectively enhances TMZ-induced apoptosis by inhibiting miR-21 via Wnt/β-catenin signaling in GBM cells. These findings support the use of SFN for potential therapeutic approach to overcome TMZ resistance in GBM treatment. Our studies indicate that sulforaphane (SFN) enhances temozolomide (TMZ)-induced apoptosis because of down-regulation of miR-21 through Wnt/β-catenin signaling in glioblastoma (GBM) cells. These findings demonstrate SFN could be considered as a potential adjuvant therapeutic agent in treating GBM patients combined with TMZ in the future to affect resistance emergence. The further explorations are essential for the clinical application of SFN in GBM patients, and our results reveal an important mechanism of SFN chemopreventive and chemotherapeutic activity. Chr17, chromosome 17. © 2015 International Society for Neurochemistry.

  3. 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

  4. A novel antithrombotic effect of sulforaphane via activation of platelet adenylate cyclase: ex vivo and in vivo studies.

    PubMed

    Jayakumar, Thanasekaran; Chen, Wei-Fan; Lu, Wan-Jung; Chou, Duen-Suey; Hsiao, George; Hsu, Chung-Yi; Sheu, Joen-Rong; Hsieh, Cheng-Ying

    2013-06-01

    study demonstrates for the first time that in addition to it originally being considered as an agent for prevention of tumor growth, sulforaphane possesses potent antiplatelet activity which may initially activate adenylate cyclase/cAMP, followed by inhibiting intracellular signals (such as the PI3-kinase/Akt and PLCγ2-PKC-p47 cascades) and ultimately inhibiting platelet activation. Therefore, this novel role of sulforaphane may represent a high therapeutic potential for treatment or prevention of cardiovascular diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Chemoprevention for advanced CR neoplasia.

    PubMed

    Moshkowitz, Menachem; Shapira, Shiran; Arber, Nadir

    2011-08-01

    Colorectal cancer (CRC) is a major health concern worldwide. In 2011 1,200,000 new cases are predicted and half of them are going to die from the disease. CRC carcinogenesis is a multi-step process that spans over 10-20 years, providing a window of opportunity for effective intervention. CRC can be prevented by life style modification and screening program. However, although these strategies are standard clinical practice, their impact is limited due to low adherence. The number of deaths due to CRC remains alarming high, and makes CRC prevention a paramount. Chemoprevention interferes with the carcinogenesis process by targeting key molecular pathways. It involves the use of a variety of natural or chemical compounds that can delay, prevent or even reverse the adenoma to carcinoma sequence. Numerous chemopreventive agents have been studied but the most efficient are the NSAID group of agents. Much of their efficacy and toxicity has been attributed to their potent inhibition of the cyclooxygenase (COX) enzymes. Chemoprevention has the potential to represent a cost-effective intervention, particularly when targeted at intermediate-risk populations, ages 61-70, following polypectomy. Chemoprevention in this setting is as very important as polyp recurrence in this population can be as high as 50%, even with surveillance colonoscopy every 1-3 years. The most challenging task is to find the proper place for these interventions in the entire effort of general wellbeing. Subjects are likely to be more adherent to prescribed regimens if cancer prevention may be combined with a cardiovascular and Alzheimer prophylaxis. Subjects with a normal colon or non advanced adenomas can be safely monitored with surveillance colonoscopy every 5-10 years. The ideal chemopreventive agent remains to be discovered with great emphasis on the need not to harm. Possibly, combinations of agents will maximize effectiveness while limiting drug toxicity. Finally, personalized approaches would

  6. Dietary derived compounds in cancer chemoprevention

    PubMed Central

    Rzeski, Wojciech

    2012-01-01

    Cancer chemoprevention is defined as the application of natural or synthetic agents to suppress or reverse cancer development and progression. In this field especially diet derived compounds have recently attracted researchers’ attention as potential therapeutics generally exerting low toxicity compared with regular drugs. This review presents a survey of recent findings concerning the most promising dietary chemopreventive agents such as green tea polyphenols (i.e. catechins), long-chain polyunsaturated fatty acids, carotenoids, glucosinolates/isothiocyanates, vitamins (i.e. vitamin D and folate) and minerals (i.e. calcium and selenium). Molecular targets involved in intrinsic pathways affected by these natural compounds are also shortly discussed. PMID:23788916

  7. Modifying the processing and handling of frozen broccoli for increased sulforaphane formation.

    PubMed

    Dosz, Edward B; Jeffery, Elizabeth H

    2013-09-01

    Frozen broccoli can provide a cheaper product, with a longer shelf life and less preparation time than fresh broccoli. We previously showed that several commercially available frozen broccoli products do not retain the ability to generate the cancer-preventative agent sulforaphane. We hypothesized that this was because the necessary hydrolyzing enzyme myrosinase was destroyed during blanching, as part of the processing that frozen broccoli undergoes. This study was carried out to determine a way to overcome loss of hydrolyzing activity. Industrial blanching usually aims to inactivate peroxidase, although lipoxygenase plays a greater role in product degradation during frozen storage of broccoli. Blanching at 86 °C or higher inactivated peroxidase, lipoxygenase, and myrosinase. Blanching at 76 °C inactivated 92% of lipoxygenase activity, whereas there was only an 18% loss in myrosinase-dependent sulforaphane formation. We considered that thawing frozen broccoli might disrupt membrane integrity, allowing myrosinase and glucoraphanin to come into contact. Thawing frozen broccoli for 9 h did not support sulforaphane formation unless an exogenous source of myrosinase was added. Thermal stability studies showed that broccoli root, as a source of myrosinase, was not more heat stable than broccoli floret. Daikon radish root supported some sulforaphane formation even when heated at 125 °C for 10 min, a time and temperature comparable to or greater than microwave cooking. Daikon radish (0.25%) added to frozen broccoli that was then allowed to thaw supported sulforaphane formation without any visual alteration to that of untreated broccoli.

  8. Cancer chemoprevention and nutriepigenetics: state of the art and future challenges.

    PubMed

    Gerhauser, Clarissa

    2013-01-01

    The term "epigenetics" refers to modifications in gene expression caused by heritable, but potentially reversible, changes in DNA methylation and chromatin structure. Epigenetic alterations have been identified as promising new targets for cancer prevention strategies as they occur early during carcinogenesis and represent potentially initiating events for cancer development. Over the past few years, nutriepigenetics - the influence of dietary components on mechanisms influencing the epigenome - has emerged as an exciting new field in current epigenetic research. During carcinogenesis, major cellular functions and pathways, including drug metabolism, cell cycle regulation, potential to repair DNA damage or to induce apoptosis, response to inflammatory stimuli, cell signalling, and cell growth control and differentiation become deregulated. Recent evidence now indicates that epigenetic alterations contribute to these cellular defects, for example epigenetic silencing of detoxifying enzymes, tumor suppressor genes, cell cycle regulators, apoptosis-inducing and DNA repair genes, nuclear receptors, signal transducers and transcription factors by promoter methylation, and modifications of histones and non-histone proteins such as p53, NF-κB, and the chaperone HSP90 by acetylation or methylation.The present review will summarize the potential of natural chemopreventive agents to counteract these cancer-related epigenetic alterations by influencing the activity or expression of DNA methyltransferases and histone modifying enzymes. Chemopreventive agents that target the epigenome include micronutrients (folate, retinoic acid, and selenium compounds), butyrate, polyphenols from green tea, apples, coffee, black raspberries, and other dietary sources, genistein and soy isoflavones, curcumin, resveratrol, dihydrocoumarin, nordihydroguaiaretic acid (NDGA), lycopene, anacardic acid, garcinol, constituents of Allium species and cruciferous vegetables, including indol-3-carbinol

  9. Resveratrol analogs: promising chemopreventive agents.

    PubMed

    Ogas, Talysa; Kondratyuk, Tamara P; Pezzuto, John M

    2013-07-01

    Although resveratrol can modulate multiple stages of carcinogenesis, by most common standards it is not a good drug candidate. Resveratrol lacks potency, high efficacy, and target specificity; it is rapidly metabolized and serum concentrations are low. Using resveratrol as a scaffold, we produced over 100 derivatives, some of which have target specificity in the nanomolar range. Aromatase inhibition was enhanced over 6000-fold by using 1,3-thiazole as the central ring of resveratrol. Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to selective QR1 induction with a CD value of 87 nM. Several derivatives have been selected for evaluation of synergistic effects. Preliminary results with pairs of compounds are promising and further experiments, in a constant multidrug manner, will allow us to create polygonograms for larger combinations of derivatives. The objective is to develop a highly efficacious cocktail of derivatives based on the structure of resveratrol.

  10. Stimulation of suicidal erythrocyte death by sulforaphane.

    PubMed

    Alzoubi, Kousi; Calabrò, Salvatrice; Faggio, Caterina; Lang, Florian

    2015-03-01

    Sulforaphane, an isothiocyanate from cruciferous vegetable, counteracts malignancy. The effect is at least in part due to the stimulation of suicidal death or apoptosis of tumour cells. Mechanisms invoked in sulforaphane-induced apoptosis include mitochondrial depolarization and altered gene expression. Despite the lack of mitochondria and nuclei, erythrocytes may, similar to apoptosis of nucleated cells, enter eryptosis, a suicidal cell death characterized by cell shrinkage and phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)]i). This study explored whether sulforaphane stimulates eryptosis. Cell volume was estimated from forward scatter, phosphatidylserine exposure at the cell surface from annexin V binding and [Ca(2+)]i from Fluo-3 fluorescence. A 48-hr treatment of human erythrocytes with sulforaphane (50-100 μM) significantly decreased forward scatter, significantly increased the percentage of annexin V binding cells and significantly increased [Ca(2+)]i. The effect of sulforaphane (100 μM) on annexin V binding was significantly blunted but not abrogated by the removal of extracellular Ca(2+). Sulforaphane (100 μM) significantly increased ceramide formation. In conclusion, sulforaphane stimulates suicidal erythrocyte death or eryptosis, an effect at least partially, but not exclusively, due to the stimulation of Ca(2+) entry and ceramide formation. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  11. Sulforaphane attenuates EGFR signaling in NSCLC cells.

    PubMed

    Chen, Chi-Yuan; Yu, Zhu-Yun; Chuang, Yen-Shu; Huang, Rui-Mei; Wang, Tzu-Chien V

    2015-06-03

    EGFR, a receptor tyrosine kinase (RTK), is frequently overexpressed and mutated in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) have been widely used in the treatment of many cancers, including NSCLC. However, intrinsic and acquired resistance to TKI remains a common obstacle. One strategy that may help overcome EGFR-TKI resistance is to target EGFR for degradation. As EGFR is a client protein of heat-shock protein 90 (HSP90) and sulforaphane is known to functionally regulate HSP90, we hypothesized that sulforaphane could attenuate EGFR-related signaling and potentially be used to treat NSCLC. Our study revealed that sulforaphane displayed antitumor activity against NSCLC cells both in vitro and in vivo. The sensitivity of NSCLC cells to sulforaphane appeared to positively correlate with the inhibition of EGFR-related signaling, which was attributed to the increased proteasomal degradation of EGFR. Combined treatment of NSCLC cells with sulforaphane plus another HSP90 inhibitor (17-AAG) enhanced the inhibition of EGFR-related signaling both in vitro and in vivo. We have shown that sulforaphane is a novel inhibitory modulator of EGFR expression and is effective in inhibiting the tumor growth of EGFR-TKI-resistant NSCLC cells. Our findings suggest that sulforaphane should be further explored for its potential clinical applications against NSCLC.

  12. Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells

    PubMed Central

    LABSCH, SABRINA; LIU, LI; BAUER, NATHALIE; ZHANG, YIYAO; ALEKSANDROWICZ, EWA; GLADKICH, JURY; SCHÖNSIEGEL, FRANK; HERR, INGRID

    2014-01-01

    Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-κB activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony-forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-κB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs. PMID:24626333

  13. Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells.

    PubMed

    Labsch, Sabrina; Liu, Li; Bauer, Nathalie; Zhang, Yiyao; Aleksandrowicz, Ewa; Gladkich, Jury; Schönsiegel, Frank; Herr, Ingrid

    2014-05-01

    Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-κB activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony-forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-κB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs.

  14. Spectroscopic characterization of lycopene extract from Lycopersicum esculentum (Tomato) and its evaluation as a chemopreventive agent against experimental hepatocarcinogenesis in mice.

    PubMed

    Gupta, Prachi; Bansal, Mohinder Pal; Koul, Ashwani

    2013-03-01

    The present study was designed to characterize the lycopene extract (LycT) prepared from tomatoes (Lycopersicum esculentum) and then to evaluate its chemopreventive efficacy in N-diethylnitrosamine (NDEA)-induced experimental hepatocarcinogenesis in female Balb/c mice. The extraction of lycopene was carried out using hexane/acetone/ethanol as an extracting medium and then characterized by ultraviolet-visible, nuclear magnetic resonance and Fourier transform infrared spectroscopy. Chemopreventive efficacy of characterized LycT in vivo was evaluated in terms of hepatic tumour incidence, multiplicity, burden, hepatosomatic index and animal survival rate. Results indicated that average lycopene content of the tomato was 11.6-14 mg/kg tomato weight. Spectroscopic data confirmed the structural characteristics of lycopene in the extract. In the animal study, reduction in tumour incidence (42.05%), tumour burden (1.39) and tumour multiplicity (3.42) was observed upon LycT pretreatment to NDEA-treated animals. Histopathological analysis unravelled that the increased survival rate in LycT + NDEA-treated animals was due to the delay in the formation of aggressive tumour nodules. These observations indicate that lycopene seems to be an able candidate for chemoprevention in hepatocarcinogenesis resulting from NDEA insults.

  15. Toward the development of chemoprevention agents. Part II: Chemo-enzymatic synthesis and anti-inflammatory activities of a new class of 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes.

    PubMed

    Gu, Keli; Bi, Lanrong; Zhao, Ming; Wang, Chao; Ju, Jingfang; Peng, Shiqi

    2007-09-15

    A new series of optically pure 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes were designed and synthesized via a chemo-enzymatic combined method to develop new chemoprevention agents. Twenty-four of newly synthesized compounds significantly inhibited xylene-induced rat ear edema and exhibited comparable or better anti-inflammatory activities than the reference drug aspirin. Treatment of these anti-inflammatory agents did not prolong the tail bleeding time in rat. In addition, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes exhibited good membrane permeability based on in vitro Caco-2 cell monolayer permeability assay. Furthermore, some preliminary structure-activity relationships were further analyzed among these compounds. Taken together, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes may represent a new class of anti-inflammatory drugs with safer pharmacological profile.

  16. Chemoprevention research: implications for primary care practice.

    PubMed

    Denicoff, A M; Padberg, R M

    2000-01-01

    The field of cancer prevention research is entering a time of growth and opportunity. This important research is identifying agents that are making a substantial difference by reducing cancer incidence in high-risk populations. Primary care providers are natural partners for this research because of their diversity, commitment to disease prevention, and long-term access to their patient population. Several national chemoprevention trials in breast and prostate cancer are open and seeking to affiliate with primary care providers. Information is provided on this research effort, the development of chemoprevention trials, and how to learn more.

  17. 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.

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

    PubMed

    Zeng, Huawei; Trujillo, Olivia N; Moyer, Mary P; Botnen, James H

    2011-01-01

    Sulforaphane (SFN) is a naturally occurring chemopreventive agent; 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 cancer and normal cells. In this study, we demonstrated that SFN (15 μmol/L) exposure (72 h) inhibited cell proliferation by up to 95% in colon cancer cells (HCT116) and by 52% in normal colon mucosa-derived (NCM460) cells. Our data also showed that SFN exposure (5 and 10 μmol/L) led to the reduction of G1 phase cell distribution and an induction of apoptosis in HCT116 cells, but to a much lesser extent in NCM460 cells. Furthermore, the examination of mitogen-activated protein kinase (MAPK) signaling status revealed that SFN upregulated the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) in NCM460 cells but not in HCT116 cells. In contrast, SFN enhanced the phosphorylation of stress-activated protein kinase (SAPK) and decreased cellular myelocytomatosis oncogene (c-Myc) expression in HCT116 cells but not NCM460 cells. Taken together, the activation of survival signaling in NCM460 cells and apoptotic signaling in HCT116 cells may play a critical role in SFN's stronger potential of inhibiting cell proliferation in colon cancer cells than in normal colon cells. Copyright © 2011, Taylor & Francis Group, LLC

  20. Sulforaphane Regulates NFE2L2/Nrf2-Dependent Xenobiotic Metabolism Phase II and Phase III Enzymes Differently in Human Colorectal Cancer and Untransformed Epithelial Colon Cells.

    PubMed

    Lubelska, Katarzyna; Wiktorska, Katarzyna; Mielczarek, Lidia; Milczarek, Małgorzata; Zbroińska-Bregisz, Ilona; Chilmonczyk, Zdzisław

    2016-01-01

    Sulforaphane (SFN), a naturally occurring chemopreventive and anticancer agent, is a nuclear factor, erythroid 2-like 2 (NFE2L2/Nrf2) inducer. Nrf2 plays a critical role in coordinating the cell defense system by initiating the transcription of cytoprotective genes, including detoxification enzymes such as NAD(P)H quinone dehydrogenase 1 (NQO1) and transport proteins such as ATP-binding cassette, subfamily C (CFTR/MRP). Recently, the essential role of Nrf2 in tumor development and progression and in the development of multidrug resistance in cancer cells has been highlighted. The aim of this study was to compare the effect of SFN on the Nrf2 system and the Nrf2-target enzymes NQO1 and MRP in human untransformed epithelial colon CRL-1790 cells and in HT-29 and Caco-2 colorectal cancer cells to elucidate the role of SFN in cancer prevention and treatment. We have demonstrated that SFN has excellent cytoprotective properties in CRL-1790 cells, as it induced Nrf2-dependent expression of MRP1 and NQO1. SFN induced Nrf2 target enzyme activity in HT-29 and Caco-2 cancer cells but regulated the Nrf2/ARE signaling pathway differently in cancer and untransformed cells.

  1. 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

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

    PubMed

    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

    2015-04-01

    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 200 μmoles/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 200 μmoles/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.

  3. 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.

  4. Sarcophine-Diol, a Skin Cancer Chemopreventive Agent, Inhibits Proliferation and Stimulates Apoptosis in Mouse Melanoma B16F10 Cell Line

    PubMed Central

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

    2011-01-01

    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

  5. Breast Cancer Profile among Patients with a History of Chemoprevention

    PubMed Central

    Pivo, Sarah; Refinetti, Ana Paula; Guth, Amber

    2016-01-01

    Purpose. This study identifies women with breast cancer who utilized chemoprevention agents prior to diagnosis and describes their patterns of disease. Methods. Our database was queried retrospectively for patients with breast cancer who reported prior use of chemoprevention. Patients were divided into primary (no history of breast cancer) and secondary (previous history of breast cancer) groups and compared to patients who never took chemoprevention. Results. 135 (6%) of 2430 women used chemoprevention. In the primary chemoprevention group (n = 18, 1%), 39% had completed >5 years of treatment, and fully 50% were on treatment at time of diagnosis. These patients were overwhelmingly diagnosed with ER/PR positive cancers (88%/65%) and were diagnosed with equal percentages (44%) of IDC and DCIS. 117 (87%) used secondary chemoprevention. Patients in this group were diagnosed with earlier stage disease and had lower rates of ER/PR-positivity (73%/65%) than the nonchemoprevention group (84%/72%). In the secondary group, 24% were on chemoprevention at time of diagnosis; 73% had completed >5 years of treatment. Conclusions. The majority of patients who used primary chemoprevention had not completed treatment prior to diagnosis, suggesting that the timing of initiation and compliance to prevention strategies are important in defining the pattern of disease in these patients. PMID:28078143

  6. Breast Cancer Profile among Patients with a History of Chemoprevention.

    PubMed

    Schnabel, Freya R; Pivo, Sarah; Chun, Jennifer; Schwartz, Shira; Refinetti, Ana Paula; Axelrod, Deborah; Guth, Amber

    2016-01-01

    Purpose. This study identifies women with breast cancer who utilized chemoprevention agents prior to diagnosis and describes their patterns of disease. Methods. Our database was queried retrospectively for patients with breast cancer who reported prior use of chemoprevention. Patients were divided into primary (no history of breast cancer) and secondary (previous history of breast cancer) groups and compared to patients who never took chemoprevention. Results. 135 (6%) of 2430 women used chemoprevention. In the primary chemoprevention group (n = 18, 1%), 39% had completed >5 years of treatment, and fully 50% were on treatment at time of diagnosis. These patients were overwhelmingly diagnosed with ER/PR positive cancers (88%/65%) and were diagnosed with equal percentages (44%) of IDC and DCIS. 117 (87%) used secondary chemoprevention. Patients in this group were diagnosed with earlier stage disease and had lower rates of ER/PR-positivity (73%/65%) than the nonchemoprevention group (84%/72%). In the secondary group, 24% were on chemoprevention at time of diagnosis; 73% had completed >5 years of treatment. Conclusions. The majority of patients who used primary chemoprevention had not completed treatment prior to diagnosis, suggesting that the timing of initiation and compliance to prevention strategies are important in defining the pattern of disease in these patients.

  7. 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

  8. 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.

  9. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds.

    PubMed

    Li, Yanyan; Wicha, Max S; Schwartz, Steven J; Sun, Duxin

    2011-09-01

    The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival.

  10. 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.

  11. Meeting Report: Pancreatic Cancer Chemoprevention Translational Workshop

    PubMed Central

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

    2016-01-01

    Pancreatic cancer is the 4th leading cause of cancer related deaths in the US with a 5 year survival rate of <10%. The Division of Cancer Prevention of the NCI sponsored the Pancreatic Cancer Chemoprevention Translational Workshop on September 10–11th 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/immuopreventative 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 NCI working group to coordinate efforts, provide a framework, and identify opportunities for chemoprevention of pancreatic cancer. PMID:27518363

  12. Optimizing thiadiazole analogues of resveratrol versus three chemopreventive targets.

    PubMed

    Mayhoub, Abdelrahman S; Marler, Laura; Kondratyuk, Tamara P; Park, Eun-Jung; Pezzuto, John M; Cushman, Mark

    2012-01-01

    Chemoprevention is an approach to decrease cancer morbidity and mortality through inhibition of carcinogenesis and prevention of disease progression. Although the trans stilbene derivative resveratrol has chemopreventive properties, its action is compromised by weak non-specific effects on many biological targets. Replacement of the stilbene ethylenic bridge of resveratrol with a 1,2,4-thiadiazole heterocycle and modification of the substituents on the two aromatic rings afforded potential chemopreventive agents with enhanced potencies and selectivities when evaluated as inhibitors of aromatase and NF-κB and inducers of quinone reductase 1 (QR1).

  13. Vitamin D in cancer chemoprevention.

    PubMed

    Giammanco, Marco; Di Majo, Danila; La Guardia, Maurizio; Aiello, Stefania; Crescimannno, Marilena; Flandina, Carla; Tumminello, Francesca M; Leto, Gaetano

    2015-01-01

    There is increasing evidence that Vitamin D (Vit D) and its metabolites, besides their well-known calcium-related functions, may also exert antiproliferative, pro-differentiating, and immune modulatory effects on tumor cells in vitro and may also delay tumor growth in vivo. The aim of this review is to provide fresh insight into the most recent advances on the role of Vit D and its analogues as chemopreventive drugs in cancer therapy. A systematic review of experimental and clinical studies on Vit D and cancer was undertaken by using the major electronic health database including ISI Web of Science, Medline, PubMed, Scopus and Google Scholar. Experimental and clinical observations suggest that Vit D and its analogues may be effective in preventing the malignant transformation and/or the progression of various types of human tumors including breast cancer, prostate cancer, colorectal cancer, and some hematological malignances. These findings suggest the possibility of the clinical use of these molecules as novel potential chemopreventive and anticancer agents.

  14. Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells.

    PubMed

    Burnett, Joseph P; Lim, Gi; Li, Yanyan; Shah, Ronak B; Lim, Rebekah; Paholak, Hayley J; McDermott, Sean P; Sun, Lichao; Tsume, Yasuhiro; Bai, Shuhua; Wicha, Max S; Sun, Duxin; Zhang, Tao

    2017-05-28

    Triple negative breast cancer (TNBC) typically exhibits rapid progression, high mortality and faster relapse rates relative to other breast cancer subtypes. In this report we examine the combination of taxanes (paclitaxel or docetaxel) with a breast cancer stem cell (CSC)-targeting agent sulforaphane for use against TNBC. We demonstrate that paclitaxel or docetaxel treatment induces IL-6 secretion and results in expansion of CSCs in TNBC cell lines. Conversely, sulforaphane is capable of preferentially eliminating CSCs, by inhibiting NF-κB p65 subunit translocation, downregulating p52 and consequent downstream transcriptional activity. Sulforaphane also reverses taxane-induced aldehyde dehydrogenase-positive (ALDH+) cell enrichment, and dramatically reduces the size and number of primary and secondary mammospheres formed. In vivo in an advanced treatment orthotopic mouse xenograft model together with extreme limiting dilution analysis (ELDA), the combination of docetaxel and sulforaphane exhibits a greater reduction in primary tumor volume and significantly reduces secondary tumor formation relative to either treatment alone. These results suggest that treatment of TNBCs with cytotoxic chemotherapy would be greatly benefited by the addition of sulforaphane to prevent expansion of and eliminate breast CSCs.

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

    PubMed

    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.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  17. 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

  18. [Coffee in Cancer Chemoprevention].

    PubMed

    Neuwirthová, J; Gál, B; Smilek, P; Urbánková, P

    Coffee consumption is associated with a reduced risk of several diseases including cancer. Its chemopreventive effect has been studied in vitro, in animal models, and more recently in humans. Several modes of action have been proposed, namely, inhibition of oxidative stress and damage, activation of metabolizing liver enzymes involved in carcinogen detoxification processes, and anti-inflammatory effects. The antioxidant activity of coffee relies partly on its chlorogenic acid content and is increased during the roasting process. Maximum antioxidant activity is observed for medium-roasted coffee. The roasting process leads to the formation of several components, e.g., melanoidins, which have antioxidant and anti-inflammatory properties. Coffee also contains two specific diterpenes, cafestol and kahweol, which have anticarcinogenic properties. Roasted coffee is a complex mixture of various chemicals. Previous studies have reported that the chemopreventive components present in coffee induce apoptosis, inhibit growth and metastasis of tumor cells, and elicit antiangiogenic effects. A meta-analysis of epidemiological studies showed that coffee consumption is associated with a lower risk of developing various malignant tumors. This review summarizes the molecular mechanisms and the experimental and epidemiological evidence supporting the chemopreventive effect of coffee.Key words: coffee - chemoprevention - antioxidative enzyme - detoxification enzyme - anti-inflammatory effect The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 11. 9. 2016Accepted: 24. 11. 2016.

  19. Keap1-Nrf2 Signaling: A Target for Cancer Prevention by Sulforaphane

    PubMed Central

    Kensler, Thomas W; Egner, Patricia A; Agyeman, Abena S.; Visvanathan, Kala; Groopman, John D; Chen, Jian-Guo; Chen, Tao-Yang; Fahey, Jed W; Talalay, Paul

    2013-01-01

    Sulforaphane is a promising agent under preclinical evaluation in many models of disease prevention. This bioactive phytochemical affects many molecular targets in cellular and animal models; however, amongst the most sensitive is Keap1, a key sensor for the adaptive stress response system regulated through the transcription factor Nrf2. Keap1 is a sulfhydryl-rich protein that represses Nrf2 signaling by facilitating the poly ubiquitination of Nrf2 thereby enabling its subsequent proteasomal degradation. Interaction of sulforaphane with Keap1 disrupts this function and allows for nuclear accumulation of Nrf2 and activation of its transcriptional program. Enhanced transcription of Nrf2 target genes provokes a strong cytoprotective response that enhances resistance to carcinogenesis and other diseases mediated by exposures to electrophiles and oxidants. Clinical evaluation of sulforaphane has been largely conducted by utilizing preparations of broccoli or broccoli sprouts rich in either sulforaphane or its precursor form in plants, a stable β-thioglucose conjugate termed glucoraphanin. We have conducted a series of clinical trials in Qidong, China, a region where exposures to food- and air-borne carcinogens has been considerable, to evaluate the suitability of broccoli sprout beverages, rich in either glucoraphanin (GRR) or sulforaphane SFR or both for their bioavailability, tolerability and pharmacodynamic action in population-based interventions. Results from these clinical trials indicate that interventions with well characterized preparations of broccoli sprouts may enhance the detoxication of aflatoxins and air-borne toxins, which may in turn attenuate their associated health risks, including cancer, in exposed individuals. PMID:22752583

  20. Chemoprevention of photocarcinogenesis by selected dietary botanicals.

    PubMed

    Baliga, Manjeshwar S; Katiyar, Santosh K

    2006-02-01

    Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation as a tumor initiator, tumor promoter and complete carcinogen, and their excessive exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. Sunscreens are useful, but their protection is not adequate to prevent the risk of UV-induced skin cancer. It may be because of inadequate use, incomplete spectral protection and toxicity. Therefore new chemopreventive methods are necessary to protect the skin from photodamaging effects of solar UV radiation. Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of skin carcinogenesis. In recent years, considerable interest has been focused on identifying naturally occurring botanicals, specifically dietary, for the prevention of photocarcinogenesis. A wide variety of botanicals, mostly dietary flavonoids or phenolic substances, have been reported to possess substantial anticarcinogenic and antimutagenic activities because of their antioxidant and antiinflammatory properties. This review summarizes chemopreventive effects of some selected botanicals, such as apigenin, curcumin, grape seed proanthocyanidins, resveratrol, silymarin, and green tea polyphenols, against photocarcinogenesis in in vitro and in vivo systems. Attention has also been focused on highlighting the mechanism of chemopreventive action of these dietary botanicals. We suggest that in addition to the use of these botanicals as dietary supplements for the protection of photocarcinogenesis, these botanicals may favorably supplement sunscreens protection and may provide additional antiphotocarcinogenic protection including the protection against other skin disorders caused by solar UV radiation.

  1. 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.

  2. Sulforaphane inhibits IL-1β-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of MMPs, COX-2, and PGE2.

    PubMed

    Choi, Yun Jung; Lee, Won-Seok; Lee, Eun-Gyeong; Sung, Myung-Soon; Yoo, Wan-Hee

    2014-10-01

    This study was performed to define the effects of sulforaphane on interleukin-1β (IL-1β)-induced proliferation of rheumatoid arthritis synovial fibroblasts (RASFs), the expression of matrix metalloproteinases (MMPs) and cyclooxygenase (COX), and the production of prostaglandin E2 (PGE2) by RASFs. The proliferation of RASFs was evaluated with CCK-8 reagent in the presence of IL-1β with/without sulforaphane. The expression of MMPs, tissue inhibitor of metalloproteinase-1, COXs, intracellular mitogen-activated protein kinase signalings, including p-ERK, p-p38, p-JNK, and nuclear factor-kappaB (NF-kB), and the production of PGE2 were examined by Western blotting or semi-quantitative RT-PCR and ELISA. Sulforaphane inhibits unstimulated and IL-1β-induced proliferation of RASFs; the expression of MMP-1, MMP-3, and COX-2 mRNA and protein; and the PGE2 production induced by IL-1β. Sulforaphane also inhibits the phosphorylation of ERK-1/2, p-38, and JNK and activation of NF-kB by IL-1β. These results indicate that sulforaphane inhibits the proliferation of synovial fibroblasts, the expression of MMPs and COX-2, and the production of PGE2, which are involved in synovitis and destruction of RA, and suggest that sulforaphane might be a new therapeutic agent for RA.

  3. Nrf2 and NF-κB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes.

    PubMed

    Negi, Geeta; Kumar, Ashutosh; Sharma, Shyam S

    2011-11-01

    High glucose driven reactive oxygen intermediates production and inflammatory damage are recognized contributors of nerve dysfunction and subsequent damage in diabetic neuropathy. Sulforaphane, a known chemotherapeutic agent holds a promise for diabetic neuropathy because of its dual antioxidant and anti-inflammatory activities. The present study investigated the effect of sulforaphane in streptozotocin (STZ) induced diabetic neuropathy in rats. For in vitro experiments neuro2a cells were incubated with sulforaphane in the presence of normal (5.5 mM) and high glucose (30 mM). For in vivo studies, sulforaphane (0.5 and 1 mg/kg) was administered six weeks post diabetes induction for two weeks. Motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and pain behavior were improved and malondialdehyde (MDA) level was reduced by sulforaphane. Antioxidant effect of sulforaphane is derived from nuclear erythroid 2-related factor 2 (Nrf2) activation as demonstrated by increased expression of Nrf2 and downstream targets hemeoxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1) in neuro2a cells and sciatic nerve of diabetic animals. Nuclear factor-kappa B (NF-κB) inhibition seemed to be responsible for antiinflammatory activity of sulforaphane as there was reduction in NF-κB expression and IκB kinase (IKK) phosphorylation along with abrogation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and tumor necrosis factor-α (TNF-α) and interleukine-6 (IL-6) levels. Here in this study we provide an evidence that sulforaphane is effective in reversing the various deficits in experimental diabetic neuropathy. This study supports the defensive role of Nrf2 in neurons under conditions of oxidative stress and also suggests that the NF-κB pathway is an important modulator of inflammatory damage in diabetic neuropathy.

  4. MicroRNA and Cancer Chemoprevention

    PubMed Central

    Yi, Bin; Piazza, Gary A.; Su, Xiulan; Xi, Yaguang

    2013-01-01

    MicroRNAs (miRNAs) are a group of naturally occurring, small, non-coding, and single-strand RNA molecules that regulate gene expression at the post-transcriptional and translational levels. By controlling the expression of oncogenic and tumor suppressor proteins, miRNAs are believed to play an important role in pathological processes associated with malignant progression including tumor cell proliferation, apoptosis, differentiation, angiogenesis, invasion and metastasis. However, relatively few studies have investigated the influence of chemopreventive agents on miRNA expression and their regulation of target genes. Given the significance of miRNAs in modulating gene expression, such research can provide insight into the pleiotropic biological effects that chemopreventive agents often display and a deeper understanding of their mechanism of action to inhibit carcinogenesis. Additionally, miRNAs can provide useful biomarkers for assessing antineoplastic activity of these agents in preclinical and clinical observations. In this review, we summarize recent publications that highlight a potentially important role of miRNAs in cancer chemoprevention research. PMID:23531448

  5. 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

  6. Selective apoptosis induction by the cancer chemopreventive agent N-(4-hydroxyphenyl)retinamide is achieved by modulating mitochondrial bioenergetics in premalignant and malignant human prostate epithelial cells.

    PubMed

    Hail, Numsen; Chen, Ping; Kepa, Jadwiga J

    2009-07-01

    Prostate tumorigenesis is coupled with an early metabolic switch in transformed prostate epithelial cells that effectively increases their mitochondrial bioenergetic capacity. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) inhibits prostate cancer development in vivo, and triggers reactive oxygen species (ROS)-dependent prostate cancer cell apoptosis in vitro. The possibility that 4HPR-induced ROS production is associated with mitochondrial bioenergetics and required for apoptosis induction in transformed prostate epithelial cells in vitro would advocate a prospective mechanistic basis for 4HPR-mediated prostate cancer chemoprevention in vivo. We investigated this tenet by comparing and contrasting 4HPR's effects on premalignant PWR-1E and malignant DU-145 human prostate epithelial cells. 4HPR promoted a dose- and/or time-dependent apoptosis induction in PWR-1E and DU-145 cells, which was preceded by and dependent on an increase in mitochondrial ROS production. In this regard, the PWR-1E cells were more sensitive than the DU-145 cells, and they consumed roughly twice as much oxygen as the DU-145 cells suggesting oxidative phosphorylation was higher in the premalignant cells. Interestingly, increasing the [Ca(2+)] in the culture medium of the PWR-1E cells attenuated their proliferation as well as their mitochondrial bioenergetic capacity and 4HPR's cytotoxic effects. Correspondingly, the respiration-deficient derivatives (i.e., rho(0) cells lacking mitochondrial DNA) of DU-145 cells were markedly resistant to 4HPR-induced ROS production and apoptosis. Together, these observations implied that the reduction of mitochondrial bioenergetics protected PWR-1E and DU-145 cells against the cytotoxic effects of 4HPR, and support the concept that oxidative phosphorylation is an essential determinant in 4HPR's apoptogenic signaling in transformed human prostate epithelial cells.

  7. Selective apoptosis induction by the cancer chemopreventive agent N-(4-hydroxyphenyl)retinamide is achieved by modulating mitochondrial bioenergetics in premalignant and malignant human prostate epithelial cells

    PubMed Central

    Hail, Numsen; Chen, Ping; Kepa, Jadwiga J.

    2010-01-01

    Prostate tumorigenesis is coupled with an early metabolic switch in transformed prostate epithelial cells that effectively increases their mitochondrial bioenergetic capacity. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) inhibits prostate cancer development in vivo, and triggers reactive oxygen species (ROS)-dependent prostate cancer cell apoptosis in vitro. The possibility that 4HPR-induced ROS production is associated with mitochondrial bioenergetics and required for apoptosis induction in transformed prostate epithelial cells in vitro would advocate a prospective mechanistic basis for 4HPR-mediated prostate cancer chemoprevention in vivo. We investigated this tenet by comparing and contrasting 4HPR's effects on premalignant PWR-1E and malignant DU-145 human prostate epithelial cells. 4HPR promoted a dose- and/or time-dependent apoptosis induction in PWR-1E and DU-145 cells, which was preceded by and dependent on an increase in mitochondrial ROS production. In this regard, the PWR-1E cells were more sensitive than the DU-145 cells, and they consumed roughly twice as much oxygen as the DU-145 cells suggesting oxidative phosphorylation was higher in the premalignant cells. Interestingly, increasing the [Ca2+] in the culture medium of the PWR-1E cells attenuated their proliferation as well as their mitochondrial bioenergetic capacity and 4HPR's cytotoxic effects. Correspondingly, the respiration-deficient derivatives (i.e., ρ0 cells lacking mitochondrial DNA) of DU-145 cells were markedly resistant to 4HPR-induced ROS production and apoptosis. Together, these observations implied that the reduction of mitochondrial bioenergetics protected PWR-1E and DU-145 cells against the cytotoxic effects of 4HPR, and support the concept that oxidative phosphorylation is an essential determinant in 4HPR's apoptogenic signaling in transformed human prostate epithelial cells. PMID:19421858

  8. Cancer chemoprevention using natural vitamin D and synthetic analogs.

    PubMed

    Guyton, K Z; Kensler, T W; Posner, G H

    2001-01-01

    Substantial epidemiologic data support a role for vitamin D in cancer prevention. However, dose-limiting hypercalcemic effects have proved a major obstacle to the development of natural vitamin D as a cancer chemopreventive. Structure-activity studies have sought to disassociate the toxicities and chemopreventive activities of vitamin D, and a number of synthetic deltanoids (vitamin D analogs) have shown considerable promise in this regard. Several such compounds have chemopreventive efficacy in preclinical studies, as does natural vitamin D. Data supporting further development of agents of this class include in vitro and in vivo evidence of antiproliferative, proapoptotic, prodifferentiating and antiangiogenic activities. Ongoing studies are aimed at further defining the molecular mechanisms through which vitamin D and synthetic deltanoids affect gene expression and cellular fate. Additional efforts are focused on establishing the chemopreventive index (efficacy vs toxicity) of each synthetic deltanoid.

  9. Mitochondria: A novel target for the chemoprevention of cancer.

    PubMed

    Hail, N

    2005-08-01

    The mitochondria have emerged as a novel target for anticancer chemotherapy. This tenet is based on the observations that several conventional and experimental chemotherapeutic agents promote the permeabilization of mitochondrial membranes in cancerous cells to initiate the release of apoptogenic mitochondrial proteins. This ability to engage mitochondrial-mediated apoptosis directly using chemotherapy may be responsible for overcoming aberrant apoptosis regulatory mechanisms commonly encountered in cancerous cells. Interestingly, several putative cancer chemopreventive agents also possess the ability to trigger apoptosis in transformed, premalignant, or malignant cells in vitro via mitochondrial membrane permeabilization. This process may occur through the regulation of Bcl-2 family members, or by the induction of the mitochondrial permeability transition. Thus, by exploiting endogenous mitochondrial-mediated apoptosis-inducing mechanisms, certain chemopreventive agents may be able to block the progression of premalignant cells to malignant cells or the dissemination of malignant cells to distant organ sites as means of modulating carcinogenesis in vivo. This review will examine cancer chemoprevention with respect to apoptosis, carcinogenesis, and the proapoptotic activity of various chemopreventive agents observed in vitro. In doing so, I will construct a paradigm supporting the notion that the mitochondria are a novel target for the chemoprevention of cancer.

  10. 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.

  11. 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.

  12. Tea as a potential chemopreventive agent in PhIP carcinogenesis: effects of green tea and black tea on PhIP-DNA adduct formation in female F-344 rats.

    PubMed

    Schut, H A; Yao, R

    2000-01-01

    chemopreventive agents in PhIP-induced tumorigenesis in the F-344 rat.

  13. 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

  14. 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.

  15. Orange juice and cancer chemoprevention.

    PubMed

    Franke, Silvia Isabel Rech; Guecheva, Temenouga Nikolova; Henriques, João Antonio Pêgas; Prá, Daniel

    2013-01-01

    Orange juice (OJ) is among the most consumed fruit juices worldwide, and its chemopreventive action is fairly addressed in the literature. This review critically presents the available evidence linking OJ with cancer chemoprevention and on discussing the putative mechanisms and negative health effects. The chemopreventive action of OJ is related to its effect on metabolic enzymes and its antiinflammatory, cytoprotective/apoptotic, hormonal, cell signaling-modulating, antioxidant, and antigenotoxic effects. Most studies on OJ are in vitro, and few are conducted in vivo. Results from in vitro studies must be interpreted carefully because these findings do not consider in vivo bioavailability. However, such results are useful for studying the impact of different processing and storage methods on OJ's chemopreventive effect. Evidence of OJ's chemoprevention in humans is limited. OJ is antimutagenic in bacteria and antigenotoxic in humans and rodents. Studies using rodent cancer models showed that OJ is cancer chemopreventive, influencing either the induction stage or the promotion stage. The composition and, therefore, the chemopreventive action of OJ might be influenced by different cultivars, climates, extraction methods, packaging, storage temperatures, and shelf lives, among other factors. Epidemiological studies and randomized controlled intervention studies in humans evaluating the chemopreventive effect of OJ, taking into consideration variability in OJ composition, are needed.

  16. Polyphenols and Prostate Cancer Chemoprevention

    DTIC Science & Technology

    2005-03-01

    prostate chemoprevention are the soy isoflavone , genistein, and the tea catechin, (-)- epigallocatechin-3-gallate (EGCG). Another polyphenol that has...resveratrol in female rats , where the low doses did not exert chemopreventive effects, we concentrated on determining if single exposure to the proposed

  17. Differential responses of skin cancer-chemopreventive agents silibinin, quercetin, and epigallocatechin 3-gallate on mitogenic signaling and cell cycle regulators in human epidermoid carcinoma A431 cells.

    PubMed

    Bhatia, N; Agarwal, C; Agarwal, R

    2001-01-01

    Silibinin, quercetin, and epigallocatechin 3-gallate (EGCG) have been shown to be skin cancer-preventive agents, albeit by several different mechanisms. Here, we assessed whether these agents show their cancer-preventive potential by a differential effect on mitogenic signaling molecules and cell cycle regulators. Treatment of human epidermoid carcinoma A431 cells with these agents inhibited the activation of the epidermal growth factor receptor and the downstream adapter protein Shc, but only silibinin showed a marked inhibition of mitogen-activated protein kinase-extracellular signal-regulated kinase-1 and -2 activation. In terms of cell cycle regulators, silibinin treatment showed an induction of Cip1/p21 and Kip1/p27 together with a significant decrease in cyclin-dependent kinase (CDK)-4, CDK2, and cyclin D1. Quercetin treatment, however, resulted in a moderate increase in Cip1/p21 with no change in Kip1/p27 and a decrease in CDK4 and cyclin D1. EGCG treatment also led to an induction of Cip1/p21 but no change in Kip1/27, CDK2, and cyclin D1 and a decrease in CDK4 only at low doses. Treatment of cells with these agents resulted in a strong dose- and time-dependent cell growth inhibition. A high dose of silibinin and low and high doses of quercetin and EGCG also led to cell death by apoptosis, suggesting that a lack of their inhibitory effect on mitogen-activated protein kinase-extracellular signal-regulated kinase-1 and -2 activation possibly "turns on" an apoptotic cell death response associated with their cancer-preventive and anticarcinogenic effects. Together, these results suggest that silibinin, quercetin, and EGCG exert their cancer-preventive effects by differential responses on mitogenic signaling and cell cycle regulators.

  18. 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.

  19. Cancer chemoprevention by nuts: evidence and promises.

    PubMed

    Falasca, Marco; Casari, Ilaria

    2012-01-01

    Chemoprevention is the use of chemical compounds to interfere with the early precancerous stages of carcinogenesis and thereby reverse tumor formation. Many chemopreventive agents, either natural or synthetic, have been identified. Some of the most promising compounds are found in vegetables and fruits. There are numerous mechanisms of action by which these components can intervene in the prevention of cancer, although they have not been fully elucidated. It is worth to note that some foods contain different bioactive compounds. Therefore the possibility exists that combinations of compounds, naturally occurring in those foods, may have a cumulative or even synergistic effect. Nuts are very rich in different bioactive compounds whose anti-cancer properties have already been described. Epidemiologic studies have already suggested that nuts consumption may be potentially beneficial in the incidence of other diseases, such as coronary heart disease and diabetes. Although the results are not conclusive, recent studies show possible cancer protective effects of nuts. This review will focus on the laboratory and clinical evidence of nuts chemopreventive and therapeutic properties.

  20. Sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide in multiple myeloma cells via stress-mediated pathways

    PubMed Central

    DOUDICAN, NICOLE A.; WEN, SHIH YA; MAZUMDER, AMITABHA; ORLOW, SETH J.

    2012-01-01

    Persistent paraprotein production in plasma cells necessitates a highly developed rough endoplasmic reticulum (ER) that is unusually susceptible to perturbations in protein synthesis. This biology is believed to account for the exquisite sensitivity of multiple myeloma (MM) to the proteasomal inhibitor bortezomib (BTZ). Despite remarkable response rates to BTZ in MM, BTZ carries the potential for serious side-effects and development of resistance. We, therefore, sought to identify therapeutic combinations that effectively disrupt proteostasis in order to provide new potential treatments for MM. We found that sulforaphane, a dietary isothiocyanate found in cruciferous vegetables, inhibits TNFα-induced Iκβ proteasomal degradation in a manner similar to BTZ. Like BTZ, sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide (ATO), an agent with clinical activity in MM. ATO and sulforaphane co-treatment augmented apoptotic induction as demonstrated by cleavage of caspase-3, -4 and PARP. The enhanced apoptotic response was dependent upon production of reactive oxygen species (ROS) as demonstrated by glutathione depletion and partial inhibition of the apoptotic cascade after pretreatment with the radical scavenger N-acetyl-cysteine (NAC). Combination treatment resulted in enhanced ER stress signaling and activation of the unfolded protein response (UPR), indicative of perturbation of proteostasis. Specifically, combination treatment caused elevated expression of the molecular chaperone HSP90 (heat shock protein 90) along with increased PERK (protein kinase RNA-like endoplasmic reticulum kinase) and eIF2α phosphorylation and XBP1 (X-box binding protein 1) splicing, key indicators of UPR activation. Moreover, increased splicing of XBP1 was apparent upon combination treatment compared to treatment with either agent alone. Sulforaphane in combination with ATO effectively disrupts protein homeostasis through ROS generation and induction of ER stress to

  1. 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

    2015-12-12

    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.

  2. 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

  3. 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

  4. 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.

  5. Implications of Cancer Stem Cell Theory for Cancer Chemoprevention by Natural Dietary Compounds

    PubMed Central

    Li, Yanyan; Wicha, Max S.; Schwartz, Steven J.; Sun, Duxin

    2011-01-01

    The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anti-cancer drugs targeting cancer stem cells. Naturally-occurring dietary compounds have received increasing attention in cancer chemoprevention. The anti-cancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog, and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine, and vitamin D3, are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival. PMID:21295962

  6. Retinoids in lung cancer chemoprevention and treatment.

    PubMed

    Toma, S; Raffo, P; Isnardi, L; Palumbo, R

    1999-01-01

    In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as

  7. Study of post-natal effect of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. III. Inhibitory action of indomethacin, voltaren, theophylline and epsilon-aminocaproic acid.

    PubMed

    Alexandrov, V A; Bespalov, V G; Petrov, A S; Troyan, D N; Lidaks MYu

    1996-09-01

    The influence of the arachidonic acid metabolism inhibitors, indomethacin and voltaren; an inhibitor of phosphodiesterase activity, theophylline and the protease inhibitor epsilonaminocaproic acid (EACA) on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day after conception. Indomethacin and voltaren (20 p.p.m. in drinking water), theophylline (0.01% in diet) and EACA (1000 p.p.m. in drinking water) were given to the offspring throughout their post-natal life until all survivors were killed at 12 months. In the ENU-only control groups, 100% of the offspring developed tumors of brain, spinal cord, peripheral nervous system or kidneys, with a total average number of 3.1 tumors per rat. The most marked inhibitory effect was exerted by theophylline, which significantly decreased the incidence and multiplicity of total tumors, and at all main sites selectively (brain, spinal cord, peripheral nerves and kidneys). It also prolonged average survival time of the offspring. Indomethacin and voltaren significantly decreased total tumor incidence and multiplicity and brain tumor incidence and multiplicity. Indomethacin also decreased kidney tumor multiplicity and voltaren diminished spinal cord tumor multiplicity. EACA decreased multiplicities of total, brain, peripheral nerve and kidney tumors, and diminished the incidence of brain tumors. These chemopreventive agents decreased tumor incidences 20-33% and tumor multiplicities 1.4-2.7 times, compared with the ENU-only controls.

  8. Chemopreventive agents modulate the protein expression profile of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone plus benzo[a]pyrene-induced lung tumors in A/J mice.

    PubMed

    Kassie, Fekadu; Anderson, Lorraine B; Higgins, Leeann; Pan, Yunqian; Matise, Ilze; Negia, Mesfin; Upadhyaya, Pramod; Wang, Mingyao; Hecht, Stephen S

    2008-03-01

    We used isobaric tag labeling coupled with mass spectrometry to compare the relative abundance of proteins in lung tumors from A/J mice treated with a mixture of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene versus normal mouse lung tissues. Levels of 59 proteins changed-30 increased and 29 decreased-in tumor tissues versus normal tissues. Among proteins that showed increased levels in tumor tissues versus normal tissues were glycolytic enzymes, ribosomal proteins, fatty acid synthase, cathepsins D and H and carbonic anhydrase 2. On the other hand, the levels of cytochrome P450 enzymes 2B10 and 2F2, glutathione S-transferases mu-1, procollagen VI, Clara cell 10 kDA (CC10) protein, histones, receptor advanced glycation end product, and lung carbonyl reductase were lower in tumor tissues versus normal lung tissues. Upon dietary administration of a combination of N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine plus myo-inositol or indole-3-carbinol to carcinogen-treated mice, the relative abundance of 60S ribosomal protein L4 and carbonic anhydrase in tumor tissues decreased whereas that of histones, glutathione S-transferases mu, receptor advanced glycation end product, transglutaminase, and procollagen VI increased. Western assays with lung tissue homogenates not only verified the proteomics results for selected proteins but also showed differential expression of hypoxia inducible factor-1alpha, a transcription factor for most of the proteins that showed changes in relative abundance. This is the first report on the application of quantitative proteomics to study the relative abundance of proteins in a mouse model of lung carcinogenesis. These proteins may have utility for development of candidate lung cancer biomarkers and as targets of chemopreventive/chemotherapeutic agents.

  9. Modulating Polo-Like Kinase 1 as a Means for Cancer Chemoprevention

    PubMed Central

    Schmit, Travis L.; Ledesma, Mark C.; Ahmad, Nihal

    2010-01-01

    Naturally occurring agents have always been appreciated for their medicinal value for both their chemopreventive and therapeutic effects against cancer. In fact, the majority of the drugs we use today, including the anti-cancer agents, were originally derived from natural compounds, either in their native form or modified to enhance their bioavailability or specificity. It is believed that for maximum effectiveness, it will useful to design novel target-based agents for chemoprevention as well as the treatment of cancer. Recent studies have shown that the serine/threonine kinase polo-like kinase (Plk) 1 is widely overexpressed in a variety of cancers and is being increasingly appreciated as a target for cancer management. Additionally, several chemopreventive agents have been shown to inhibit Plk1 in cancer cells. In this review, we will discuss if Plk1 could also be a target for designing novel strategies for cancer chemoprevention. PMID:20107874

  10. A worked example of "best fit" framework synthesis: a systematic review of views concerning the taking of some potential chemopreventive agents.

    PubMed

    Carroll, Christopher; Booth, Andrew; Cooper, Katy

    2011-03-16

    A variety of different approaches to the synthesis of qualitative data are advocated in the literature. The aim of this paper is to describe the application of a pragmatic method of qualitative evidence synthesis and the lessons learned from adopting this "best fit" framework synthesis approach. An evaluation of framework synthesis as an approach to the qualitative systematic review of evidence exploring the views of adults to the taking of potential agents within the context of the primary prevention of colorectal cancer. Twenty papers from North America, Australia, the UK and Europe met the criteria for inclusion. Fourteen themes were identified a priori from a related, existing conceptual model identified in the literature, which were then used to code the extracted data. Further analysis resulted in the generation of a more sophisticated model with additional themes. The synthesis required a combination of secondary framework and thematic analysis approaches and was conducted within a health technology assessment timeframe. The novel and pragmatic "best fit" approach to framework synthesis developed and described here was found to be fit for purpose. Future research should seek to test further this approach to qualitative data synthesis.

  11. Sulforaphane alleviates scopolamine-induced memory impairment in mice.

    PubMed

    Lee, Siyoung; Kim, Jisung; Seo, Sang Gwon; Choi, Bo-Ryoung; Han, Jung-Soo; Lee, Ki Won; Kim, Jiyoung

    2014-07-01

    Sulforaphane, an organosulfur compound present in cruciferous vegetables, has been shown to exert neuroprotective effects in experimental in vitro and in vivo models of neurodegeneration. To determine whether sulforaphane can preserve cognitive function, we examined its effects on scopolamine-induced memory impairment in mice using the Morris water maze test. Sulforaphane (10 or 50mg/kg) was administered to C57BL/6 mice by oral gavage for 14 days (days 1-14), and memory impairment was induced by intraperitoneal injection of scopolamine (1mg/kg) for 7 days (days 8-14). Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity in the hippocampus and frontal cortex, as indicated by a decreased acetylcholine (ACh) level and an increased acetylcholinesterase (AChE) activity. Sulforaphane significantly attenuated the scopolamine-induced memory impairment and improved cholinergic system reactivity, as indicated by an increased ACh level, decreased AChE activity, and increased choline acetyltransferase (ChAT) expression in the hippocampus and frontal cortex. These effects of sulforaphane on cholinergic system reactivity were confirmed in vitro. Sulforaphane (10 or 20μM) increased the ACh level, decreased the AChE activity, and increased ChAT expression in scopolamine-treated primary cortical neurons. These observations suggest that sulforaphane might exert a significant neuroprotective effect on cholinergic deficit and cognitive impairment. Copyright © 2014. Published by Elsevier Ltd.

  12. In vitro absorption and metabolism of a citrus chemopreventive agent, auraptene, and its modifying effects on xenobiotic enzyme activities in mouse livers.

    PubMed

    Murakami, A; Wada, K; Ueda, N; Sasaki, K; Haga, M; Kuki, W; Takahashi, Y; Yonei, H; Koshimizu, K; Ohigashi, H

    2000-01-01

    We previously reported that auraptene (7-geranyloxycoumarin, AUR), widely occurring in citrus fruit, is a structurally novel type of effective cancer-preventive agent, as manifested in several rodent models. However, its bio-availability and metabolism in biological systems have yet to be investigated. In the present study, we examined the chemical stability of AUR at pH 1.57 and 37 degrees C (as a stomach digestion model) and observed its stoichiometric conversion to umbelliferone [7-hydroxycoumarin, UMB; half-life (t1/2) = 15 h; 7-ethoxycoumarin (ETC) was stable for 24 h]. Differentiated Caco-2 cells, a human colorectal adenocarcinoma cell line, were used as a small intestine model. ETC permeated the basolateral (portal vein) side of Caco-2 cells in a time-dependent manner; AUR slightly permeated the cells, but with an intracellular accumulation. Epoxyauraptene and UMB were detected when AUR was treated with the rat liver S-9 mixture. ETC was also converted to UMB, but its t1/2 of two hours was much shorter than that of AUR (> 24 h). This suggests that AUR, bearing a geranyloxyl side chain, is a relatively metabolism-resistant substrate for cytochrome P-450 enzymes and, thus, is stable in the liver compared with ETC. Oral administration of AUR by gavage at 50-200 mg/kg body wt dose dependently induced glutathione S-transferase (GST) activity in mouse livers without affecting cytochrome P-450 activity. Using 10 coumarin-related compounds, we found that only those coumarins having a 7-alkyloxyl group induced GST, but not cytochrome P-450, activity. The present study presumes that AUR accumulates in the epithelial cells of the small intestine and then gradually permeates into the portal vein. Stable localizability of AUR in the colon and liver may be associated with the induction of GST activity, which is important as the action mechanism for suppression of rodent chemical carcinogenesis.

  13. Chemoprevention in familial adenomatous polyposis.

    PubMed

    Kim, Brian; Giardiello, Francis M

    2011-08-01

    Familial adenomatous polyposis (FAP) predictably leads to adenomas and eventual adenocarcinomas in the lower gastrointestinal tract and less frequently, the upper gastrointestinal tract. Chemopreventive strategies have been studied in FAP patients to delay the development of adenomas in the upper and lower gastrointestinal tract, as well as to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery with colectomy and ileorectal anastamosis (IRA). The nonsteroidal anti-inflammatory drug (NSAID) sulindac and selective cyclooxygenase-2 (COX-2) inhibitor celecoxib reduce polyposis of the retained rectum after colectomy with IRA. Reports of cardiovascular risks of some NSAIDs and selective COX-2 inhibitors have led to promising studies of lower doses in combination with ursodeoxycholic acid, statin, and difluoromethylornithine. Curcumin and eicosapentaenoic acid show efficacy in small clinical trials of FAP chemoprevention. This article will review the concept of chemoprevention and the current clinical literature in FAP chemoprevention.

  14. Chemoprevention in familial adenomatous polyposis

    PubMed Central

    Kim, Brian; Giardiello, Francis M.

    2013-01-01

    Familial adenomatous polyposis (FAP) predictably leads to adenomas and eventual adenocarcinomas in the lower gastrointestinal tract and less frequently, the upper gastrointestinal tract. Chemopreventive strategies have been studied in FAP patients to delay the development of adenomas in the upper and lower gastrointestinal tract, as well as to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery with colectomy and ileorectal anastamosis (IRA). The nonsteroidal anti-inflammatory drug (NSAID) sulindac and selective cyclooxygenase-2 (COX-2) inhibitor celecoxib reduce polyposis of the retained rectum after colectomy with IRA. Reports of cardiovascular risks of some NSAIDs and selective COX-2 inhibitors have led to promising studies of lower doses in combination with ursodeoxycholic acid, statin, and difluoromethylornithine. Curcumin and eicosapentaenoic acid show efficacy in small clinical trials of FAP chemoprevention. This article will review the concept of chemoprevention and the current clinical literature in FAP chemoprevention. PMID:22122775

  15. Endoplasmic reticulum stress mediates sulforaphane-induced apoptosis of HepG2 human hepatocellular carcinoma cells.

    PubMed

    Zou, Xiang; Qu, Zhongyuan; Fang, Yueni; Shi, Xin; Ji, Yubin

    2017-01-01

    Sulforaphane (SFN) is a naturally occurring chemopreventive agent, which effectively inhibits proliferation of HepG2 human hepatocellular carcinoma cells via mitochondria‑mediated apoptosis. Endoplasmic reticulum stress is considered the most important cause of cell apoptosis; therefore, the present study aimed to determine whether the endoplasmic reticulum pathway was involved in SFN-induced apoptosis of HepG2 cells. An MTT assay was used to detect the inhibitory effects of SFN on HepG2 cells. Fluorescence microscopy was used to observe the morphological changes in apoptotic cells, and western blot analysis was conducted to detect the expression of binding immunoglobulin protein (Bip)/glucose-regulated protein 78 (GRP78), X‑box binding protein‑1 (XBP‑1) and BH3 interacting domain death agonist (Bid). Furthermore, flow cytometry was used to determine the apoptotic rate of HepG2 cells, and the protein expression of C/EBP homologous protein (CHOP)/growth arrest‑ and DNA damage‑inducible gene 153 (GADD153) and caspase-12 in HepG2 cells. The results indicated that SFN significantly inhibited the proliferation of HepG2 cells; the half maximal inhibitory concentration values were 32.03±0.96, 20.90±1.96 and 13.87±0.44 µmol/l, following treatment with SFN for 24, 48 and 72 h, respectively. Following 48 h of SFN treatment (10, 20 and 40 µmol/l), the apoptotic rates of HepG2 cells were 31.8, 61.3 and 77.1%, respectively. Furthermore, after 48 h of exposure to SFN, the cells presented typical morphological alterations of apoptosis, as detected under fluorescence microscopy. Treatment with SFN for 48 h also significantly upregulated the protein expression levels of Bip/GRP78, XBP‑1, caspase‑12, CHOP/GADD153 and Bid in HepG2 cells. In conclusion, endoplasmic reticulum stress may be considered the most important mechanism underlying SFN-induced apoptosis in HepG2 cells.

  16. Oxidative Stress: A Promising Target for Chemoprevention

    PubMed Central

    John, AM Sashi Papu; Ankem, Murali K; Damodaran, Chendil

    2016-01-01

    Cancer is a leading cause of death worldwide, and treating advanced stages of cancer remains clinically challenging. Epidemiological studies have shown that oxidants and free radicals induced DNA damage is one of the predominant causative factors for cancer pathogenesis. Hence, oxidants are attractive targets for chemoprevention as well as therapy. Dietary agents are known to exert an anti-oxidant property which is one of the most efficient preventive strategy in cancer progression. In this article, we highlight dietary agents can potentially target oxidative stress, in turn delaying, preventing, or treating cancer development. Some of these agents are currently in use in basic research, while some have been launched successfully into clinical trials. PMID:27088073

  17. Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3β/β-catenin signaling pathways.

    PubMed

    Wang, Da-Xuan; Zou, Yu-Jiao; Zhuang, Xi-Bin; Chen, Shu-Xing; Lin, Yong; Li, Wen-Lan; Lin, Jun-Jin; Lin, Zhi-Qiang

    2017-02-01

    Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 μmol/L, respectively. At low concentrations (1-5 μmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3β and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3β/β-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or

  18. Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3β/β-catenin signaling pathways

    PubMed Central

    Wang, Da-xuan; Zou, Yu-jiao; Zhuang, Xi-bin; Chen, Shu-xing; Lin, Yong; Li, Wen-lan; Lin, Jun-jin; Lin, Zhi-qiang

    2017-01-01

    Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 μmol/L, respectively. At low concentrations (1–5 μmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3β and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3β/β-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or

  19. Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways.

    PubMed

    Ramos, Sonia

    2008-05-01

    Prevention of cancer through dietary intervention recently has received an increasing interest, and dietary polyphenols have become not only important potential chemopreventive, but also therapeutic, natural agents. Polyphenols have been reported to interfere at the initiation, promotion and progression of cancer. They might lead to the modulation of proteins in diverse pathways and require the integration of different signals for the final chemopreventive or therapeutic effect. Polyphenols have been demonstrated to act on multiple key elements in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis and metastasis; however, these molecular mechanisms of action are not completely characterized and many features remain to be elucidated. The aim of this review is to provide insights into the molecular basis of potential chemopreventive and therapeutic activities of dietary polyphenols with emphasis in their ability to control intracellular signalling cascades considered as relevant targets in a cancer preventive approach.

  20. Chemopreventive compounds--view from the other side.

    PubMed

    Hodek, P; Krízková, J; Burdová, K; Sulc, M; Kizek, R; Hudecek, J; Stiborová, M

    2009-06-15

    Increasing attention is being paid to the possibility of applying chemopreventive agents for the protection of individuals from cancer risk. The beneficial potential of chemoprotective compounds is usually well documented by extensive experimental data. To assure the desired effect, these compounds are frequently concentrated to produce dietary supplements for human use. The additive and synergistic effects of other food constituents are, however, frequently ignored. Even natural chemopreventive compounds have to be considered as xenobiotics. Thus, as much attention has to be paid to their testing prior to their wide application as is usual in drug development for human treatment. Unfortunately, much of the research in this area is solely based on simplified in vitro systems that cannot take into account the complexity of biotransformation processes, e.g. chemopreventive compound-drug interaction, effect on metabolism of endogenic compounds. Hence, the predicted chemopreventive potential is not attained in respect of cancer prevention; moreover, the administration of high doses of chemopreventive compounds might be even detrimental for the human health.

  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 17β-Estradiol enhances sulforaphane cardioprotection against oxidative stress.

    PubMed

    Angeloni, Cristina; Teti, Gabriella; Barbalace, Maria Cristina; Malaguti, Marco; Falconi, Mirella; Hrelia, Silvana

    2017-01-12

    The lower incidence of ischemic heart disease in female with respect to male gender suggests the possibility that female sex hormones could have specific effects in cardiovascular protection. 17β-Estradiol is the predominant premenopausal circulating form of estrogen and has a protective role on the cardiovascular system. Recent evidences suggest that gender can influence the response to cardiovascular medications; therefore, we hypothesized that sex hormones could also modulate the cardioprotective effects of nutraceutical compounds, such as the isothiocyanate sulforaphane, present in Brassica vegetables. This study was designed to explore the protective effects of sulforaphane in the presence of 17β-estradiol against H2O2-induced oxidative stress in primary cultures of rat cardiomyocytes. Interestingly, 17β-estradiol enhanced sulforaphane protective activity against H2O2-induced cell death with respect to sulforaphane or 17β-estradiol alone as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyl-tetrazolium bromide and lactate dehydrogenase assays. Moreover, 17β-estradiol boosted sulforaphane ability to counteract oxidative stress, reducing intracellular reactive oxygen species and 8-hydroxy-2'-deoxyguanosine levels and increasing the expression of phase II enzymes. Using specific antagonists of estrogen receptor α and β, we observed that these effects are not mediated by estrogen receptors. Otherwise, ERK1/2 and Akt signaling pathways seem to be involved, as the presence of specific inhibitors of these kinases reduced the protective effect of sulforaphane in the presence of 17β-estradiol. Sulforaphane and 17β-estradiol co-treatment counteracted cell morphology alterations induced by H2O2 as evidenced by transmission electron microscopy. Our results demonstrated, for the first time, that estrogens could enhance sulforaphane protective effects, suggesting that nutraceutical efficacy might be modulated by sex hormones.

  7. Modification of Keap1 Cysteine Residues by Sulforaphane

    PubMed Central

    Hu, Chenqi; Eggler, Aimee L.; Mesecar, Andrew D.; van Breemen, Richard B.

    2011-01-01

    Activation of the transcription factor NF-E2-related factor-2 (Nrf2) through modification of Kelch-like ECH-associated protein 1 (Keap1) cysteines, leading to up-regulation of the antioxidant response element (ARE), is an important mechanism of cellular defense against reactive oxygen species and xenobiotic electrophiles. Sulforaphane, occurring in cruciferous vegetables such as broccoli, is a potent natural ARE activator that functions by modifying Keap1 cysteine residues, but there are conflicting in vitro and in vivo data regarding which of these cysteine residues react. Although most biological data indicate that modification of C151 is essential for sulforaphane action, some recent studies using mass spectrometry have failed to identify C151 as a site of Keap1 sulforaphane reaction. We have reconciled these conflicting data using mass spectrometry with a revised sample preparation protocol and confirmed that C151 is indeed among the most readily modified cysteines of Keap1 by sulforaphane. Previous mass spectrometry-based studies used iodoacetamide during sample preparation to derivatize free cysteine sulfhydryl groups causing loss of sulforaphane from highly reactive and reversible cysteine residues on Keap1 including C151. By omitting iodoacetamide from the protocol and reducing sample preparation time, our mass spectrometry-based studies now confirm previous cell-based studies which showed that sulforaphane reacts with at least four cysteine residues of Keap1 including C151. PMID:21391649

  8. Protection of retinal function by sulforaphane following retinal ischemic injury.

    PubMed

    Ambrecht, Lindsay A; Perlman, Jay I; McDonnell, James F; Zhai, Yougang; Qiao, Liang; Bu, Ping

    2015-09-01

    Sulforaphane, a precursor of glucosinolate in cruciferous vegetables such as broccoli and cauliflower, has been shown to protect brain ischemic injury. In this study, we examined the effect of systemic administration of sulforaphane on retinal ischemic reperfusion injury. Intraocular pressure was elevated in two groups of C57BL/6 mice (n = 8 per group) for 45 min to induce retinal ischemic reperfusion injury. Following retinal ischemic reperfusion injury, vehicle (1% DMSO saline) or sulforaphane (25 mg/kg/day) was administered intraperitoneally daily for 5 days. Scotopic electroretinography (ERG) was used to quantify retinal function prior to and one-week after retinal ischemic insult. Retinal morphology was examined one week after ischemic insult. Following ischemic reperfusion injury, ERG a- and b-wave amplitudes were significantly reduced in the control mice. Sulforaphane treatment significantly attenuated ischemic-induced loss of retinal function as compared to vehicle treated mice. In vehicle treated mice, ischemic reperfusion injury produced marked thinning of the inner retinal layers, but the thinning of the inner retinal layers appeared significantly less with sulforaphane treatment. Thus, sulforaphane may be beneficial in the treatment of retinal disorders with ischemic reperfusion injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Electrophilic tuning of the chemoprotective natural product sulforaphane

    PubMed Central

    Ahn, Young-Hoon; Hwang, Yousang; Liu, Hua; Wang, Xiu Jun; Zhang, Ying; Stephenson, Katherine K.; Boronina, Tatiana N.; Cole, Robert N.; Dinkova-Kostova, Albena T.; Talalay, Paul; Cole, Philip A.

    2010-01-01

    Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase 2 cytoprotective enzymes and can protect against electrophiles including carcinogens, oxidative stress, and inflammation. The mechanism of action of sulforaphane is believed to involve modifications of critical cysteine residues of Keap1, which lead to stabilization of Nrf2 to activate the antioxidant response element of phase 2 enzymes. However, the dithiocarbamate functional group formed by a reversible reaction between isothiocyanate of sulforaphane and sulfhydryl nucleophiles of Keap1 is kinetically labile, and such modification in intact cells has not yet been demonstrated. Here we designed sulforaphane analogs with replacement of the reactive isothiocyanate by the more gentle electrophilic sulfoxythiocarbamate group that also selectively targets cysteine residues in proteins but forms stable thiocarbamate adducts. Twenty-four sulfoxythiocarbamate analogs were synthesized that retain the structural features important for high potency in sulforaphane analogs: the sulfoxide or keto group and its appropriate distance to electrophilic functional group. Evaluation in various cell lines including hepatoma cells, retinal pigment epithelial cells, and keratinocytes as well as in mouse skin shows that these analogs maintain high potency and efficacy for phase 2 enzyme induction as well as the inhibitory effect on lipopolysaccharide-induced nitric oxide formation like sulforaphane. We further show in living cells that a sulfoxythiocarbamate analog can label Keap1 on several key cysteine residues as well as other cellular proteins offering new insights into the mechanism of chemoprotection. PMID:20439747

  10. Sulforaphane induced adipolysis via hormone sensitive lipase activation, regulated by AMPK signaling pathway.

    PubMed

    Lee, Ju-Hee; Moon, Myung-Hee; Jeong, Jae-Kyo; Park, Yang-Gyu; Lee, You-Jin; Seol, Jae-Won; Park, Sang-Youel

    2012-10-05

    Sulforaphane, an aliphatic isothiocyanate derived from cruciferous vegetables, is known for its antidiabetic properties. The effects of sulforaphane on lipid metabolism in adipocytes are not clearly understood. Here, we investigated whether sulforaphane stimulates lipolysis. Mature adipocytes were incubated with sulforaphane for 24h and analyzed using a lipolysis assay which quantified glycerol released into the medium. We investigated gene expression of hormone-sensitive lipase (HSL), and levels of HSL phosphorylation and AMP-activated protein kinase on sulforaphane-mediated lipolysis in adipocytes. Sulforaphane promoted lipolysis and increased both HSL gene expression and HSL activation. Sulforaphane suppressed AMPK phosphorylation at Thr-172 in a dose-dependent manner, which was associated with a decrease in HSL phosphorylation at Ser-565, enhancing the phosphorylation of HSL Ser-563. Taken together, these results suggest that sulforaphane promotes lipolysis via hormone sensitive lipase activation mediated by decreasing AMPK signal activation in adipocytes. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Keap1 eye on the target: chemoprevention of liver cancer.

    PubMed

    Yates, Melinda Sue; Kensler, Thomas Wells

    2007-09-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, causing nearly 600,000 deaths each year. Increased risk of HCC due to chronic infection with hepatitis B virus (HBV) and exposure to dietary aflatoxins is responsible for many of these deaths. Prevention strategies targeting HBV infection and aflatoxin exposure could dramatically impact the rates of HCC. Universal HBV vaccination programs have begun in some high-risk areas. Strategies to reduce aflatoxin contamination in food stores have also been implemented. However, complete elimination of aflatoxin contamination might not be possible. For this reason, chemoprevention strategies which alter aflatoxin disposition are a practical strategy to reduce the incidence of HCC in populations with high dietary aflatoxin exposure. The mechanisms of aflatoxin-induced hepatocarcinogenesis are well known. This knowledge provides the basis for evaluation of both exposures to aflatoxin, as well as modulation of aflatoxin disposition by chemopreventive agents. Products of aflatoxin DNA damage and toxicity as well as other metabolites can be used as biomarkers to evaluate modulation of aflatoxin disposition. Modulation of aflatoxin disposition can be achieved through induction of conjugating and cytoprotective enzymes. Many of these enzymes are regulated through Kelch ECH-associating protein 1 (Keap1)-NF-E2-related factor 2(Nrf2)-antioxidant response element (ARE) signaling, making this pathway an important molecular target for chemoprevention. Rodent studies have identified several classes of chemopreventive agents which induce cytoprotective genes. These inducers include phenolic antioxidants, dithiolethiones, isothiocyanates, and triterpenoids. Furthermore, clinical interventions have shown that inducers of Keap1-Nrf2- ARE signaling increase cytoprotective enzyme expression, resulting in modulation of aflatoxin disposition. Much work remains to be done in order to take promising chemopreventive agents

  12. Sulforaphane Inhibits Mitochondrial Permeability Transition and Oxidative Stress

    PubMed Central

    Greco, Tiffany; Shafer, Jonathan; Fiskum, Gary

    2012-01-01

    Exposure of mitochondria to oxidative stress and elevated Ca2+ promotes opening of the mitochondrial permeability transition pore (PTP), resulting in membrane depolarization, uncoupling of oxidative phosphorylation, and potentially cell death. This study tested the hypothesis that treatment of rats with sulforaphane (SFP), an activator of the Nrf2 pathway of antioxidant gene expression, increases the resistance of liver mitochondria to redox-regulated PTP opening and elevates mitochondrial levels of antioxidants. Rats were injected with SFP or drug vehicle and liver mitochondria were isolated 40 hr later. Respiring mitochondria actively accumulated added Ca2+, which was then released through PTP opening induced by agents that either cause an oxidized shift in the mitochondrial redox state or that directly oxidize protein thiol groups. SFP treatment of rats inhibited the rate of pro-oxidant-induced mitochondrial Ca2+ release and increased expression of the glutathione peroxidase/reductase system, thioredoxin, and malic enzyme. These results are the first to demonstrate that SFP treatment of animals increases liver mitochondrial antioxidant defenses and inhibits redox-sensitive PTP opening. This novel form of preconditioning could protect against a variety of pathologies that include oxidative stress and mitochondrial dysfunction in their etiologies. PMID:21986339

  13. Moringa oleifera Lam: Targeting Chemoprevention.

    PubMed

    Karim, Nurul Ashikin Abd; Ibrahim, Muhammad Din; Kntayya, Saie Brindha; Rukayadi, Yaya; Hamid, Hazrulizawati Abd; Razis, Ahmad Faizal Abdull

    2016-01-01

    Moringa oleifera Lam, family Moringaceae, is a perennial plant which is called various names, but is locally known in Malaysia as "murungai" or "kelor". Glucomoringin, a glucosinolate with from M. oleifera is a major secondary metabolite compound. The seeds and leaves of the plant are reported to have the highest amount of glucosinolates. M. oleifera is well known for its many uses health and benefits. It is claimed to have nutritional, medicinal and chemopreventive potentials. Chemopreventive effects of M. oleifera are expected due to the existence of glucosinolate which it is reported to have the ability to induce apoptosis in anticancer studies. Furthermore, chemopreventive value of M. oleifera has been demonstrated in studies utilizing its leaf extract to inhibit the growth of human cancer cell lines. This review highlights the advantages of M. oleifera targeting chemoprevention where glucosinolates could help to slow the process of carcinogenesis through several molecular targets. It is also includes inhibition of carcinogen activation and induction of carcinogen detoxification, anti-inflammatory, anti-tumor cell proliferation, induction of apoptosis and inhibition of tumor angiogenesis. Finally, for synergistic effects of M. oleifera with other drugs and safety, essential for chemoprevention, it is important that it safe to be consumed by human body and works well. Although there is promising evidence about M. oleifera in chemoprevention, extensive research needs to be done due to the expected rise of cancer in coming years and to gain more information about the mechanisms involved in M. oleifera influence, which could be a good source to inhibit several major mechanisms involved in cancer development.

  14. Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer.

    PubMed

    Marin, Jose J G; Sanchez de Medina, Fermin; Castaño, Beatriz; Bujanda, Luis; Romero, Marta R; Martinez-Augustin, Olga; Moral-Avila, Rosario Del; Briz, Oscar

    2012-05-01

    Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in industrialized countries. Chemoprevention is a promising approach, but studies demonstrating their usefulness in large populations are still needed. Among several compounds with chemopreventive ability, cyclooxygenase inhibitors have received particular attention. However, these agents are not without side effects, which must be weighed against their beneficial actions. Early diagnosis is critical in the management of CRC patients, because, in early stages, surgery is curative in >90% of cases. If diagnosis occurs at stages II and III, which is often the case, neoadjuvant chemotherapy and radiotherapy before surgery are, in a few cases, recommended. Because of the high risk of recurrence in advanced cancers, chemotherapy is maintained after tumor resection. Chemotherapy is also indicated when the patient has metastases and in advanced cancer located in the rectum. In the last decade, the use of anticancer drugs in monotherapy or in combined regimens has markedly increased the survival of patients with CRC at stages III and IV. Although the rate of success is higher than in other gastrointestinal tumors, adverse effects and development of chemoresistance are important limitations to pharmacological therapy. Genetic profiling regarding mechanisms of chemoresistance are needed to carry out individualized prediction of the lack of effectiveness of pharmacological regimens. This would minimize side effects and prevent the selection of aggressive, cross-resistant clones, as well as avoiding undesirable delays in the use of the most efficient therapeutic approaches to treat these patients.

  15. 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

  16. 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.

  17. 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.

  18. Adlay (薏苡 yì yĭ; “soft-shelled job's tears”; the seeds of Coix lachryma-jobi L. var. ma-yuen Stapf) is a Potential Cancer Chemopreventive Agent toward Multistage Carcinogenesis Processes

    PubMed Central

    Kuo, Ching-Chuan; Chen, Huang-Hui; Chiang, Wenchang

    2012-01-01

    Adlay (薏苡 yì yĭ “soft-shelled job's tears”, the seeds of Coix lachryma-jobi L. var. ma-yuen Stapf) is a grass crop that has long been used in traditional Chinese medicine (TCM) and as a nourishing food in China for the treatment of warts, chapped skin, rheumatism, neuralgia, inflammatory, and neoplastic diseases. In addition, adlay also has been said to have stomachic, diuretic, antipholgistic, anodynic, and antispasmodic effects. Carcinogenesis is a multistage process that begins with exposure of viruses or chemicals that are found in the environment. Chemoprevention refers to the use of natural or synthetic, non-toxic chemical substances to reverse, repress, or prevent carcinogenesis. In this review, we summarize recent research attempting to study the chemopreventive blocking and suppressing potential of adlay and its active components in scavenging electrophiles and reactive oxygen species, antimutagenicity, enhancing Nrf2-mediated detoxification and antioxidant effect, altering carcinogen metabolism, suppressing proliferation, decreasing inflammation, and enhancing antitumor immunity. In addition, several active components with diverse chemopreventive properties have been also mentioned in this review article. PMID:24716141

  19. Adlay ( yì yĭ; "soft-shelled job's tears"; the seeds of Coix lachryma-jobi L. var. ma-yuen Stapf) is a Potential Cancer Chemopreventive Agent toward Multistage Carcinogenesis Processes.

    PubMed

    Kuo, Ching-Chuan; Chen, Huang-Hui; Chiang, Wenchang

    2012-10-01

    Adlay ( yì yĭ "soft-shelled job's tears", the seeds of Coix lachryma-jobi L. var. ma-yuen Stapf) is a grass crop that has long been used in traditional Chinese medicine (TCM) and as a nourishing food in China for the treatment of warts, chapped skin, rheumatism, neuralgia, inflammatory, and neoplastic diseases. In addition, adlay also has been said to have stomachic, diuretic, antipholgistic, anodynic, and antispasmodic effects. Carcinogenesis is a multistage process that begins with exposure of viruses or chemicals that are found in the environment. Chemoprevention refers to the use of natural or synthetic, non-toxic chemical substances to reverse, repress, or prevent carcinogenesis. In this review, we summarize recent research attempting to study the chemopreventive blocking and suppressing potential of adlay and its active components in scavenging electrophiles and reactive oxygen species, antimutagenicity, enhancing Nrf2-mediated detoxification and antioxidant effect, altering carcinogen metabolism, suppressing proliferation, decreasing inflammation, and enhancing antitumor immunity. In addition, several active components with diverse chemopreventive properties have been also mentioned in this review article.

  20. Influence of Sulforaphane Metabolites on Activities of Human Drug-Metabolizing Cytochrome P450 and Determination of Sulforaphane in Human Liver Cells.

    PubMed

    Vanduchova, Alena; Tomankova, Veronika; Anzenbacher, Pavel; Anzenbacherova, Eva

    2016-12-01

    The influence of metabolites of sulforaphane, natural compounds present in broccoli (Brassica oleracea var. botrytis italica) and in other cruciferous vegetables, on drug-metabolizing cytochrome P450 (CYP) enzymes in human liver microsomes and possible entry of sulforaphane into human hepatic cells were investigated. Metabolites studied are compounds derived from sulforaphane by the mercapturic acid pathway (conjugation with glutathione and by following reactions), namely sulforaphane glutathione and sulforaphane cysteine conjugates and sulforaphane-N-acetylcysteine. Their possible effect on four drug-metabolizing CYP enzymes, CYP3A4 (midazolam 1'-hydroxylation), CYP2D6 (bufuralol 1'-hydroxylation), CYP1A2 (7-ethoxyresorufin O-deethylation), and CYP2B6 (7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation), was tested. Inhibition of four prototypical CYP activities by sulforaphane metabolites was studied in pooled human liver microsomes. Sulforaphane metabolites did not considerably affect biological function of drug-metabolizing CYPs in human liver microsomes except for CYP2D6, which was found to be inhibited down to 73-78% of the original activity. Analysis of the entry of sulforaphane into human hepatocytes was done by cell disruption by sonication, methylene chloride extraction, and modified high-performance liquid chromatography method. The results have shown penetration of sulforaphane into the human hepatic cells.

  1. Sulforaphane inhibits phorbol ester-stimulated IKK-NF-κB signaling and COX-2 expression in human mammary epithelial cells by targeting NF-κB activating kinase and ERK.

    PubMed

    Kim, Ha-Na; Kim, Do-Hee; Kim, Eun-Hee; Lee, Mee-Hyun; Kundu, Joydeb Kumar; Na, Hye-Kyung; Cha, Young-Nam; Surh, Young-Joon

    2014-08-28

    Sulforaphane, an isothiocyanate present in cruciferous vegetables, has been reported to possess anti-inflammatory and cancer chemopreventive properties. However, the molecular mechanisms by which sulforaphane suppresses inflammation and carcinogenesis are yet to be fully elucidated. Since the aberrant expression of cyclooxygenase-2 (COX-2) links inflammation and cancer, the present study was aimed to elucidate the mechanisms by which sulforaphane modulates COX-2 overexpression in human mammary epithelial (MCF-10A) cells stimulated with a prototypic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment of MCF-10A cells with sulforaphane significantly inhibited TPA-induced expression of COX-2 protein and its mRNA transcript. Transient transfection of cells with deletion mutant constructs of COX-2 promoter revealed that the transcription factor nuclear factor-kappaB (NF-κB) plays a key role in TPA-induced COX-2 expression in MCF-10A cells. Pretreatment with sulforaphane significantly attenuated nuclear localization, DNA binding and the transcriptional activity of NF-κB through inhibition of phosphorylation and subsequent degradation of IκBα in MCF-10A cells stimulated with TPA. Sulforaphane also attenuated TPA-induced activation of IκB kinases (IKK), NF-κB-activating kinase (NAK) and extracellular signal-regulated kinase-1/2 (ERK1/2). Pharmacological inhibition of IKK or transient transfection of cells with dominant-negative mutant forms of this kinase abrogated TPA-induced NF-κB activation and COX-2 expression. In addition, the blockade of ERK1/2 activation negated the catalytic activity of IKKα, but not that of IKKβ, whereas silencing NAK by specific siRNA abrogated the IKKβ activity in TPA-treated cells. Taken together, sulforaphane inhibits TPA-induced NF-κB activation and COX-2 expression in MCF-10A cells by blocking two distinct signaling pathways mediated by ERK1/2-IKKα and NAK-IKKβ. Copyright © 2014 Elsevier Ireland Ltd. All rights

  2. Evaluation of Brazilian plants on cancer chemoprevention targets in vitro.

    PubMed

    Endringer, Denise C; Valadares, Ydia M; Campana, Priscilla R V; Campos, Jussara J; Guimarães, Keller G; Pezzuto, John M; Braga, Fernão C

    2010-06-01

    Cancer is a leading cause of death worldwide. Cancer chemoprevention is one of the promising strategies to decrease its incidence and both plant extracts and natural products may constitute sources of new chemoprevention agents. Some Brazilian species popularly used to treat inflammatory conditions were selected for evaluation for cancer chemoprevention. A total of 32 extracts/fractions from Hancornia speciosa, Davilla elliptica, Jacaranda caroba, Mansoa hirsuta, Remija ferrugina, Solanum paniculatum and Xyris pterygoblephara, along with a mixture of ursolic and oleanolic acids obtained from J. caroba and a dihydroisocoumarin isolated from aerial parts of X. pterygoblephara were tested for their cancer chemoprevention activity [inhibition of 12-O-tetradecanoyl-13-acetate (TPA)-mediated NF-kappaB activation, ornithine decarboxylase (ODC) and cyclooxygenase-1 (COX-1); induction of antioxidant response element (ARE)]. Several extracts/fractions were active in more than one assay and those from H. speciosa, M. hirsuta and J. caroba mediated strong responses with NF-kappaB, COX-1 and ARE, respectively.

  3. [Aberrant crypt foci as biomarkers in chemoprevention for colorectal cancer].

    PubMed

    Katsuki, S; Oui, M; Takayama, T; Takahashi, Y; Shuichi, N; Niitsu, Y

    1998-06-01

    Aberrant crypt foci (ACF) are small lesions identifiable in whole-mount preparations of normal-appearing human colonic mucosa with the aid of methyleneblue staining under stereoscopic microscope. Highly frequent mutations of K-ras genes were found, and increased proliferative activities were also observed. Therefore, K-ras gene mutation may have some role in formation of ACF. Using rat experimental model, formation of ACF was shown to be enhanced by cancer promoters (such as secondary bile acids), and to be suppressed by chemopreventive agents (deoxycholic acid and aspirin). Based on these findings, ACF are considered to be precursors of colon cancer. We demonstrated that ACF are the precursors of adenoma-carcinoma sequence. Moreover, we showed that ACF may be suitable biomarkers of chemopreventive agents for colon cancers.

  4. Screening of new chemopreventive compounds from Digitalis purpurea.

    PubMed

    Lee, J Y; Woo, E; Kang, K W

    2006-04-01

    Chemopreventive agents induce a battery of genes whose protein products can protect cells from chemical-induced carcinogenesis. In this study, we isolated four different glycosides (1 acteoside; 2 purpureaside A; 3 calceolarioside B; and 4, plantainoside D) from the leaves of Digitalis purpurea and studied their abilities to induce glutathione S-transferase (GST) and their protective efficiencies against aflatoxin B1-induced cytotoxicity in H4IIE cells. Of these four glycosides, acteoside significantly inhibited the cytotoxicity induced by aflatoxin B1 (AFB1) and also selectively increased GSTalpha protein levels. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays, revealed that GSTalpha induction by acteoside might be associated with Nrf2/ARE activation. The results suggest that acteoside possesses a potent hepatoprotective effect against AFB1 and that it can be applied as a potential chemopreventive agent.

  5. 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

  6. Sulforaphane retards the growth of UM-UC-3 xenographs, induces apoptosis, and reduces survivin in athymic mice.

    PubMed

    Wang, Fengqian; Shan, Yujuan

    2012-05-01

    Sulforaphane (SFN), an isothiocyanate that exists exclusively in cruciferous vegetables, may be the most promising preventive agent for bladder cancer (BC) to date. We previously observed that SFN dramatically inhibits human BC T24 cells in vitro. Our hypothesis is that SFN may attenuate BC growth. To test our hypothesis, we investigated the effect of SFN on human BC UM-UC-3 cell xenografts implanted into athymic mice. Sulforaphane extract was routinely prepared in our laboratory, and its content was measured with high-performance liquid chromatography. Athymic mice were injected subcutaneously with a UM-UC-3 cell suspension (2.0×10(6) cells/200 μL per mouse) and randomly divided into 2 groups. The positive control group was orally gavaged with water, and the treatment group was orally administered SFN from broccoli sprout (12 mg/kg body weight) for 5 weeks. At the end of the experiment, tumor tissues were harvested and processed for hematoxylin and eosin staining and immunohistochemistry. The average tumor volume decreased from 4.1±1.67 cm(3) in the positive control mice to 1.5±0.72 cm(3) in the SFN-treated mice, evidencing an inhibitory rate of 63%. The SFN extract also reduced the appearance of tumors, including karyopyknosis and angiogenesis. Sulforaphane extract induced caspase 3 and cytochrome c expression but reduced the expression of survivin. Sulforaphane extract retards the growth of UM-UC-3 xenografts in vivo, confirming its future potential in BC therapy.

  7. Sulforaphane inhibits the Th2 immune response in ovalbumin-induced asthma.

    PubMed

    Park, Jun Ho; Kim, Jong Won; Lee, Chang-Min; Kim, Yeong Dae; Chung, Sung Woon; Jung, In Duk; Noh, Kyung Tae; Park, Jin Wook; Heo, Deok Rim; Shin, Yong Kyoo; Seo, Jong Keun; Park, Yeong-Min

    2012-05-01

    Sulforaphane (1-isothiocyanato-4-(methylsulfinyl)-butane), belonging to a family of natural compounds that are abundant in broccoli, has received significant therapeutic interest in recent years. However, the molecular basis of its effects remains to be elucidated. In this study, we attempt to determine whether sulforaphane regulates the inflammatory response in an ovalbumin (OVA)-induced murine asthma model. Mice were sensitized with OVA, treated with sulforaphane, and then challenged with OVA. Sulforaphane administration significantly alleviated the OVA-induced airway hyperresponsiveness to inhaled methacholine. Additionally, sulforaphane suppressed the increase in the levels of SOCS-3 and GATA-3 and IL-4 expression in the OVA-challenged mice. Collectively, our results demonstrate that sulforaphane regulates Th2 immune responses. This sutdy provides novel insights into the regulatory role of sulforaphane in allergen-induced Th2 inflammation and airway responses, which indicates its therapeutic potential for asthma and other allergic diseases.

  8. 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

  9. Biomarkers and their use in cervical cancer chemoprevention.

    PubMed

    Vlastos, Anne Thérèse; Schottenfeld, David; Follen, Michele

    2003-06-01

    Cervical cancer chemoprevention agents under study include diet and micronutrients (particularly beta-carotene, folate, and vitamins A, C, and E); medications such as retinoids (retinyl acetate gel, all-trans-retinoic acid, and 4-hydroxyphenylretinamide) that are chemically related to micronutrients; and other chemopreventives meant to affect the carcinogenic process at the cellular level, including such polyamine synthesis inhibitors as alpha-difluoromethylornithine. Agents become reasonable candidates for study when they have a biologic rationale, they are of low toxicity, and they can be taken for a long period of time. Since the human papillomavirus (HPV) is the major etiologic agent, the medication should show activity against HPV-positive preinvasive and invasive cell lines. The medication needs to be of low toxicity because it may be taken for long periods of time and less toxicity is tolerated in the precancerous setting. Until 1995, none of the studies used surrogate end point biomarkers (SEBs), relying instead on histologic and colposcopic regression as end points. All studies typically included subjects with cervical intraepithelial neoplasia. Conclusions to be drawn from these studies include the following: Though micronutrients are logical candidates for chemoprevention, they haven't worked consistently, and the reasons remain unclear. Furthermore, SEBs need to be validated in phase I trials. Finally, a better understanding of the role of HPV needs elucidation, including an understanding of the relationship of the medication to HPV status and of the immunobiology of HPV throughout the trial.

  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. Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2005-10-01

    coupled device camera . The interrogated tissue area was 2 mm in diameter. Fluorescence emission spectra ranging from 320 to 850 nm were collected...properties of normal and neoplastic human cervical tissue," Laser Surg. Med. 13, 646-655 (1993). 48. K. T. Schomacker, J. K. Frisoli, C. C. Compton , T. J...undergo apoptosis in response to certain physio- in mitochondrial finction in both normal and cancer cells. In logical stimuli and cytotoxic agents

  12. Sulforaphane as a potential protective phytochemical against neurodegenerative diseases.

    PubMed

    Tarozzi, Andrea; Angeloni, Cristina; Malaguti, Marco; Morroni, Fabiana; Hrelia, Silvana; Hrelia, Patrizia

    2013-01-01

    A wide variety of acute and chronic neurodegenerative diseases, including ischemic/traumatic brain injury, Alzheimer's disease, and Parkinson's disease, share common characteristics such as oxidative stress, misfolded proteins, excitotoxicity, inflammation, and neuronal loss. As no drugs are available to prevent the progression of these neurological disorders, intervention strategies using phytochemicals have been proposed as an alternative form of treatment. Among phytochemicals, isothiocyanate sulforaphane, derived from the hydrolysis of the glucosinolate glucoraphanin mainly present in Brassica vegetables, has demonstrated neuroprotective effects in several in vitro and in vivo studies. In particular, evidence suggests that sulforaphane beneficial effects could be mainly ascribed to its peculiar ability to activate the Nrf2/ARE pathway. Therefore, sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing neurodegeneration.

  13. Sulforaphane as a Potential Protective Phytochemical against Neurodegenerative Diseases

    PubMed Central

    Tarozzi, Andrea; Angeloni, Cristina; Malaguti, Marco; Morroni, Fabiana; Hrelia, Silvana; Hrelia, Patrizia

    2013-01-01

    A wide variety of acute and chronic neurodegenerative diseases, including ischemic/traumatic brain injury, Alzheimer's disease, and Parkinson's disease, share common characteristics such as oxidative stress, misfolded proteins, excitotoxicity, inflammation, and neuronal loss. As no drugs are available to prevent the progression of these neurological disorders, intervention strategies using phytochemicals have been proposed as an alternative form of treatment. Among phytochemicals, isothiocyanate sulforaphane, derived from the hydrolysis of the glucosinolate glucoraphanin mainly present in Brassica vegetables, has demonstrated neuroprotective effects in several in vitro and in vivo studies. In particular, evidence suggests that sulforaphane beneficial effects could be mainly ascribed to its peculiar ability to activate the Nrf2/ARE pathway. Therefore, sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing neurodegeneration. PMID:23983898

  14. Protein Kinase Cβ Is an Effective Target for Chemoprevention of Colon Cancer

    PubMed Central

    Fields, Alan P.; Calcagno, Shelly R.; Krishna, Murli; Rak, Sofija; Leitges, Michael; Murray, Nicole R.

    2009-01-01

    Colon cancer develops over a period of 10 to 15 years, providing a window of opportunity for chemoprevention and early intervention. However, few molecular targets for effective colon cancer chemoprevention have been characterized and validated. Protein kinase CβII (PKCβII) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased β-catenin accumulation. In this study, we test the hypothesis that PKCβII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCβ-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCβII-mediated tumor cell proliferation and β-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCβII- and β-catenin/T-cell factor–regulated genes PKCβII, cyclooxygenase II, and vascular endothelial growth factor, three genes implicated in colon carcinogenesis. Our results show that enzastaurin is an effective chemopreventive agent in a mouse model of sporadic colon cancer that significantly reduces both tumor initiation and progression by inhibiting expression of proproliferative genes. Thus, PKCβII is an important target for colon cancer chemoprevention and the PKCβ-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer. PMID:19221092

  15. Organofluorine Isoselenocyanate Analogues of Sulforaphane: Synthesis and Anticancer Activity.

    PubMed

    Cierpiał, Tomasz; Łuczak, Jerzy; Kwiatkowska, Małgorzata; Kiełbasiński, Piotr; Mielczarek, Lidia; Wiktorska, Katarzyna; Chilmonczyk, Zdzisław; Milczarek, Małgorzata; Karwowska, Katarzyna

    2016-10-07

    A series of previously unknown sulforaphane analogues with organofluorine substituents bonded to the sulfinyl sulfur atom, an isoselenocyanate moiety in place of the isothiocyanate group, the central sulfur atom in various oxidation states, and different numbers of methylene groups in the central alkyl chain were synthesized and fully characterized. All new compounds were tested for their biological properties in vitro and demonstrated much higher anticancer activity against two breast cancer cell lines than that shown by native sulforaphane; at the same time, the compounds were less toxic for normal cells. The influence of the particular structural changes in the molecules on the cytotoxicity is discussed.

  16. Nicotinamide for skin cancer chemoprevention.

    PubMed

    Damian, Diona L

    2017-03-20

    Nicotinamide (vitamin B3 ) has a range of photoprotective effects in vitro and in vivo; it enhances DNA repair, reduces UV radiation-induced suppression of skin immune responses, modulates inflammatory cytokine production and skin barrier function and restores cellular energy levels after UV exposure. Pharmacological doses of nicotinamide have been shown to reduce actinic keratoses and nonmelanoma skin cancer incidence in high-risk individuals, making this a nontoxic and accessible option for skin cancer chemoprevention in this population.

  17. Sulforaphane protects the heart from doxorubicin-induced toxicity

    PubMed Central

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

    2015-01-01

    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

  18. Chemoprevention of Cigarette Smoke–Induced Alterations of MicroRNA Expression in Rat Lungs

    PubMed Central

    Izzotti, Alberto; Calin, George A.; Steele, Vernon E.; Cartiglia, Cristina; Longobardi, Mariagrazia; Croce, Carlo M.; De Flora, Silvio

    2015-01-01

    We previously showed that exposure to environmental cigarette smoke (ECS) for 28 days causes extensive downregulation of microRNA expression in the lungs of rats, resulting in the overexpression of multiple genes and proteins. In the present study, we evaluated by microarray the expression of 484 microRNAs in the lungs of either ECS-free or ECS-exposed rats treated with the orally administered chemopreventive agents N-acetylcysteine, oltipraz, indole-3-carbinol, 5,6-benzoflavone, and phenethyl isothiocyanate (as single agents or in combinations). This is the first study of microRNA modulation by chemopreventive agents in nonmalignant tissues. Scatterplot, hierarchical cluster, and principal component analyses of microarray and quantitative PCR data showed that none of the above chemopreventive regimens appreciably affected the baseline microRNA expression, indicating potential safety. On the other hand, all of them attenuated ECS-induced alterations but to a variable extent and with different patterns, indicating potential preventive efficacy. The main ECS-altered functions that were modulated by chemopreventive agents included cell proliferation, apoptosis, differentiation, Ras activation, P53 functions, NF-κB pathway, transforming growth factor–related stress response, and angiogenesis. Some micro-RNAs known to be polymorphic in humans were downregulated by ECS and were protected by chemopreventive agents. This study provides proof-of-concept and validation of technology that we are further refining to screen and prioritize potential agents for continued development and to help elucidate their biological effects and mechanisms. Therefore, microRNA analysis may provide a new tool for predicting at early carcinogenesis stages both the potential safety and efficacy of cancer chemopreventive agents. PMID:20051373

  19. Sulforaphane protects against acetaminophen-induced hepatotoxicity.

    PubMed

    Noh, Jung-Ran; Kim, Yong-Hoon; Hwang, Jung Hwan; Choi, Dong-Hee; Kim, Kyoung-Shim; Oh, Won-Keun; Lee, Chul-Ho

    2015-06-01

    Oxidative stress is closely associated with acetaminophen (APAP)-induced toxicity. Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. This study investigated whether sulforaphane (SFN), as a HO-1 inducer, plays a protective role against APAP hepatotoxicity in vitro and in vivo. Pretreatment of primary hepatocyte with SFN induced nuclear factor E2-factor related factor (Nrf2) target gene expression, especially HO-1 mRNA and protein expression, and suppressed APAP-induced glutathione (GSH) depletion and lipid peroxidation, which eventually leads to hepatocyte cell death. A comparable effect was observed in mice treated with APAP. Mice were treated with 300 mg/kg APAP 30 min after SFN (5 mg/kg) administration and were then sacrificed after 6 h. APAP alone caused severe liver injuries as characterized by increased plasma AST and ALT levels, GSH depletion, apoptosis, and 4-hydroxynonenal (4-HNE) formations. This APAP-induced liver damage was significantly attenuated by pretreatment with SFN. Furthermore, while hepatic reactive oxygen species (ROS) levels were increased by APAP exposure, pretreatment with SFN completely blocked ROS formation. These results suggest that SFN plays a protective role against APAP-mediated hepatotoxicity through antioxidant effects mediated by HO-1 induction. SFN has preventive action in oxidative stress-mediated liver injury.

  20. Chemoprevention of prostate cancer.

    PubMed

    Brand, Timothy C; Canby-Hagino, Edith D; Pratap Kumar, A; Ghosh, Rita; Leach, Robin J; Thompson, Ian M

    2006-08-01

    Prostate cancer is a common malignancy with multiple potential opportunities for cancer prevention. As the genetic basis of this malignancy is further understood, prevention strategies will be developed for individual patients based on specific risk factors and pathways of carcinogenesis. The PCPT has conclusively proven that prostate cancer prevention is possible. The results of the SELECT should be available within several years. An enormous challenge for the medical community will be the development of an efficient strategy to evaluate the substantial number of dietary, behavioral, and pharmacologic prevention opportunities. Ultimately, the goal of prostate can-cer prevention is to (1) identify men who are destined to develop clinically significant prostate cancer, and (2) provide individualized agents to prevent disease development.

  1. Green tea polyphenols for prostate cancer chemoprevention: A translational perspective

    PubMed Central

    Johnson, J.J.; Bailey, H.H.; Mukhtar, H.

    2009-01-01

    Every year nearly 200,000 men in the United States are diagnosed with prostate cancer (PCa), and another 29,000 men succumb to the disease. Within certain regions of the world population based studies have identified a possible role for green tea in the prevention of certain cancers, especially PCa. One constituent in particular, epigallocatechin-3-gallate also known as EGCG has been shown in cell culture models to decrease cell viability and promote apoptosis in multiple cancer cell lines including PCa with no effect on non-cancerous cell lines. In addition, animal models have consistently shown that standardized green tea polyphenols when administered in drinking water delay the development and progression of PCa. Altogether, three clinical trials have been performed in PCa patients and suggest that green tea may have a distinct role as a chemopreventive agent. This review will present the available data for standardized green tea polyphenols in regard to PCa chemoprevention that will include epidemiological, mechanism based studies, safety, pharmacokinetics, and applicable clinical trials. The data that has been collected so far suggests that green tea may be a promising agent for PCa chemoprevention and further clinical trials of participants at risk of PCa or early stage PCa are warranted. PMID:19959000

  2. Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass?

    PubMed Central

    Walle, Thomas

    2007-01-01

    Dietary flavonoids and other polyphenols show great potential as cancer chemopreventive agents in cell culture studies. This does not translate well into in vivo activity, because of extensive conjugative metabolism of these compounds in the intestine and liver. This paper presents a review of a flavonoid subclass in which all hydroxyl groups are capped by methylation. This results in dramatically increased metabolic stability and membrane transport in the intestine/liver, thus improving oral bioavailability. The methoxyflavones also show increased cancer chemopreventive properties. At the cancer initiation stage, bioactivation of polyaromatic hydrocarbon carcinogens and binding to DNA are markedly diminished through effects on CYP1A1/1B1 transcription but also through direct interactions with the proteins. At the cancer promotion stage, the proliferation of cancer cells, but not normal cells, is inhibited with greater potency than with the unmethylated flavones. Limited mechanistic experiments, such as of effects on cell cycle regulation, indicate that the mechanisms of methoxyflavone activities are unique, including aromatase inhibition. The cancer preventive effects and mechanisms of the polymethoxyflavones, such as tangeretin and nobiletin, are discussed in comparison. It is concluded that the methoxyflavones have properties that may make them particularly useful as cancer chemopreventive agents. PMID:17574860

  3. Heating decreases epithiospecifier protein activity and increases sulforaphane formation in broccoli.

    PubMed

    Matusheski, Nathan V; Juvik, John A; Jeffery, Elizabeth H

    2004-05-01

    Sulforaphane, an isothiocyanate from broccoli, is one of the most potent food-derived anticarcinogens. This compound is not present in the intact vegetable, rather it is formed from its glucosinolate precursor, glucoraphanin, by the action of myrosinase, a thioglucosidase enzyme, when broccoli tissue is crushed or chewed. However, a number of studies have demonstrated that sulforaphane yield from glucoraphanin is low, and that a non-bioactive nitrile analog, sulforaphane nitrile, is the primary hydrolysis product when plant tissue is crushed at room temperature. Recent evidence suggests that in Arabidopsis, nitrile formation from glucosinolates is controlled by a heat-sensitive protein, epithiospecifier protein (ESP), a non-catalytic cofactor of myrosinase. Our objectives were to examine the effects of heating broccoli florets and sprouts on sulforaphane and sulforaphane nitrile formation, to determine if broccoli contains ESP activity, then to correlate heat-dependent changes in ESP activity, sulforaphane content and bioactivity, as measured by induction of the phase II detoxification enzyme quinone reductase (QR) in cell culture. Heating fresh broccoli florets or broccoli sprouts to 60 degrees C prior to homogenization simultaneously increased sulforaphane formation and decreased sulforaphane nitrile formation. A significant loss of ESP activity paralleled the decrease in sulforaphane nitrile formation. Heating to 70 degrees C and above decreased the formation of both products in broccoli florets, but not in broccoli sprouts. The induction of QR in cultured mouse hepatoma Hepa lclc7 cells paralleled increases in sulforaphane formation.

  4. 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.

  5. 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

  6. 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

    2016-05-24

    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".

  7. [Effect of tBHQ and sulforaphane on Nrf2-ARE signaling pathway of Caco2 cells].

    PubMed

    Wu, Xiao-yuan; Qu, Li-yan; Quan, Kang; Jiang, Yan-ling; Tang, Xiu-wen

    2010-01-01

    To investigate the effect of tBHQ and sulforaphane on the protein expression in Nrf2-ARE signaling pathway of Caco2 cells. Human colorectal carcinoma Caco2 cells were treated with 20 micromol/L tBHQ and 5 micromol/L sulforaphane (SFN) respectively. Real time PCR, Western blotting and immunoflourescence staining (IF) were performed to measure the target gene expression. Nrf2, AKR1C1 and NQO1 protein expressions were increased time-dependently in Caco2 cells after treatment with tBHQ and SFN. Time-course experiments showed that tBHQ and SFN increased the accumulation of Nrf2, and concomitantly increased the protein levels of AKR1C1 and NQO1. Real-time PCR and Western blotting showed that tBHQ and SFN significantly increased the expression of Nrf2 at 8h after the treatment, and AKR1C1 and NQO1 at 16 h. Confocal microscopy technique showed that Nrf2 accumulated in the nucleus at 6-8 h after treatment with tBHQ. After 1 h treatment with tBHQ the nuclear Nrf2 maintained at elevated level for at least 4 h with tBHQ withdrawn. tBHQ and SFN induced nuclear accumulation of Nrf2 and activated Nrf2-dependent regulation of ARE-mediated gene expression in Caco2 cells. In addition, the results provide experimental evidence for choosing the dose and frequency of the inducer in cancer chemoprevention study and in developing inhibitors of Nrf2-ARE signaling pathway.

  8. Cancer chemoprevention and mitochondria: targeting apoptosis in transformed cells via the disruption of mitochondrial bioenergetics/redox state.

    PubMed

    Hail, Numsen; Lotan, Reuben

    2009-01-01

    Cancer chemoprevention employs agents that block, hinder, or reverse tumorigenesis to prevent malignancy. Several putative cancer chemopreventive agents promote apoptosis in transformed cells initiated in animal carcinogenesis models or identified in human subjects, and/or in tumor cells cultured in vitro. Consequently, apoptosis induction is increasingly valued as a biologically significant anticancer mechanism in the arena of chemoprevention. In vitro studies suggest that the permeabilization of mitochondrial membranes is an important mechanistic determinant associated with the apoptosis induced by these agents. Mitochondrial membrane permeabilization (MMP) may occur via the control of proapoptotic Bcl-2 family members, and/or by the induction of the mitochondrial permeability transition. Both of these cell death-inducing regulatory mechanisms are ultimately responsive to the bioenergetic status/redox state of mitochondria. Interestingly, in addition to inducing MMP, various chemopreventive agents can directly modulate mitochondrial bioenergetics and/or redox tone in transformed cells. This review will examine prospective mechanisms associated with the disruption of mitochondrial function by chemopreventive agents that affect MMP and apoptosis. In doing so, we will construct a paradigm supporting the notion that the bioenergetic and/or redox characteristics of the mitochondria in transformed cells are important targets in the chemoprevention of cancer.

  9. Cactus pear: a natural product in cancer chemoprevention

    PubMed Central

    Zou, Da-ming; Brewer, Molly; Garcia, Francisco; Feugang, Jean M; Wang, Jian; Zang, Roungyu; Liu, Huaguang; Zou, Changping

    2005-01-01

    Background Cancer chemoprevention is a new approach in cancer prevention, in which chemical agents are used to prevent cancer in normal and/or high-risk populations. Although chemoprevention has shown promise in some epithelial cancers, currently available preventive agents are limited and the agents are costly, generally with side effects. Natural products, such as grape seed, green tea, and certain herbs have demonstrated anti-cancer effects. To find a natural product that can be used in chemoprevention of cancer, we tested Arizona cactus fruit solution, the aqueous extracts of cactus pear, for its anti-cancer effects in cultured cells and in an animal model. Method Aqueous extracts of cactus pear were used to treat immortalized ovarian and cervical epithelial cells, as well as ovarian, cervical, and bladder cancer cells. Aqueous extracts of cactus pear were used at six concentrations (0, 0.5, 1, 5, 10 or 25%) to treat cells for 1, 3, or 5 days. Growth inhibition, apoptosis induction, and cell cycle changes were analyzed in the cultured cells; the suppression of tumor growth in nude mice was evaluated and compared with the effect of a synthetic retinoid N-(4-hydroxyphernyl) retinamide (4-HPR), which is currently used as a chemoprevention agent. Immunohistochemistry staining of tissue samples from animal tumors was performed to examine the gene expression. Results Cells exposed to cactus pear extracts had a significant increase in apoptosis and growth inhibition in both immortalized epithelial cells and cancer cells in a dose- and time-dependent manner. It also affected cell cycle of cancer cells by increasing G1 and decreasing G2 and S phases. Both 4-HPR and cactus pear extracts significantly suppressed tumor growth in nude mice, increased annexin IV expression, and decreased VEGF expression. Conclusion Arizona cactus pear extracts effectively inhibited cell growth in several different immortalized and cancer cell cultures, suppressed tumor growth in nude mice

  10. Cactus pear: a natural product in cancer chemoprevention.

    PubMed

    Zou, Da-ming; Brewer, Molly; Garcia, Francisco; Feugang, Jean M; Wang, Jian; Zang, Roungyu; Liu, Huaguang; Zou, Changping

    2005-09-08

    Cancer chemoprevention is a new approach in cancer prevention, in which chemical agents are used to prevent cancer in normal and/or high-risk populations. Although chemoprevention has shown promise in some epithelial cancers, currently available preventive agents are limited and the agents are costly, generally with side effects. Natural products, such as grape seed, green tea, and certain herbs have demonstrated anti-cancer effects. To find a natural product that can be used in chemoprevention of cancer, we tested Arizona cactus fruit solution, the aqueous extracts of cactus pear, for its anti-cancer effects in cultured cells and in an animal model. Aqueous extracts of cactus pear were used to treat immortalized ovarian and cervical epithelial cells, as well as ovarian, cervical, and bladder cancer cells. Aqueous extracts of cactus pear were used at six concentrations (0, 0.5, 1, 5, 10 or 25%) to treat cells for 1, 3, or 5 days. Growth inhibition, apoptosis induction, and cell cycle changes were analyzed in the cultured cells; the suppression of tumor growth in nude mice was evaluated and compared with the effect of a synthetic retinoid N-(4-hydroxyphernyl) retinamide (4-HPR), which is currently used as a chemoprevention agent. Immunohistochemistry staining of tissue samples from animal tumors was performed to examine the gene expression. Cells exposed to cactus pear extracts had a significant increase in apoptosis and growth inhibition in both immortalized epithelial cells and cancer cells in a dose- and time-dependent manner. It also affected cell cycle of cancer cells by increasing G1 and decreasing G2 and S phases. Both 4-HPR and cactus pear extracts significantly suppressed tumor growth in nude mice, increased annexin IV expression, and decreased VEGF expression. Arizona cactus pear extracts effectively inhibited cell growth in several different immortalized and cancer cell cultures, suppressed tumor growth in nude mice, and modulated expression of tumor

  11. Synergistic chemopreventive effects of nobiletin and atorvastatin on colon carcinogenesis.

    PubMed

    Wu, Xian; Song, Mingyue; Qiu, Peiju; Rakariyatham, Kanyasiri; Li, Fang; Gao, Zili; Cai, Xiaokun; Wang, Minqi; Xu, Fei; Zheng, Jinkai; Xiao, Hang

    2017-04-01

    Different cancer chemopreventive agents may act synergistically and their combination may produce enhanced protective effects against carcinogenesis than each individual agent alone. Herein, we investigated the chemopreventive effects of nobiletin (NBT, a citrus polymethoxyflavone) and atorvastatin (ATST, a lipid-lowering drug) in colon cancer cells/macrophages and an azoxymethane (AOM)-induced colon carcinogenesis rat model. The results demonstrated that co-treatments of NBT/ATST produced enhanced growth inhibitory and anti-inflammatory effects on the colon cancer cells and macrophages, respectively. Isobologram analysis confirmed that these interactions between NBT and ATST were synergistic. NBT/ATST co-treatment also synergistically induced extensive cell cycle arrest and apoptosis in colon cancer cells. Oral administration of NBT (0.1%, w/w in diet) or ATST (0.04%, w/w in diet) significantly decreased colonic tumor incidence and multiplicity in AOM-treated rats. Most importantly, co-treatment of NBT/ATST at their half doses (0.05% NBT + 0.02% ATST, w/w in diet) resulted in even stronger inhibitory effects on colonic tumor incidence and multiplicity than did NBT or ATST alone at higher doses. Statistical analysis confirmed that the enhanced chemopreventive activities against colon carcinogenesis in rats by the NBT/ATST combination were highly synergistic. Our results further demonstrated that NBT/ATST co-treatment profoundly modulated key cellular signaling regulators associated with inflammation, cell proliferation, cell cycle progression, apoptosis, angiogenesis and metastasis in the colon of AOM-treated rats. In conclusion, for the first time, our results demonstrated a strong synergy in inhibiting colon carcinogenesis produced by the co-treatment of NBT and ATST, which provided a scientific basis for using NBT in combination with ATST for colon cancer chemoprevention in humans. © The Author 2017. Published by Oxford University Press. All rights reserved

  12. Randomized Phase II Trial of Sulindac for Lung Cancer Chemoprevention

    PubMed Central

    Limburg, Paul J.; Mandrekar, Sumithra J.; Aubry, Marie Christine; Ziegler, Katie L. Allen; Zhang, Jun; Yi, Joanne E.; Henry, Michael; Tazelaar, Henry D.; Lam, Stephen; McWilliams, Annette; Midthun, David E.; Edell, Eric S.; Rickman, Otis B.; Mazzone, Peter; Tockman, Melvyn; Beamis, John F.; Lamb, Carla; Simoff, Michael; Loprinzi, Charles; Szabo, Eva; Jett, James

    2012-01-01

    Introduction Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). Methods At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. Results Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92). Conclusions Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention

  13. Randomized phase II trial of sulindac for lung cancer chemoprevention.

    PubMed

    Limburg, Paul J; Mandrekar, Sumithra J; Aubry, Marie Christine; Ziegler, Katie L Allen; Zhang, Jun; Yi, Joanne E; Henry, Michael; Tazelaar, Henry D; Lam, Stephen; McWilliams, Annette; Midthun, David E; Edell, Eric S; Rickman, Otis B; Mazzone, Peter; Tockman, Melvyn; Beamis, John F; Lamb, Carla; Simoff, Michael; Loprinzi, Charles; Szabo, Eva; Jett, James

    2013-03-01

    Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150mg bid or an identical placebo bid for 6 months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. Slower than anticipated recruitment led to trial closure after randomizing participants (n=31 and n=30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p=0.0005) and sulindac (30 versus 10; p=0.0003) arms, but the difference between arms was not statistically significant (p=0.92). Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention. Copyright © 2012 Elsevier Ireland Ltd. All rights

  14. 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

  15. Chemoprevention of lung carcinogenesis in addicted smokers and ex-smokers.

    PubMed

    Hecht, Stephen S; Kassie, Fekadu; Hatsukami, Dorothy K

    2009-07-01

    Chemoprevention of lung carcinogenesis is one approach to controlling the epidemic of lung cancer caused by cigarette smoking. The target for chemoprevention should be the activities of the multiple carcinogens, toxicants, co-carcinogens, tumour promoters and inflammatory compounds in cigarette smoke. At present there are many agents, both synthetic and naturally occurring, that prevent lung tumour development in well-established animal models. It seems likely that logically constructed mixtures of these agents, developed from the ground up, will be necessary for the prevention of lung carcinogenesis.

  16. Chemoprevention of Lung Carcinogenesis in Addicted Smokers and Ex-Smokers

    PubMed Central

    Hecht, Stephen S.; Kassie, Fekadu; Hatsukami, Dorothy K.

    2013-01-01

    Chemoprevention of lung carcinogenesis is one approach to controlling the epidemic of lung cancer caused by cigarette smoking. The target for chemoprevention should be the activities of the multiple carcinogens, toxicants, co-carcinogens, tumor promoters and inflammatory compounds in cigarette smoke. There are presently many agents both synthetic and naturally occurring that prevent lung tumor development in well established animal models. It seems likely that logically constructed mixtures of these agents, developed from the ground up, will be necessary for prevention of lung carcinogenesis PMID:19550424

  17. Tea in chemoprevention of cancer.

    PubMed

    Katiyar, S; Mukhtar, H

    1996-02-01

    This review summarizes available information on epidemiological and experimental data showing an association of tea consumption with cancer prevention. Studies showing cancer risk associated with tea consumption are also summarized. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Experimental studies demonstrating the chemopreventive effects of tea have been conducted principally with green tea; limited studies have also assessed the usefulness of black tea. Majority of these studies have been carried out in skin tumor model system where consumption through drinking water of water extracts of tea or a polyphenolic fraction isolated from tea has been shown to afford protection against chemical carcinogen- or ultraviolet radiation-induced skin tumorigenesis. Tea consumption has also been shown to afford protection against chemical carcinogen-induced lung, forestomach, esophagus, duodenum, pancreas, liver, breast and colon carcinogenesis in specific bioassay models. Evidence has also accumulated showing that tea polyphenols prevent tumor promoter- and ultraviolet B-induced inflammatory responses in murine skin. The species and strains of animals, dose, route, frequency and duration of carcinogen administration, as well as types, route of administration and duration of tea or its polyphenolic component(s) treatment are described in detail. A brief description regarding mechanism(s) responsible for the broad chemopreventive effects of tea is provided. Epidemiologic studies, though inconclusive, in general suggest a possible preventive effect of tea consumption on human cancer. On the basis of available information, epidemiologic and experimental studies are ongoing to draw the possible relationship between tea consumption and cancer causation and prevention. Appropriate strategies for future clinical chemoprevention trials to translate animal data to human cancer risk are warranted.

  18. Proteomic Analysis of Genistein Mammary Cancer Chemoprevention

    DTIC Science & Technology

    2007-07-01

    to collect a higher yield of proteins and hopefully allow success. 15. SUBJECT TERMS Genistein , Breast Cancer Chemoprevention, Proteomics, Rats ...AD_________________ Award Number: DAMD17-03-1-0433 TITLE: Proteomic Analysis of Genistein ...SUBTITLE 5a. CONTRACT NUMBER Proteomic Analysis of Genistein Mammary Cancer Chemoprevention 5b. GRANT NUMBER DAMD17-03-1-0433 5c. PROGRAM

  19. Prostate Cancer Prevention by Sulforaphane, a Novel Dietary Histone Deacetylase Inhibitor

    DTIC Science & Technology

    2008-01-01

    sulforaphane , a novel dietary histone deacetylase inhibitor PRINCIPAL INVESTIGATOR: Yu Zhen CONTRACTING ORGANIZATION: Oregon State...ANNUAL 3. DATES COVERED 1 JAN 2007 - 31 DEC 2007 4. TITLE AND SUBTITLE Prostate cancer prevention by sulforaphane , a novel dietary histone deacetylase...Prostate cancer is the second leading cause of cancer related death in men. To test Sulforaphane (SFN) as a novel histone deacetylases (HDAC) inhibitor

  20. Sulforaphane prevents human platelet aggregation through inhibiting the phosphatidylinositol 3-kinase/Akt pathway.

    PubMed

    Chuang, Wen-Ying; Kung, Po-Hsiung; Kuo, Chih-Yun; Wu, Chin-Chung

    2013-06-01

    Sulforaphane, a dietary isothiocyanate found in cruciferous vegetables, has been shown to exert beneficial effects in animal models of cardiovascular diseases. However, its effect on platelet aggregation, which is a critical factor in arterial thrombosis, is still unclear. In the present study, we show that sulforaphane inhibited human platelet aggregation caused by different receptor agonists, including collagen, U46619 (a thromboxane A2 mimic), protease-activated receptor 1 agonist peptide (PAR1-AP), and an ADP P2Y12 receptor agonist. Moreover, sulforaphane significantly reduced thrombus formation on a collagen-coated surface under whole blood flow conditions. In exploring the underlying mechanism, we found that sulforaphane specifically prevented phosphatidylinositol 3-kinase (PI3K)/Akt signalling, without markedly affecting other signlaling pathways involved in platelet aggregation, such as protein kinase C activation, calcium mobilisation, and protein tyrosine phosphorylation. Although sulforaphane did not directly inhibit the catalytic activity of PI3K, it caused ubiquitination of the regulatory p85 subunit of PI3K, and prevented PI3K translocation to membranes. In addition, sulforaphane caused ubiquitination and degradation of phosphoinositide-dependent kinase 1 (PDK1), which is required for Akt activation. Therefore, sulforaphane is able to inhibit the PI3K/Akt pathway at two distinct sites. In conclusion, we have demonstrated that sulforaphane prevented platelet aggregation and reduced thrombus formation in flow conditions; our data also support that the inhibition of the PI3K/Akt pathway by sulforaphane contributes it antiplatelet effects.

  1. 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

    2014-08-18

    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.

  2. Cancer Chemoprevention by Dietary Polyphenols: Promising Role for Epigenetics

    PubMed Central

    Link, Alexander; Balaguer, Francesc; Goel, Ajay

    2010-01-01

    Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression. In mammals, epigenetic mechanisms include changes in DNA methylation, histone modifications and non-coding RNAs. Although epigenetic changes are heritable in somatic cells, these modifications are also potentially reversible, which makes them attractive and promising avenues for tailoring cancer preventive and therapeutic strategies. Burgeoning evidence in the last decade has provided unprecedented clues that diet and environmental factors directly influence epigenetic mechanisms in humans. Dietary polyphenols from green tea, turmeric, soybeans, broccoli and others have shown to possess multiple cell-regulatory activities within cancer cells. More recently, we have begun to understand that some of the dietary polyphenols may exert their chemopreventive effects in part by modulating various components of the epigenetic machinery in humans. In this article, we first discuss the contribution of diet and environmental factors on epigenetic alterations; subsequently, we provide a comprehensive review of literature on the role of various dietary polyphenols. In particular, we summarize the current knowledge on a large number of dietary agents and their effects on DNA methylation, histone modifications and regulation of expression of non-coding miRNAs in various in vitro and in vivo models. We emphasize how increased understanding of the chemopreventive effects of dietary polyphenols on specific epigenetic alterations may provide unique and yet unexplored novel and highly effective chemopreventive strategies for reducing the health burden of cancer and other diseases in humans. PMID:20599773

  3. 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

  4. Chemoprevention of Head and Neck Squamous Cell Carcinoma through Inhibition of NF-κB Signaling

    PubMed Central

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

    2013-01-01

    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

  5. Genetic and epigenetic studies for determining molecular targets of natural product anticancer agents.

    PubMed

    Wang, Yujiong; Li, Yong; Liu, Xiaoming; Cho, William C S

    2013-06-01

    Cancer is a disease caused by a series of genetic and epigenetic alterations. Therefore, agents targeting the genetic and/or epigenetic machinery offer potential for the development of anticancer drugs. Accumulating evidence has demonstrated that some common natural products [such as epigallocatechin-3-gallate (EGCG), curcumin, genistein, sulforaphane (SFN) and resveratrol] have anticancer properties through the mechanisms of altering epigenetic processes [including DNA methylation, histone modification, chromatin remodeling, microRNA (miRNA) regulation] and targeting cancer stem cells (CSCs). These bioactive compounds are able to revert epigenetic alterations in a variety of cancers in vitro and in vivo. They exert anticancer effects by targeting various signaling pathways related to the initiation, progression and metastasis of cancer. It appears that natural products hold great promise for cancer prevention and treatment by altering various epigenetic modifications. This review aims to discuss our current understanding of genetic and epigenetic targets of natural products and the effects of some common natural products on cancer chemoprevention and treatment.

  6. A Chemoprevention Trial to Study the Effects of High Tea Consumption on Smoking-Related Oxidative Stress

    DTIC Science & Technology

    2008-02-01

    conducting a 6-month randomized, controlled, double-blinded chemopreventive trial in a group of COPD subjects who are being randomized to green or...pulmonary disease ( COPD ) [1,2]. Changes in dietary habits with the intake of more cancer-chemopreventive agents appear to be a practical approach...for cancer prevention in subjects with increased oxidative stress as is the case of subjects with COPD and ≥ 25 pack/year of smoking history. The

  7. A Chemoprevention Trial to Study the Effects of High Tea Consumption on Smoking-Related Oxidative Stress

    DTIC Science & Technology

    2009-02-01

    We completed c a 6-month randomized, controlled, double-blinded chemopreventive trial in a group of COPD subjects who are being randomized to green...disease ( COPD ) [1,2]. Changes in dietary habits with the intake of more cancer-chemopreventive agents appear to be a practical approach for cancer...prevention in subjects with increased oxidative stress as is the case of subjects with COPD and ≥ 25 pack/year of smoking history. The present

  8. Sulforaphane alleviates muscular dystrophy in mdx mice by activation of Nrf2.

    PubMed

    Sun, Chengcao; Yang, Cuili; Xue, Ruilin; Li, Shujun; Zhang, Ting; Pan, Lei; Ma, Xuejiao; Wang, Liang; Li, Dejia

    2015-01-15

    Sulforaphane (SFN), one of the most important isothiocyanates in the human diet, is known to have chemo-preventive and antioxidant activities in different tissues via activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. However, its effects on muscular dystrophy remain unknown. This work was undertaken to evaluate the effects of SFN on Duchenne muscular dystrophy. Four-week-old mdx mice were treated with SFN by gavage (2 mg·kg body wt(-1)·day(-1) for 8 wk), and our results demonstrated that SFN treatment increased the expression and activity of muscle phase II enzymes NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1 with a Nrf2-dependent manner. SFN significantly increased skeletal muscle mass, muscle force (∼30%), running distance (∼20%), and GSH-to-GSSG ratio (∼3.2-fold) of mdx mice and decreased the activities of plasma creatine phosphokinase (∼45%) and lactate dehydrogenase (∼40%), gastrocnemius hypertrophy (∼25%), myocardial hypertrophy (∼20%), and malondialdehyde levels (∼60%). Furthermore, SFN treatment also reduced the central nucleation (∼40%), fiber size variability, and inflammation and improved the sarcolemmal integrity of mdx mice. Collectively, these results show that SFN can improve muscle function and pathology and protect dystrophic muscle from oxidative damage in mdx mice associated with Nrf2 signaling pathway, which indicate Nrf2 may have clinical implications for the treatment of patients with muscular dystrophy.

  9. Sulforaphane treatment protects skeletal muscle against damage induced by exhaustive exercise in rats.

    PubMed

    Malaguti, Marco; Angeloni, Cristina; Garatachea, Nuria; Baldini, Marta; Leoncini, Emanuela; Collado, Pilar S; Teti, Gabriella; Falconi, Mirella; Gonzalez-Gallego, Javier; Hrelia, Silvana

    2009-10-01

    Sulforaphane (SF), one of the most important isothiocyanates in the human diet, present in cruciferous vegetables, is known to have chemopreventive activities in different tissues. No data are available on its effects in the prevention of skeletal muscle damage. In this study, we investigated the potential protective effects of SF treatment on muscle damage and oxidative stress induced by an acute bout of exhaustive exercise in rats. Male Wistar rats were treated with SF (25 mg/kg body wt ip) for 3 days before undergoing an acute exhaustive exercise protocol in a treadmill (+7% slope and 24 m/min). Acute exercise resulted in a significant increase in plasma lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities. It also resulted in a significant increase in thiobarbituric acid-reactive substances, in a significant decrease in tissue total antioxidant capacity, and in a significant decrease in NAD(P)H:quinone oxidoreductase 1 (NQO1) expression and activity in vastus lateralis muscle. SF treatment significantly increased muscle NQO1, glutathione-S-transferase, and glutathione reductase expression and activity, with no effect on glutathione peroxidase and thioredoxin reductase. The observed SF-induced upregulation of phase II enzymes was accompanied by a significant increase in nuclear erythroid 2 p45-related factor 2 expression and correlated with a significant increase in total antioxidant capacity and a decrease in plasma LDH and CPK activities. Our data demonstrate that SF acts as an indirect antioxidant in skeletal muscle and could play a critical role in the modulation of the muscle redox environment, leading to the prevention of exhaustive exercise-induced muscle damage.

  10. 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

  11. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors

    PubMed Central

    Fahey, Jed W.; Haristoy, Xavier; Dolan, Patrick M.; Kensler, Thomas W.; Scholtus, Isabelle; Stephenson, Katherine K.; Talalay, Paul; Lozniewski, Alain

    2002-01-01

    Gastric infection with Helicobacter pylori is a cosmopolitan problem, and is especially common in developing regions where there is also a high prevalence of gastric cancer. These infections are known to cause gastritis and peptic ulcers, and dramatically enhance the risk of gastric cancer. Eradication of this organism is an important medical goal that is complicated by the development of resistance to conventional antimicrobial agents and by the persistence of a low level reservoir of H. pylori within gastric epithelial cells. Moreover, economic and practical problems preclude widespread and intensive use of antibiotics in most developing regions. We have found that sulforaphane [(−)-1-isothiocyanato-(4R)-(methylsulfinyl)butane], an isothiocyanate abundant as its glucosinolate precursor in certain varieties of broccoli and broccoli sprouts, is a potent bacteriostatic agent against 3 reference strains and 45 clinical isolates of H. pylori [minimal inhibitory concentration (MIC) for 90% of the strains is ≤4 μg/ml], irrespective of their resistance to conventional antibiotics. Further, brief exposure to sulforaphane was bactericidal, and eliminated intracellular H. pylori from a human epithelial cell line (HEp-2). In complementary experiments, sulforaphane blocked benzo[a]pyrene-evoked forestomach tumors in ICR mice. This protection resulted from induction of phase 2 detoxication and antioxidant enzymes, and was abrogated in mice lacking the nrf2 gene, which regulates phase 2 enzymes. Thus, the dual actions of sulforaphane in inhibiting Helicobacter infections and blocking gastric tumor formation offer hope that these mechanisms might function synergistically to provide diet-based protection against gastric cancer in humans. PMID:12032331

  12. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors.

    PubMed

    Fahey, Jed W; Haristoy, Xavier; Dolan, Patrick M; Kensler, Thomas W; Scholtus, Isabelle; Stephenson, Katherine K; Talalay, Paul; Lozniewski, Alain

    2002-05-28

    Gastric infection with Helicobacter pylori is a cosmopolitan problem, and is especially common in developing regions where there is also a high prevalence of gastric cancer. These infections are known to cause gastritis and peptic ulcers, and dramatically enhance the risk of gastric cancer. Eradication of this organism is an important medical goal that is complicated by the development of resistance to conventional antimicrobial agents and by the persistence of a low level reservoir of H. pylori within gastric epithelial cells. Moreover, economic and practical problems preclude widespread and intensive use of antibiotics in most developing regions. We have found that sulforaphane [(-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane], an isothiocyanate abundant as its glucosinolate precursor in certain varieties of broccoli and broccoli sprouts, is a potent bacteriostatic agent against 3 reference strains and 45 clinical isolates of H. pylori [minimal inhibitory concentration (MIC) for 90% of the strains is sulforaphane was bactericidal, and eliminated intracellular H. pylori from a human epithelial cell line (HEp-2). In complementary experiments, sulforaphane blocked benzo[a]pyrene-evoked forestomach tumors in ICR mice. This protection resulted from induction of phase 2 detoxication and antioxidant enzymes, and was abrogated in mice lacking the nrf2 gene, which regulates phase 2 enzymes. Thus, the dual actions of sulforaphane in inhibiting Helicobacter infections and blocking gastric tumor formation offer hope that these mechanisms might function synergistically to provide diet-based protection against gastric cancer in humans.

  13. Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways.

    PubMed

    Brown, Robert H; Reynolds, Curt; Brooker, Allison; Talalay, Paul; Fahey, Jed W

    2015-09-15

    It is widely recognized that deep inspiration (DI), either before methacholine (MCh) challenge (Bronchoprotection, BP) or after MCh challenge (Bronchodilation, BD) protects against this challenge in healthy individuals, but not in asthmatics. Sulforaphane, a dietary antioxidant and antiinflammatory phytochemical derived from broccoli, may affect the pulmonary bronchoconstrictor responses to MCh and the responses to DI in asthmatic patients. Forty-five moderate asthmatics were administered sulforaphane (100 μmol daily for 14 days), BP, BD, lung volumes by body-plethsmography, and airway morphology by computed tomography (CT) were measured pre- and post sulforaphane consumption. Sulforaphane ameliorated the bronchoconstrictor effects of MCh on FEV1 significantly (on average by 21 %; p = 0.01) in 60 % of these asthmatics. Interestingly, in 20 % of the asthmatics, sulforaphane aggravated the bronchoconstrictor effects of MCh and in a similar number was without effect, documenting the great heterogeneity of the responsiveness of these individuals to sulforaphane. Moreover, in individuals in whom the FEV1 response to MCh challenge decreased after sulforaphane administration, i.e., sulforaphane was protective, the activities of Nrf2-regulated antioxidant and anti-inflammatory genes decreased. In contrast, individuals in whom sulforaphane treatment enhanced the FEV1 response to MCh, had increased expression of the activities of these genes. High resolution CT scans disclosed that in asthmatics sulforaphane treatment resulted in a significant reduction in specific airway resistance and also increased small airway luminal area and airway trapping modestly but significantly. These findings suggest the potential value of blocking the bronchoconstrictor hyperresponsiveness in some types of asthmatics by phytochemicals such as sulforaphane.

  14. New concepts in selenium chemoprevention.

    PubMed

    Ip, Clement; Dong, Yan; Ganther, Howard E

    2002-01-01

    This article highlights some recent advances in selenium cancer chemoprevention research. It has been well documented that the chemical transformation of selenium to a monomethylated metabolite is an important step in achieving cancer prevention. Studies with the rat mammary carcinogenesis model suggested that methylselenocysteine (MSC), a good precursor for generating methylselenol endogenously, is able to block clonal expansion of premalignant lesions in the mammary gland. This finding supports the notion that selenium intervenes at an early stage of carcinogenesis. In addition to decreasing cell proliferation of the transformed colonies in vivo, MSC also enhances apoptosis. These same cellular responses are replicated with human premalignant breast cells grown in culture. cDNA microarray analysis indicated that selenium affects a multitude of molecular targets. Based on this information, a number of signaling pathways are proposed that could potentially provide insight into how selenium might block cell cycle progression and induce cell death.

  15. Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention.

    PubMed

    Lissa, Delphine; Senovilla, Laura; Rello-Varona, Santiago; Vitale, Ilio; Michaud, Mickaël; Pietrocola, Federico; Boilève, Alice; Obrist, Florine; Bordenave, Chloé; Garcia, Pauline; Michels, Judith; Jemaà, Mohamed; Kepp, Oliver; Castedo, Maria; Kroemer, Guido

    2014-02-25

    Tetraploidy constitutes a genomically metastable state that can lead to aneuploidy and genomic instability. Tetraploid cells are frequently found in preneoplastic lesions, including intestinal cancers arising due to the inactivation of the tumor suppressor adenomatous polyposis coli (APC). Using a phenotypic screen, we identified resveratrol as an agent that selectively reduces the fitness of tetraploid cells by slowing down their cell cycle progression and by stimulating the intrinsic pathway of apoptosis. Selective killing of tetraploid cells was observed for a series of additional agents that indirectly or directly stimulate AMP-activated protein kinase (AMPK) including salicylate, whose chemopreventive action has been established by epidemiological studies and clinical trials. Both resveratrol and salicylate reduced the formation of tetraploid or higher-order polyploid cells resulting from the culture of human colon carcinoma cell lines or primary mouse epithelial cells lacking tumor protein p53 (TP53, best known as p53) in the presence of antimitotic agents, as determined by cytofluorometric and videomicroscopic assays. Moreover, oral treatment with either resveratrol or aspirin, the prodrug of salicylate, repressed the accumulation of tetraploid intestinal epithelial cells in the Apc(Min/+) mouse model of colon cancer. Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.

  16. Microwave Heating Modelling of a Green Smoothie. Effects on Glucoraphanin, Sulforaphane and S-Methyl Cysteine Sulphoxide Changes during Storage.

    PubMed

    Castillejo, Noelia; Martínez Hernández, Ginés Benito; Lozano Guerrero, Antonio José; Pedreño Molina, Juan Luis; Gómez, Perla A; Aguayo, Encarna; Artés, Francisco; Artés Hernández, Francisco

    2017-09-08

    The heating of a green smoothie during an innovative semi-continuous microwave treatment (MW; 9 kW for 15 s) was modelled. Thermal and dielectric properties of the samples were previously determined. Furthermore, the heating effect on the main chemopreventive compounds of the smoothie and during its subsequent storage up to 30 days at 5 or 15 °C were studied. Such results were compared to conventional pasteurization (CP; 90 °C for 45 s) while unheated fresh blended samples were used as control (CTRL). A procedure was developed to predict the temperature distribution in samples inside the MW oven with the help of numerical tools. MW-treated samples showed the highest sulforaphane formation after 20 days, regardless of the storage temperature, while its content was 2-fold reduced in CP samples. Storage of the smoothie at 5 °C is crucial for maximizing the levels of the bioactive compound S-methyl cysteine sulphoxide. The proposed MW treatment can be used by the food industry to obtain an excellent homogeneous heating of a green smoothie product retaining high levels of bioactive compounds during subsequent retail/domestic storage up to one month at 5 °C. This article is protected by copyright. All rights reserved.

  17. Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells

    PubMed Central

    Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng; Palomera-Sanchez, Zoraya; Maier, Claudia S; Williams, David E; Dashwood, Roderick H; Perez, Viviana I; Ho, Emily

    2015-01-01

    Scope The phytochemical sulforaphane has been shown to decrease prostate cancer metastases in a genetic mouse model of prostate carcinogenesis, though the mechanism of action is not fully known. Sulforaphane has been reported to stimulate autophagy, and modulation of autophagy has been proposed to influence sulforaphane cytotoxicity; however, no conclusions about autophagy can be drawn without assessing autophagic flux, which has not been characterized in prostate cancer cells following sulforaphane treatment. Methods and Results We conducted an investigation to assess the impact of sulforaphane on autophagic flux in two metastatic prostate cancer cell lines at a concentration shown to decrease metastasis in vivo. Autophagic flux was assessed by multiple autophagy related proteins and substrates. We found that sulforaphane can stimulate autophagic flux and cell death only at high concentrations, above what has been observed in vivo. Conclusion These results suggest that sulforaphane does not directly stimulate autophagy or cell death in metastatic prostate cancer cells under physiologically relevant conditions, but instead supports the involvement of in vivo factors as important effectors of sulforaphane- mediated prostate cancer suppression. PMID:26108801

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

    PubMed

    Wang, Grace C; Farnham, Mark; Jeffery, Elizabeth H

    2012-07-11

    In broccoli, sulforaphane forms when the glucosinolate glucoraphanin is hydrolyzed by the endogenous plant thiohydrolase myrosinase. A myrosinase cofactor directs hydrolysis away from the formation of bioactive sulforaphane and toward an inactive product, sulforaphane nitrile. The cofactor is more heat sensitive than myrosinase, presenting an opportunity to preferentially direct hydrolysis toward sulforaphane formation through regulation of thermal processing. Four broccoli cultivars were microwave heated, boiled, or steamed for various lengths of time. Production of nitrile during hydrolysis of unheated broccoli varied among cultivars from 91 to 52% of hydrolysis products (Pinnacle > Marathon > Patriot > Brigadier). Boiling and microwave heating caused an initial loss of nitrile, with a concomitant increase in sulforaphane, followed by loss of sulforaphane, all within 1 min. In contrast, steaming enhanced sulforaphane yield between 1.0 and 3.0 min in all but Brigadier. These data are proof of concept that steaming for 1.0-3.0 min provides less nitrile and more sulforaphane yield from a broccoli meal.

  19. Sulforaphane-induced autophagy flux prevents prion protein-mediated neurotoxicity through AMPK pathway.

    PubMed

    Lee, J-H; Jeong, J-K; Park, S-Y

    2014-10-10

    Prion diseases are neurodegenerative and infectious disorders that involve accumulation of misfolded scrapie prion protein, and which are characterized by spongiform degeneration. Autophagy, a major homeostatic process responsible for the degradation of cytoplasmic components, has garnered attention as the potential target for neurodegenerative diseases such as prion disease. We focused on protective effects of sulforaphane found in cruciferous vegetables on prion-mediated neurotoxicity and the mechanism of sulforaphane related to autophagy. In human neuroblastoma cells, sulforaphane protected prion protein (PrP) (106-126)-mediated neurotoxicity and increased autophagy flux marker microtubule-associated protein 1 light chain 3-II protein levels, following a decrease of p62 protein level. Pharmacological and genetical inhibition of autophagy by 3MA, wortmannin and knockdown of autophagy-related 5 (ATG5) led to block the effect of sulforaphane against PrP (106-126)-induced neurotoxicity. Furthermore we demonstrated that both sulforaphane-induced autophagy and protective effect of sulforaphane against PrP (106-126)-induced neurotoxicity are dependent on the AMP-activated protein kinase (AMPK) signaling. The present results indicated that sulforaphane of cruciferous vegetables enhanced autophagy flux led to the protection effects against prion-mediated neurotoxicity, which was regulated by AMPK signaling pathways in human neuron cells. Our data also suggest that sulforaphane has a potential value as a therapeutic tool in neurodegenerative disease including prion diseases. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Sulforaphane protects H9c2 cardiomyocytes from angiotensin II-induced hypertrophy.

    PubMed

    Wu, Q-Q; Zong, J; Gao, L; Dai, J; Yang, Z; Xu, M; Fang, Y; Ma, Z-G; Tang, Q-Z

    2014-05-01

    Cardiac hypertrophy is an adaptive process of the heart in response to various stimuli, but sustained cardiac hypertrophy will finally lead to heart failure. Sulforaphane-extracted from cruciferous vegetables of the genus Brassica such as broccoli, brussels sprouts, and cabbage-has been evaluated for its anticarcinogenic and antioxidant effects. To investigate the effect of sulforaphane on angiotensin II (Ang II)-induced cardiac hypertrophy in vitro. Embryonic rat heart-derived H9c2 cells were co-incubated with sulforaphane and Ang II. The cell surface area and mRNA levels of hypertrophic markers were measured to clarify the effect of sulforaphane on cardiac hypertrophy. The underlying mechanism was further investigated by detecting the activation of Akt and NF-κB signaling pathways. We found that H9c2 cells pretreated with sulforaphane were protected from Ang II-induced hypertrophy. The increasing mRNA levels of ANP, BNP, and β-MHC in Ang II-stimulated cells were also down-regulated after sulforaphane treatment. Moreover, sulforaphane repressed the Ang II-induced phosphorylation of Akt, GSK3β, mTOR, eIF4e, as well as of IκBα and NF-κB. Based on our results, sulforaphane attenuates Ang II-induced hypertrophy of H9c2 cardiomyocytes mediated by the inhibition of intracellular signaling pathways including Akt and NF-κB.

  1. Sulforaphane epigenetically enhances neuronal BDNF expression and TrkB signaling pathways.

    PubMed

    Kim, Jisung; Lee, Siyoung; Choi, Bo-Ryoung; Yang, Hee; Hwang, Youjin; Park, Jung Han Yoon; LaFerla, Frank M; Han, Jung-Soo; Lee, Ki Won; Kim, Jiyoung

    2017-02-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin that supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. We investigated the effect of sulforaphane, a hydrolysis product of glucoraphanin present in Brassica vegetables, on neuronal BDNF expression and its synaptic signaling pathways. Mouse primary cortical neurons and a triple-transgenic mouse model of Alzheimer's disease (3 × Tg-AD) were used to study the effect of sulforaphane. Sulforaphane enhanced neuronal BDNF expression and increased levels of neuronal and synaptic molecules such as MAP2, synaptophysin, and PSD-95 in primary cortical neurons and 3 × Tg-AD mice. Sulforaphane elevated levels of synaptic TrkB signaling pathway components, including CREB, CaMKII, ERK, and Akt in both primary cortical neurons and 3 × Tg-AD mice. Sulforaphane increased global acetylation of histone 3 (H3) and H4, inhibited HDAC activity, and decreased the level of HDAC2 in primary cortical neurons. Chromatin immunoprecipitation analysis revealed that sulforaphane increased acetylated H3 and H4 at BDNF promoters, suggesting that sulforaphane regulates BDNF expression via HDAC inhibition. These findings suggest that sulforaphane has the potential to prevent neuronal disorders such as Alzheimer's disease by epigenetically enhancing neuronal BDNF expression and its TrkB signaling pathways. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Sulforaphane mitigates cadmium-induced toxicity pattern in human peripheral blood lymphocytes and monocytes.

    PubMed

    Alkharashi, Nouf Abdulkareem Omer; Periasamy, Vaiyapuri Subbarayan; Athinarayanan, Jegan; Alshatwi, Ali A

    2017-10-01

    Cadmium (Cd) is a highly toxic and widely distributed heavy metal that induces various diseases in humans through environmental exposure. Therefore, alleviation of Cd-induced toxicity in living organisms is necessary. In this study, we investigated the protective role of sulforaphane on Cd-induced toxicity in human peripheral blood lymphocytes and monocytes. Sulforaphane did not show any major reduction in the viability of lymphocytes and monocytes. However, Cd treatment at a concentration of 50μM induced around 69% cell death. Treatment of IC10-Cd and 100μM sulforaphane combination for 24 and 48h increased viability by 2 and 9% in cells subjected to Cd toxicity, respectively. In addition, IC25 of Cd and 100μM sulforaphane combination recovered 17-20% of cell viability. Cd induced apoptotic and necrotic cell death. Sulforaphane treatment reduced Cd-induced cell death in lymphocytes and monocytes. Our results clearly indicate that when the cells were treated with Cd+sulforaphane combination, sulforaphane decreased the Cd-induced cytotoxic effect in lymphocytes and monocytes. In addition, sulforaphane concentration plays a major role in the alleviation of Cd-induced toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Complementary medicine, chemoprevention, and staging of prostate cancer.

    PubMed

    Crawford, E David

    2003-01-01

    The 13th International Prostate Cancer Update was held in Vail, Colorado, in February 2003. This article provides an overview of the high points in the areas of complementary medicine, chemoprevention, and staging that were discussed at this meeting. M. Scott Lucia, MD, addressed the use of various hormonal agents, antiproliferative or differentiating agents, antiinflammatory agents, and antioxidants in patients with prostate cancer. Wael A. Sakr, MD, provided an overview of prognostic markers for this disease. Arturo Mendoza-Valdes, MD, explored the potential role of exercise for patients with prostate cancer, and Bruce Sodee, MD, described some exciting new developments in prostate imaging. E. David Crawford, MD, discussed the ongoing Prostate Cancer Prevention Trial.

  4. Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice.

    PubMed

    Socała, Katarzyna; Nieoczym, Dorota; Kowalczuk-Vasilev, Edyta; Wyska, Elżbieta; Wlaź, Piotr

    2017-07-01

    Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD50 value of sulforaphane in mice was estimated at 212.67mg/kg, while the TD50 value - at 191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (200mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Hz-induced psychomotor seizure. At doses of 10-200mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150-300mg/kg), hypothermia (at 150-300mg/kg), impairment of motor coordination (at 200-300mg/kg), decrease in skeletal muscle strength (at 250-300mg/kg), and deaths (at 200-300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200mg

  5. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2000-10-01

    Since reduction of ovulation is protective against ovarian cancer, prevention may represent a feasible approach to decreasing mortality . To achieve a...potent apoptotic effect on ovarian epithelial cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and women...A chemoprevention trial is ongoing in chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian epithelium of women undergoing oophorectomy.

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

    PubMed

    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.

  7. 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

  8. Prostate cancer chemoprevention in men of African descent: current state of the art and opportunities for future research.

    PubMed

    Chornokur, Ganna; Kumar, Nagi B

    2013-08-01

    Prostate cancer is the most frequently diagnosed malignancy in men. However, African American/Black men are 60 % more likely to be diagnosed with and 2.4 times more likely to die from prostate cancer, compared to Non-Hispanic White men. Despite the increased burden of this malignancy, no evidence-based recommendation regarding prostate cancer screening exists for the high-risk population. Moreover, in addition to screening and detection, African American men may constitute a prime population for chemoprevention. Early detection and chemoprevention may thus represent an integral part of prostate cancer control in this population. Importantly, recent research has elucidated biological differences in the prostate tumors of African American compared to European American men. The latter may enable a more favorable response in African American men to specific chemopreventive agents that target relevant signal transduction pathways. Based on this evolving evidence, the aims of this review are threefold. First, we aim to summarize the biological differences that were reported in the prostate tumors of African American and European American men. Second, we will review the single- and multi-target chemopreventive agents placing specific emphasis on the pathways implicated in prostate carcinogenesis. And lastly, we will discuss the most promising nutraceutical chemopreventive compounds. Our review underscores the promise of chemoprevention in prostate cancer control, as well as provides justification for further investment in this filed to ultimately reduce prostate cancer morbidity and mortality in this high-risk population of African American men.

  9. Prognostic factors, predictive markers and cancer biology: the triad for successful oral cancer chemoprevention.

    PubMed

    Monteiro de Oliveira Novaes, Jose Augusto; William, William N

    2016-10-01

    Oral squamous cell carcinomas represent a significant cancer burden worldwide. Unfortunately, chemoprevention strategies investigated to date have failed to produce an agent considered standard of care to prevent oral cancers. Nonetheless, recent advances in clinical trial design may streamline drug development in this setting. In this manuscript, we review some of these improvements, including risk prediction tools based on molecular markers that help select patients most suitable for chemoprevention. We also discuss the opportunities that novel preclinical models and modern molecular profiling techniques will bring to the prevention field in the near future, and propose a clinical trials framework that incorporates molecular prognostic factors, predictive markers and cancer biology as a roadmap to improve chemoprevention strategies for oral cancers.

  10. 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.

  11. Mechanistic Role of MicroRNA in Cancer Chemoprevention by Nonsteroidal Anti-inflammatory Drugs

    PubMed Central

    Ma, Ruixia; Yi, Bin; Piazza, Gary A.; Xi, Yaguang

    2015-01-01

    Over the past several decades, studies have documented the significance of nonsteroidal anti-inflammatory drugs (NSAIDs) on cancer chemoprevention by lowering incidence and slowing down progression of malignant disease, which consequently lead to decline of cancer-related mortality and improvement of disease progression free survival (PFS). Inhibition of cyclooxygenase (COX) has been primarily believed to be the key mechanism responsible for anticancer activity of NSAIDs, while the serious toxicity caused by COX inhibitory effect reduces the enthusiasm to use NSAIDs as chemoprevention agents in the clinic. Recently, more and more studies demonstrate that non-COX inhibitory mechanisms may account for anticancer properties of NSAIDs, at least partially, which potentially support the indication of NSAIDs on cancer chemoprevention. MicroRNAs (miRNAs) are a set of non-coding and small RNA molecules with master regulatory effect on over 30% human genes through the post-transcriptional and translational modulation. Although miRNAs have been reported to be involved in many normal and pathological processes including cell proliferation, apoptosis, differentiation, as well as tumorigenesis, their roles in NSAIDs' properties of cancer chemoprevention have not yet been studied exclusively. Here, we will review the prior studies reporting interactions between miRNAs and COX/non-COX pathways with intent to provide insights into better understanding molecular mechanisms of cancer chemoprevention by NSAIDs. PMID:26213681

  12. Sulforaphane reduces advanced glycation end products (AGEs)-induced inflammation in endothelial cells and rat aorta.

    PubMed

    Matsui, T; Nakamura, N; Ojima, A; Nishino, Y; Yamagishi, S-I

    2016-09-01

    Advanced glycation end products (AGEs)-receptor RAGE interaction evokes oxidative stress and inflammatory reactions, thereby being involved in endothelial cell (EC) damage in diabetes. Sulforaphane is generated from glucoraphanin, a naturally occurring isothiocyanate found in widely consumed cruciferous vegetables, by myrosinase. Sulforaphane has been reported to protect against oxidative stress-mediated cell and tissue injury. However, effects of sulforaphane on AGEs-induced vascular damage remain unclear. In this study, we investigated whether and how sulforaphane could inhibit inflammation in AGEs-exposed human umbilical vein ECs (HUVECs) and AGEs-injected rat aorta. Sulforaphane treatment for 4 or 24 h dose-dependently inhibited the AGEs-induced increase in RAGE, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecular-1 (VCAM-1) gene expression in HUVECs. AGEs significantly stimulated MCP-1 production by, and THP-1 cell adhesion to, HUVECs, both of which were prevented by 1.6 μM sulforaphane. Sulforaphane significantly suppressed oxidative stress generation and NADPH oxidase activation evoked by AGEs in HUVECs. Furthermore, aortic RAGE, ICAM-1 and VCAM-1 expression in AGEs-injected rats were increased, which were suppressed by simultaneous infusion of sulforaphane. The present study demonstrated for the first time that sulforaphane could inhibit inflammation in AGEs-exposed HUVECs and AGEs-infused rat aorta partly by suppressing RAGE expression through its anti-oxidative properties. Inhibition of the AGEs-RAGE axis by sulforaphane might be a novel therapeutic target for vascular injury in diabetes. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  13. Sulforaphane inhibits mitotic clonal expansion during adipogenesis through cell cycle arrest.

    PubMed

    Choi, Kyeong-Mi; Lee, Youn-Sun; Sin, Dong-Mi; Lee, Seunghyun; Lee, Mi Kyeong; Lee, Yong-Moon; Hong, Jin-Tae; Yun, Yeo-Pyo; Yoo, Hwan-Soo

    2012-07-01

    Obesity is a risk factor for numerous metabolic disorders such as type 2 diabetes, hypertension, and coronary heart disease. Adipocyte differentiation is triggered by adipocyte hyperplasia, which leads to obesity. In this study, the inhibitory effect of sulforaphane, an isothiocyanate, on adipogenesis in 3T3-L1 cells was investigated. Sulforaphane decreased the accumulation of lipid droplets stained with Oil Red O and inhibited the elevation of triglycerides in the adipocytes (half-maximal inhibitory concentration = 7.3 µmol/l). The expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), major transcription factors for adipocyte differentiation, was significantly reduced by sulforaphane. The major effects of sulforaphane on the inhibition of adipocyte differentiation occurred during the early stage of adipogenesis. Thus, the expression of C/EBPβ, an early-stage biomarker of adipogenesis, decreased in a concentration-dependent manner when the adipocytes were exposed to sulforaphane (0, 5, 10, and 20 µmol/l). The proliferation of adipocytes treated with 20 µmol/l sulforaphane for 24 and 48 h was also suppressed. These results indicate that sulforaphane may specifically affect mitotic clonal expansion to inhibit adipocyte differentiation. Sulforaphane arrested the cell cycle at the G(0)/G(1) phase, increased p27 expression, and decreased retinoblastoma (Rb) phosphorylation. Additionally, sulforaphane modestly decreased the phosphorylation of ERK1/2 and Akt. Our results indicate that the inhibition of early-stage adipocyte differentiation by sulforaphane may be associated with cell cycle arrest at the G(0)/G(1) phase through upregulation of p27 expression.

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

    PubMed

    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. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. 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

  16. Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat.

    PubMed

    McCormick, D L; Rao, K V

    1999-01-01

    The high incidence and long latent period of prostate cancer make it an ideal target for chemoprevention. We have evaluated a series of agents for chemopreventive efficacy using a model in which hormone-dependent prostate cancers are induced in the Wistar-Unilever (WU) rat by sequential treatment with antiandrogen (cyproterone acetate), androgen (testosterone propionate), and direct-acting chemical carcinogen (N-methyl-N-nitrosourea), followed by chronic androgen stimulation (testosterone). This regimen reproducibly induces prostate cancers in high incidence, with no gross toxicity and a low incidence of neoplasia in the seminal vesicle and other non-target tissues. Dehydroepiandrosterone (DHEA) and 9-cis-retinoic acid (9-cis-RA) are the most active agents identified to date. DHEA inhibits prostate cancer induction both when chronic administration is begun prior to carcinogen exposure, and when administration is delayed until preneoplastic prostate lesions are present. 9-cis-RA is the most potent inhibitor of prostate carcinogenesis identified; a study to determine the efficacy of delayed administration of 9-cis-RA is in progress. Liarozole fumarate confers modest protection against prostate carcinogenesis, while N-(4-hydroxyphenyl)retinamide (fenretinide), alpha-difluoromethylornithine, oltipraz, DL-alpha-tocopherol acetate (vitamin E), and L-selenomethionine are inactive. Chemoprevention efficacy evaluations in the WU rat will support the identification of agents that merit study for prostate cancer chemoprevention in humans.

  17. Interactions of the Major Metabolite of the Cancer Chemopreventive Drug Oltipraz with Cytochrome C: A Novel Pathway for Cancer Chemoprevention

    PubMed Central

    Velayutham, Murugesan; Muthukumaran, Rajendra B.; Sostaric, Joe Z.; McCraken, John; Fishbein, James C.; Zweier, Jay L.

    2009-01-01

    The major metabolite of the cancer chemopreventive agent oltipraz (OLT), a pyrrolopyrazine thione (PPD), has been shown to be a phase two enzyme inducer, an activity thought to be key to the cancer chemopreventive action of the parent compound. In cells, mitochondria are the major source of reactive oxygen species (ROS) and cytochrome c (cyt c) is known to participate in mitochondrial electron transport and confer antioxidant and peroxidase activities. To understand possible mechanisms by which PPD acts as a phase two enzyme inducer, a study of its interaction with cyt c was undertaken. UV-visible spectroscopic results demonstrate that PPD is capable of reducing oxidized cyt c. The reduced cyt c is stable for a long period of time in the absence of an oxidizing agent. In the presence of ferricyanide, the reduced cyt c is rapidly oxidized back to its oxidized form. Further, UV-visible spectroscopic studies show that during the reduction process the co-ordination environment and redox state of iron in cyt c is changed. Low temperature EPR studies show that during the reduction process, the heme iron changes from a low spin state of s = ½ to a low spin state of s = 0. Room temperature EPR studies demonstrate that PPD inhibits the peroxidase activity of cyt c. EPR spin trapping experiments using DMPO show that PPD inhibits the superoxide radical scavenging activity of oxidized cyt c. From these results, we propose that PPD interacts with cyt c, binding to and then reducing the heme, and this may enhance ROS levels in mitochondria. This in turn could contribute to the mechanism by which the parent compound, oltipraz, might trigger the cancer chemopreventive increase in transcription of phase 2 enzymes. The modifications of cyt c function by the oltipraz metabolite may have implications for the regulation of apoptotic cell death. PMID:17761303

  18. 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

  19. 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.

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

    PubMed

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

    2015-09-01

    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.

  1. 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

  2. Phytochemicals as Anticancer and Chemopreventive Topoisomerase II Poisons

    PubMed Central

    Ketron, Adam C.

    2013-01-01

    Phytochemicals are a rich source of anticancer drugs and chemopreventive agents. Several of these chemicals appear to exert at least some of their effects through interactions with topoisomerase II, an essential enzyme that regulates DNA supercoiling and removes knots and tangles from the genome. Topoisomerase II-active phytochemicals function by stabilizing covalent protein-cleaved DNA complexes that are intermediates in the catalytic cycle of the enzyme. As a result, these compounds convert topoisomerase II to a cellular toxin that fragments the genome. Because of their mode of action, they are referred to as topoisomerase II poisons as opposed to catalytic inhibitors. The first sections of this article discuss DNA topology, the catalytic cycle of topoisomerase II, and the two mechanisms (interfacial vs. covalent) by which different classes of topoisomerase II poisons alter enzyme activity. Subsequent sections discuss the effects of several phytochemicals on the type II enzyme, including demethyl-epipodophyllotoxins (semisynthetic anticancer drugs) as well as flavones, flavonols, isoflavones, catechins, isothiocyanates, and curcumin (dietary chemopreventive agents). Finally, the leukemogenic potential of topoisomerase II-targeted phytochemicals is described. PMID:24678287

  3. Dietary chemoprevention of colorectal cancer.

    PubMed

    Forte, Angelo; De Sanctis, Rita; Leonetti, Giovanni; Manfredelli, Simone; Urbano, Vincenzo; Bezzi, Marcello

    2008-01-01

    Colorectal cancer is the second cause of morbidity and death in Italy. Genetic and environmental factors, i.e. inappropriate nutrition, are strongly involved in the aetiology of colon cancer. In the present review the authors analyze the possible mechanisms by which certain nutritive factors may interfere with the complex process of carcinogenesis. The authors identify studies by a literature search of Medline from January 1, 1970, through December 31, 2006. The mechanism of every protective compound is detailed, in particular the impact of antioxidant vitamins and minerals on tumor development. At present, the data suggest that vegetables are associated with lower risk and that their fbre content alone does not account for this association. Further, meat consumption is associated with an increased risk but this, too, is not explained solely by its fat content. Several microconstituents of the diet may be associated with reduced risk, including folate, methionine, calcium and vitamin D. Short chain fatty acids also contribute to colonic health. Nevertheless agricultural products contain several dangerous pesticides. Mutagenic compounds, particularly heterocyclic amines, produced when protein is cooked, plausibly explain the meat association. Healthy nutrition is a necessary but not sufficient condition for colon cancer prevention: accepted the feasibility of an accurate control on every patient's diet, fequently the difficulty encountered in nutritional chemoprevention is to establish individual metabolic profiles.

  4. 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

  5. Chemical genomics of cancer chemopreventive dithiolethiones

    PubMed Central

    Tran, Quynh T.; Xu, Lijing; Phan, Vinhthuy; Goodwin, Shirlean B.; Rahman, Mostafizur; Jin, Victor X.; Sutter, Carrie H.; Roebuck, Bill D.; Kensler, Thomas W.; George, E.Olusegun; Sutter, Thomas R.

    2009-01-01

    3H-1,2-dithiole-3-thione (D3T) and its analogues 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (OLT) and 5-tert-butyl-3H-1,2-dithiole-3-thione (TBD) are chemopreventive agents that block or diminish early stages of carcinogenesis by inducing activities of detoxication enzymes. While OLT has been used in clinical trials, TBD has been shown to be more efficacious and possibly less toxic than OLT in animals. Here, we utilize a robust and high-resolution chemical genomics procedure to examine the pharmacological structure–activity relationships of these compounds in livers of male rats by microarray analyses. We identified 226 differentially expressed genes that were common to all treatments. Functional analysis identified the relation of these genes to glutathione metabolism and the nuclear factor, erythroid derived 2-related factor 2 pathway (Nrf2) that is known to regulate many of the protective actions of dithiolethiones. OLT and TBD were shown to have similar efficacies and both were weaker than D3T. In addition, we identified 40 genes whose responses were common to OLT and TBD, yet distinct from D3T. As inhibition of cytochrome P450 (CYP) has been associated with the effects of OLT on CYP expression, we determined the half maximal inhibitory concentration (IC50) values for inhibition of CYP1A2. The rank order of inhibitor potency was OLT ≫ TBD ≫ D3T, with IC50 values estimated as 0.2, 12.8 and >100 μM, respectively. Functional analysis revealed that OLT and TBD, in addition to their effects on CYP, modulate liver lipid metabolism, especially fatty acids. Together, these findings provide new insight into the actions of clinically relevant and lead dithiolethione analogues. PMID:19126641

  6. 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

  7. Review paper: Cancer chemopreventive compounds and canine cancer.

    PubMed

    Baek, S J; McEntee, M F; Legendre, A M

    2009-07-01

    Canine cancer has become more prevalent in recent years because of increased life expectancy and greater attention to the health of pets. The range of cancers seen in dogs is as diverse as that in human patients, and despite more intensive therapeutic interventions, fatality rates remain unacceptably high in both species. Chemoprevention is therefore an important means of confronting this disease. Because domestic pets share our environment, greater cross-application and study of the protumorigenic and antitumorigenic factors in our shared environment will benefit all species, leading to the development of new families of less toxic antitumorigenic compounds based on novel and established molecular targets. Currently, the most interesting cancer preventive agents are nonsteroidal anti-inflammatory drugs, peroxisome proliferator-activated receptor-gamma ligands, and dietary compounds. This article provides an overview of what is known about how these agents affect molecular signaling in neoplastic disease, with reference to reported application and/or study in dogs where available.

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

    PubMed

    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).

  9. 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

  10. [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.

  11. Immunomodulatory activity of Sulforaphane, a naturally occurring isothiocyanate from broccoli (Brassica oleracea).

    PubMed

    Thejass, P; Kuttan, G

    2007-08-01

    The effect of Sulforaphane on the immune system was studied using BALB/c mice. Intraperitoneal administration of five doses of Sulforaphane (500 microg/dose/animal/day) was found to enhance the total WBC count (12,950 cells/mm3) on 9th day. Bone marrow cellularity (23 x 10(6) cells/femur) and number of alpha-esterase positive cells (1346.66/4000 cells) were also increased by the administration of Sulforaphane. Treatment with Sulforaphane along with the antigen, sheep red blood cells (SRBC), produced an enhancement in the circulating antibody titre and the number of plaque forming cells (PFC) in the spleen. Maximum number of PFC (315.83 PFC/10(6) spleen cells) was obtained on the 6th day. Administration of Sulforaphane also showed an enhancement in the phagocytic activity of peritoneal macrophages. Moreover administration of Sulforaphane significantly reduced the elevated level of TNF-alpha production by LPS stimulated macrophages. These results indicate the immunomodulatory activity of Sulforaphane.

  12. 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. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  13. Anticancer and cancer chemopreventive potential of grape seed extract and other grape-based products.

    PubMed

    Kaur, Manjinder; Agarwal, Chapla; Agarwal, Rajesh

    2009-09-01

    With emerging trends in the incidence of cancer of various organ sites, additional approaches are needed to control human malignancies. Intervention or prevention of cancer by dietary constituents, a strategy defined as chemoprevention, holds great promise in our conquest to control cancer, because it can be implemented on a broader population base with less economic burden. Consistent with this, several epidemiological studies have shown that populations that consume diets rich in fruits and vegetables have an overall lower cancer incidence. Based on these encouraging observations, research efforts from across the globe have focused on identifying, characterizing, and providing scientific basis to the efficacy of various phytonutrients in an effort to develop effective strategy to control various human malignancies. Cancer induction, growth, and progression are multi-step events and numerous studies have demonstrated that various dietary agents interfere with these stages of cancer, thus blocking malignancy. Fruits and vegetables represent untapped reservoir of various nutritive and nonnutritive phytochemicals with potential cancer chemopreventive activity. Grapes and grape-based products are one such class of dietary products that have shown cancer chemopreventive potential and are also known to improve overall human health. This review focuses on recent advancements in cancer chemopreventive and anticancer efficacy of grape seed extract and other grape-based products. Overall, completed studies from various scientific groups conclude that both grapes and grape-based products are excellent sources of various anticancer agents and their regular consumption should thus be beneficial to the general population.

  14. Antiplatelet activity of L-sulforaphane by regulation of platelet activation factors, glycoprotein IIb/IIIa and thromboxane A2.

    PubMed

    Oh, Chung-Hun; Shin, Jang-In; Mo, Sang Joon; Yun, Sung-Jo; Kim, Sung-Hoon; Rhee, Yun-Hee

    2013-07-01

    L-sulforaphane was identified as an anticarcinogen that could produce quinine reductase and a phase II detoxification enzyme. In recent decades, multi-effects of L-sulforaphane may have been investigated, but, to the authors' knowledge, the antiplatelet activation of L-sulforaphane has not been studied yet.In this study, 2 μg/ml of collagen, 50 μg/ml of ADP and 5 μg/ml of thrombin were used for platelet aggregations with or without L-sulforaphane. L-sulforaphane inhibited the platelet aggregation dose-dependently. Among these platelet activators, collagen was most inhibited by L-sulforaphane, which markedly decreased collagen-induced glycoprotein IIb/IIIa activation and thromboxane A2 (TxA2) formation in vitro. L-sulforaphane also reduced the collagen and epinephrine-induced pulmonary embolism, but did not affect prothrombin time (PT) in vivo. This finding demonstrated that L-sulforaphane inhibited the platelet activation through an intrinsic pathway.L-sulforaphane had a beneficial effect on various pathophysiological pathways of the collagen-induced platelet aggregation and thrombus formation as a selective inhibition of cyclooxygenase and glycoprotein IIb/IIIa antagonist. Thus, we recommend L-sulforaphane as a potential antithrombotic drug.

  15. 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.

  16. 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

  17. Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines.

    PubMed

    Araújo, João R; Gonçalves, Pedro; Martel, Fátima

    2011-02-01

    Colorectal cancer (CRC) is the second most fatal and the third most diagnosed type of cancer worldwide. Despite having multifactorial causes, most CRC cases are mainly determined by dietary factors. In recent years, a large number of studies have attributed a protective effect to polyphenols and foods containing these compounds (fruits and vegetables) against CRC. Indeed, polyphenols have been reported to interfere with cancer initiation, promotion, and progression, acting as chemopreventive agents. The aim of this review is to summarize the main chemopreventive properties of some polyphenols (quercetin, rutin, myricetin, chrysin, epigallocatechin-3-gallate, epicatechin, catechin, resveratrol, and xanthohumol) against CRC, observed in cell culture models. From the data reviewed in this article, it can be concluded that these compounds inhibit cell growth, by inducing cell cycle arrest and/or apoptosis; inhibit proliferation, angiogenesis, and/or metastasis; and exhibit anti-inflammatory and/or antioxidant effects. In turn, these effects involve multiple molecular and biochemical mechanisms of action, which are still not completely characterized. Thus, caution is mandatory when attempting to extrapolate the observations obtained in CRC cell line studies to humans. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. 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.

  19. Chemoprevention of pulmonary carcinogenesis by myo-inositol.

    PubMed

    Wattenberg, L W

    1999-01-01

    This abstract summarizes material presented at the "First International Symposium on Disease Prevention by IP6 and other Rice Components "held in Kyoto, Japan in June, 1998. The presentation deals primarily with studies of chemoprevention of pulmonary carcinogenesis by myo-inositol. This compound is largely formed by the dephosphorylation of inositol hexaphosphate (IP6, phytate) within the gastrointestinal tract in humans and animals. myo-Inositol is one of a relatively few compounds that has an inhibitory effect on carcinogenesis of the lung in experimental animals when administered during the post-initiation period. It prevents pulmonary adenoma formation in A/J mice when fed in the diet subsequent to administrations of benzo[a]pyrene or the tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to the mice. A second compound, dexamethasone, also prevents pulmonary neoplasia under the same conditions. Experiments in which both myo-inositol and dexamethasone were administered together in the diet showed an additive inhibitory effect. The significance and utility of the chemopreventive properties of these agents remains to be determined.

  20. 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

  1. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  2. Separation and Purification of Sulforaphane from Broccoli by Solid Phase Extraction

    PubMed Central

    Han, Dandan; Row, Kyung Ho

    2011-01-01

    A simple solid-phase extraction (SPE) method for the determination of sulforaphane in broccoli has been developed. The optimal conditions were found to be use of a silica SPE cartridge, and ethyl acetate and dichloromethane as washing and eluting solvents, respectively, which could eliminate interferences originating from the broccoli matrix. The extracts were sufficiently clean to be directly injected into high-performance liquid chromatography (HPLC) for further chromatographic analysis. Good linearity was obtained from 0.05 to 200 μg/mL (r = 0.998) for sulforaphane with the relative standard deviations less than 3.6%. The mean recoveries of sulforaphane from broccoli were more than 90.8% and the detection limit (S/N = 3:1) was 0.02 μg/mL. The SPE method provides a higher yield of sulforaphane from crude extracts compared to conventional liquid-liquid extraction. PMID:21673926

  3. Bioavailability and kinetics of sulforaphane in humans after consumption of cooked versus raw broccoli.

    PubMed

    Vermeulen, Martijn; Klöpping-Ketelaars, Ineke W A A; van den Berg, Robin; Vaes, Wouter H J

    2008-11-26

    The aim of this study was to determine the bioavailability and kinetics of the supposed anticarcinogen sulforaphane, the hydrolysis product of glucoraphanin, from raw and cooked broccoli. Eight men consumed 200 g of crushed broccoli, raw or cooked, with a warm meal in a randomized, free-living, open cross-over trial. Higher amounts of sulforaphane were found in the blood and urine when broccoli was eaten raw (bioavailability of 37%) versus cooked (3.4%, p ) 0.002). Absorption of sulforaphane was delayed when cooked broccoli was consumed (peak plasma time ) 6 h) versus raw broccoli (1.6 h, p ) 0.001). Excretion half-lives were comparable, 2.6 and 2.4 h on average, for raw and cooked broccoli, respectively (p ) 0.5). This study gives complete kinetic data and shows that consumption of raw broccoli results in faster absorption, higher bioavailability, and higher peak plasma amounts of sulforaphane, compared to cooked broccoli.

  4. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2001-10-01

    Prevention may represent a feasible approach to decreasing ovarian cancer mortality . To achieve a better understanding of the etiology of ovarian...Progestins have a potent apoptotic effect on ovarian epithelial cells and we have shown that levonorgestrel dramatically decreases ovarian cancer incidence...effective chemoprevention strategies that might decrease mortality from this disease.

  5. New enantiomeric fluorine-containing derivatives of sulforaphane: synthesis, absolute configurations and biological activity.

    PubMed

    Kiełbasiński, Piotr; Łuczak, Jerzy; Cierpiał, Tomasz; Błaszczyk, Jarosław; Sieroń, Lesław; Wiktorska, Katarzyna; Lubelska, Katarzyna; Milczarek, Małgorzata; Chilmończyk, Zdzisław

    2014-04-09

    Three pairs of enantiomers of the unknown sulforaphane analogs bearing organofluorine substituents bonded to the sulfinyl sulfur atom and having different number of methylene groups in the central carbon chain were synthesized and fully characterized, including determination of their absolute configurations. All the new compounds were tested in vitro for their cytotoxicity against melanoma cells to show increased activity in comparison with the natural sulforaphane. The influence of the particular structural changes in the molecule on the cytotoxicity is discussed.

  6. Sulforaphane induces reactive oxygen species-mediated mitotic arrest and subsequent apoptosis in human bladder cancer 5637 cells.

    PubMed

    Park, Hyun Soo; Han, Min Ho; Kim, Gi-Young; Moon, Sung-Kwon; Kim, Wun-Jae; Hwang, Hye Jin; Park, Kun Young; Choi, Yung Hyun

    2014-02-01

    The present study was undertaken to determine whether sulforaphane-derived reactive oxygen species (ROS) might cause growth arrest and apoptosis in human bladder cancer 5637 cells. Our results show that the reduced viability of 5637 cells by sulforaphane is due to mitotic arrest, but not the G2 phase. The sulforaphane-induced mitotic arrest correlated with an induction of cyclin B1 and phosphorylation of Cdk1, as well as a concomitant increased complex between cyclin B1 and Cdk1. Sulforaphane-induced apoptosis was associated with the activation of caspase-8 and -9, the initiators caspases of the extrinsic and intrinsic apoptotic pathways, respectively, and activation of effector caspase-3 and cleavage of poly (ADP-ribose) polymerase. However, blockage of caspase activation inhibited apoptosis and abrogated growth inhibition in sulforaphane-treated 5637 cells. This study further investigated the roles of ROS with respect to mitotic arrest and the apoptotic effect of sulforaphane, and the maximum level of ROS accumulation was observed 3h after sulforaphane treatment. However, a ROS scavenger, N-acetyl-L-cysteine, notably attenuated sulforaphane-mediated apoptosis as well as mitotic arrest. Overall, these results suggest that sulforaphane induces mitotic arrest and apoptosis of 5637 cells via a ROS-dependent pathway. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Sulforaphane targets cancer stemness and tumor initiating properties in oral squamous cell carcinomas via miR-200c induction.

    PubMed

    Liu, Chia-Ming; Peng, Chih-Yu; Liao, Yi-Wen; Lu, Ming-Yi; Tsai, Meng-Lun; Yeh, Jung-Chun; Yu, Chuan-Hang; Yu, Cheng-Chia

    2017-01-01

    Cancer stem cells (CSCs) are deemed as the driving force of tumorigenesis in oral squamous cell carcinomas (OSCCs). In this study, we investigated the chemotherapeutic effect of sulforaphane, a dietary component from broccoli sprouts, on targeting OSCC-CSCs. The effect of sulforaphane on normal oral epithelial cells (SG) and sphere-forming OSCC-CSCs isolated from SAS and GNM cells was examined. ALDH1 activity and CD44 positivity of OSCC-CSCs with sulforaphane treatment was assessed by flow cytometry analysis. In vitro and in vivo tumorigenicity assays of OSCC-CSCs with sulforaphane treatment were presented. We observed that the sulforaphane dose-dependently eliminated the proliferation rate of OSCC-CSCs, whereas the inhibition on SG cells proliferation was limited. Cancer stemness properties including self-renewal, CD44 positivity, and ALDH1 activity were also decreased in OSCC-CSCs with different doses of sulforaphane treatment. Moreover, sulforaphane treatment of OSCC-CSCs decreased the migration, invasion, clonogenicity, and in vivo tumorigenicity of xenograghts. Sulforaphane treatment resulted in a dose-dependent increase in the levels of tumor suppressive miR200c. These lines of evidence suggest that sulforaphane can suppress the cancer stemness and tumor-initiating properties in OSCC-CSCs both in vitro and in vivo. Copyright © 2016. Published by Elsevier B.V.

  8. 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

  9. 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

  10. Chemopreventive properties of dietary rice bran: current status and future prospects.

    PubMed

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

    2012-09-01

    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.

  11. 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

  12. COX-Independent Mechanisms of Cancer Chemoprevention by Anti-Inflammatory Drugs

    PubMed Central

    Gurpinar, Evrim; Grizzle, William E.; Piazza, Gary A.

    2013-01-01

    Epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2 selective inhibitors, reduce the risk of developing cancer. Experimental studies in human cancer cell lines and rodent models of carcinogenesis support these observations by providing strong evidence for the antineoplastic properties of NSAIDs. The involvement of COX-2 in tumorigenesis and its overexpression in various cancer tissues suggest that inhibition of COX-2 is responsible for the chemopreventive efficacy of these agents. However, the precise mechanisms by which NSAIDs exert their antiproliferative effects are still a matter of debate. Numerous other studies have shown that NSAIDs can act through COX-independent mechanisms. This review provides a detailed description of the major COX-independent molecular targets of NSAIDs and discusses how these targets may be involved in their anticancer effects. Toxicities resulting from COX inhibition and the suppression of prostaglandin synthesis preclude the long-term use of NSAIDs for cancer chemoprevention. Furthermore, chemopreventive efficacy is incomplete and treatment often leads to the development of resistance. Identification of alternative NSAID targets and elucidation of the biochemical processes by which they inhibit tumor growth could lead to the development of safer and more efficacious drugs for cancer chemoprevention. PMID:23875171

  13. Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence.

    PubMed

    Kotecha, Ritesh; Takami, Akiyoshi; Espinoza, J Luis

    2016-08-09

    Cancer chemoprevention involves the use of different natural or biologic agents to inhibit or reverse tumor growth. Epidemiological and pre-clinical data suggest that various natural phytochemicals and dietary compounds possess chemopreventive properties, and in-vitro and animal studies support that these compounds may modulate signaling pathways involved in cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials and have shown variable results. In this review, we summarize the data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations.

  14. Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence

    PubMed Central

    Kotecha, Ritesh; Takami, Akiyoshi; Espinoza, J. Luis

    2016-01-01

    Cancer chemoprevention involves the use of different natural or biologic agents to inhibit or reverse tumor growth. Epidemiological and pre-clinical data suggest that various natural phytochemicals and dietary compounds possess chemopreventive properties, and in-vitro and animal studies support that these compounds may modulate signaling pathways involved in cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials and have shown variable results. In this review, we summarize the data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations. PMID:27232756

  15. Cancer chemoprevention: selenium as a prooxidant, not an antioxidant.

    PubMed

    Drake, E N

    2006-01-01

    Although the average daily dietary selenium (Se) intake in the United States is consistently above the adult RDA of 55 microg Se/day, supranutritional supplements of 200 microg Se/day have been shown to provide chemopreventive benefits against several cancers, particularly prostate cancer. The hypothesis herein contends that selenium compounds with the greatest anticarcinogenic potency are likely to be sodium selenite with Se in the +4 oxidation state and methylseleninic acid. These compounds exert their cancer chemopreventive effects by directly oxidizing critical thiol-containing cellular substrates, and are more effective than the more frequently preferred (used) supplements of selenomethionine and Se-methylselenocysteine that lack oxidation capability. Selenate (+6 Se) the immediate precursor of selenite (+4 Se) can be metabolically reduced, and although less potent than the +4 Se compounds cited above, appears to be a more effective anticarcinogen than organic forms of dietary selenium. Apoptosis, an important, Se-induced anticarcinogenic mechanism, is accomplished by the direct oxidation of vicinal sulfhydryl groups in cysteine clusters within the catalytic domains of cellular enzymes (e.g., protein kinase C), and by the production of CH3Se-, which reacts with O2 to generate superoxide and other reactive oxygen species (ROS). Activated oncogenes "prime" cells for Se-induced prooxidative apoptosis thereby providing the needed margin for "killing" cancer cells while leaving normal, healthy cells unharmed. Selenoethers, such as selenomethionine and Se-methylselenocysteine are not oxidizing agents, and first, must be converted to methylselenol (CH3Se-) that can be directly oxidized to methylseleninic acid. The addition of methioninase, to selenomethionine, or beta-lyase to Se-methylselenocysteine, rapidly produces significant amounts of methylselenol, which may be oxidized to methylseleninic acid or may react with O2 to produce superoxide and ROS, resulting in

  16. Sulforaphane induces differential modulation of mitochondrial biogenesis and dynamics in normal cells and tumor cells.

    PubMed

    Negrette-Guzmán, Mario; Huerta-Yepez, Sara; Vega, Mario I; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; Medina-Campos, Omar Noel; Rodríguez, Esteban; Tapia, Edilia; Pedraza-Chaverri, José

    2017-02-01

    Antioxidant-based chemotherapy has been intensely debated. Herein, we show that sulforaphane (SFN) induced mitochondrial biogenesis followed by mitochondrial fusion in a kidney cell line commonly used in nephroprotective models. At the same concentration and exposure time, SFN induced cell death in prostate cancer cells accompanied by mitochondrial biogenesis and fragmentation. Stabilization of the nuclear factor E2-related factor-2 (Nrf2) could be associated with these effects in the tumor cell line. An increase in the peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) level and a decrease in the hypoxia-inducible factor-1α (HIF1α) level would suggest a possible metabolic shift. The knockdown in the nuclear respiratory factor-1 (NRF1) attenuated the SFN-induced effect on prostate cancer cells demonstrating that mitochondrial biogenesis plays an important role in cell death for this kind of tumor cells. This evidence supports SFN as a potential antineoplastic agent that could inhibit tumor development and could protect normal tissues by modulating common processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Differential effects of phenethyl isothiocyanate and D,L-sulforaphane on Toll-like receptor 3 signaling

    PubMed Central

    Zhu, Jianzhong; Ghosh, Arundhati; Coyle, Elizabeth M.; Lee, Joomin; Hahm, Eun-Ryeong; Singh, Shivendra V.; Sarkar, Saumendra N.

    2013-01-01

    Naturally occurring isothiocyanates (ITC) from cruciferous vegetables are widely studied for their cancer chemopreventive effects. Here we investigated the effects of ITC on Toll-like receptor (TLR) signaling, and found that two most promising ITCs, phenethyl isothiocyanate (PEITC) and D,L-sulforaphane (SFN), have differential effects on dsRNA mediated innate immune signaling through TLR3. PEITC preferentially inhibited TLR3 mediated IRF3 signaling and downstream gene expression in vivo and in vitro, whereas SFN caused inhibition of TLR3 mediated NF-κB signaling and downstream gene expression. Mechanistically, PEITC inhibited ligand (dsRNA) dependent dimerization of TLR3 resulting in inhibition of signaling through IRF3. On the other hand, SFN did not disrupt TLR3 dimerization indicating that it affects further downstream pathway resulting in NF-κB inhibition. In order to examine the biological significance of these findings in the context of anti-tumor activities of these compounds, we used two approaches: (a) first, we showed that dsRNA mediated apoptosis of tumor cells via TLR3 was inhibited in the presence of PEITC, whereas this response was augmented by SFN treatment; (b) second, in a separate assay measuring anchorage independent growth and colony formation by immortalized fibroblasts we made similar observations. Here again, PEITC antagonized dsRNA mediated inhibition of colony formation while SFN enhanced the inhibition. These results indicate biologically relevant functional differences between two structurally similar ITC and may provide important insights in therapeutic development of these compounds targeted to specific cancer. PMID:23509350

  18. Selection of topically applied non-steroidal anti-inflammatory drugs for oral cancer chemoprevention.

    PubMed

    Sood, Sandeep; Shiff, Steven J; Yang, Chung S; Chen, Xiaoxin

    2005-07-01

    Topical delivery of non-steroidal anti-inflammatory drugs through the oral mucosa has been used for oral cancer chemoprevention. Local permeation of these agents has been one of the major concerns. Here we propose an approach to predict the permeability of topically applied agents for oral cancer chemoprevention. In theory, the total flux through the oral mucosa (Jmax) can be estimated by adding the transcellular flux (JTC) and the paracellular flux (JPC). To target the Cox-2 enzyme in oral epithelial cells, it is desirable to maximize the theoretical activity index, the ratio of JTC and IC50 of a Cox-2 inhibitor (JTC/IC50-Cox-2). Among the 12 commonly used NSAIDs, celecoxib, nimesulide and ibuprofen had the highest values and may be the agents of choice to target Cox-2 in oral epithelial cells through topical application. Based on these calculations, a long-term chemopreventive experiment using celecoxib (3% or 6%) through topical application was performed in a DMBA induced hamster oral cancer model. Both 3% and 6% reduced the incidence of squamous cell carcinoma at the post-initiation stage.

  19. The chemopreventive activity of apple against carcinogenesis: antioxidant activity and cell cycle control.

    PubMed

    Ribeiro, Flávia A P; Gomes de Moura, Carolina F; Aguiar, Odair; de Oliveira, Flavia; Spadari, Regina C; Oliveira, Nara R C; Oshima, Celina T F; Ribeiro, Daniel A

    2014-09-01

    Apples and their derivatives are rich in phytochemicals, including flavonoids (catechins, flavonols, quercetin) and phenolic acids (quercetin glycosides, catechin, epicatechin, procyanidins), vitamins, and fibers, that confer an important antioxidant property. Chemoprevention is defined by the use of natural or synthetic agents to interfere with the progression, reverse, or inhibit carcinogenesis, thereby reducing the risk of developing clinically invasive disease. The aim of this article is to present data generated from the use of apples as a chemopreventive agent in carcinogenesis using in-vivo and in-vitro test systems. Apple and its bioactive compounds can exert chemopreventive properties as a result of antioxidant activity and cell cycle control. However, future focus of research on apple such as identifying the specific phytochemical responsible for the anticarcinogenic effect, timing of consumption, and adequate amount of apples to achieve the best preventive effect using human large randomized-controlled trials is needed. Furthermore, animal studies are also relevant for better understanding the role of this fruit in human health as well as modulation of degenerative diseases such as cancer. Therefore, this area warrants further investigation as a new way of thinking, which would apply not only to apples but also to other fruit used as promising therapeutic agents against human diseases.

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. Novel targets of sulforaphane in primary cardiomyocytes identified by proteomic analysis.

    PubMed

    Angeloni, Cristina; Turroni, Silvia; Bianchi, Laura; Fabbri, Daniele; Motori, Elisa; Malaguti, Marco; Leoncini, Emanuela; Maraldi, Tullia; Bini, Luca; Brigidi, Patrizia; Hrelia, Silvana

    2013-01-01

    Cardiovascular diseases represent the main cause of mortality in the industrialized world and the identification of effective preventive strategies is of fundamental importance. Sulforaphane, an isothiocyanate from cruciferous vegetables, has been shown to up-regulate phase II enzymes in cardiomyocytes and counteract oxidative stress-induced apoptosis. Aim of the present study was the identification and characterization of novel sulforaphane targets in cardiomyocytes applying a proteomic approach. Two-dimensional gel electrophoresis and mass spectrometry were used to generate protein profiles of primary neonatal rat cardiomyocytes treated and untreated with 5 µM sulforaphane for 1-48 h. According to image analysis, 64 protein spots were found as differentially expressed and their functional correlations were investigated using the MetaCore program. We mainly focused on 3 proteins: macrophage migration inhibitory factor (MIF), CLP36 or Elfin, and glyoxalase 1, due to their possible involvement in cardioprotection. Validation of the time-dependent differential expression of these proteins was performed by western blotting. In particular, to gain insight into the cardioprotective role of the modulation of glyoxalase 1 by sulforaphane, further experiments were performed using methylglyoxal to mimic glycative stress. Sulforaphane was able to counteract methylglyoxal-induced apoptosis, ROS production, and glycative stress, likely through glyoxalase 1 up-regulation. In this study, we reported for the first time new molecular targets of sulforaphane, such as MIF, CLP36 and glyoxalase 1. In particular, we gave new insights into the anti-glycative role of sulforaphane in cardiomyocytes, confirming its pleiotropic behavior in counteracting cardiovascular diseases.

  5. Sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC-05.

    PubMed

    Zhou, Lan; Yao, Qian; Li, Yan; Huang, Yun-Chao; Jiang, Hua; Wang, Chuan-Qiong; Fan, Lei

    2017-01-01

    Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non-smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL-05) to explore the value of sulforaphane in lung cancer prevention and treatment. Cell growth inhibition was determined by methyl thiazolyl tetrazolium assay; cell morphology and apoptosis were observed under transmission electron microscope; cell cycle and apoptosis rates were detected using flow cytometry; B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) messenger RNA expression were determined by quantitative PCR; and p53, p73, p53 upregulated modulator of apoptosis (PUMA), Bax, Bcl-2, and caspase-9 protein expression were detected by Western blotting. Sulforaphane inhibited XWLC-05 cell growth with inhibitory concentration (IC)50 of 4.04, 3.38, and 3.02 μg/mL at 24, 48, and 72 hours, respectively. Sulforaphane affected the XWLC-05 cell cycle as cells accumulated in the G2/M phase. The proportion of apoptotic cells observed was 27.6%. Compared with the control, the sulforaphane group showed decreased Bcl-2 and p53 expression, and significantly increased p73, PUMA, Bax, and caspase-9 protein expression (P < 0.05). Sulforaphane induces Xuanwei lung adenocarcinoma cell apoptosis. Its possible mechanism may involve the upregulation of p73 expression and its effector target genes PUMA and Bax in lung cancer cells, downregulation of the anti-apoptotic gene B cl -2, and activation of caspase-9. It may also involve downregulation of the mutant p53 protein. © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  6. Novel Targets of Sulforaphane in Primary Cardiomyocytes Identified by Proteomic Analysis

    PubMed Central

    Angeloni, Cristina; Turroni, Silvia; Bianchi, Laura; Fabbri, Daniele; Motori, Elisa; Malaguti, Marco; Leoncini, Emanuela; Maraldi, Tullia; Bini, Luca; Brigidi, Patrizia; Hrelia, Silvana

    2013-01-01

    Cardiovascular diseases represent the main cause of mortality in the industrialized world and the identification of effective preventive strategies is of fundamental importance. Sulforaphane, an isothiocyanate from cruciferous vegetables, has been shown to up-regulate phase II enzymes in cardiomyocytes and counteract oxidative stress-induced apoptosis. Aim of the present study was the identification and characterization of novel sulforaphane targets in cardiomyocytes applying a proteomic approach. Two-dimensional gel electrophoresis and mass spectrometry were used to generate protein profiles of primary neonatal rat cardiomyocytes treated and untreated with 5 µM sulforaphane for 1-48 h. According to image analysis, 64 protein spots were found as differentially expressed and their functional correlations were investigated using the MetaCore program. We mainly focused on 3 proteins: macrophage migration inhibitory factor (MIF), CLP36 or Elfin, and glyoxalase 1, due to their possible involvement in cardioprotection. Validation of the time-dependent differential expression of these proteins was performed by western blotting. In particular, to gain insight into the cardioprotective role of the modulation of glyoxalase 1 by sulforaphane, further experiments were performed using methylglyoxal to mimic glycative stress. Sulforaphane was able to counteract methylglyoxal-induced apoptosis, ROS production, and glycative stress, likely through glyoxalase 1 up-regulation. In this study, we reported for the first time new molecular targets of sulforaphane, such as MIF, CLP36 and glyoxalase 1. In particular, we gave new insights into the anti-glycative role of sulforaphane in cardiomyocytes, confirming its pleiotropic behavior in counteracting cardiovascular diseases. PMID:24349480

  7. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    1999-10-01

    Since reduction of ovulation is protective against ovarian cancer, prevention may represent a feasible approach to decreasing mortality . To achieve a...cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and women. A chernoprevention trial is ongoing in...chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian epithelium of women undergoing oophorectomy.

  8. Sulforaphane absorption and excretion following ingestion of a semi-purified broccoli powder rich in glucoraphanin and broccoli sprouts in healthy men.

    PubMed

    Cramer, Jenna M; Jeffery, Elizabeth H

    2011-01-01

    Sulforaphane (SF) is a chemopreventive isothiocyanate (ITC) derived from the myrosinase-catalyzed hydrolysis of glucoraphanin, a thioglucoside present in broccoli. Broccoli supplements often contain glucoraphanin but lack myrosinase, putting in question their ability to provide dietary SF. This study compared the relative absorption of SF from air-dried broccoli sprouts rich in myrosinase and a glucoraphanin-rich broccoli powder lacking myrosinase, individually and in combination. Subjects (n=4) each consumed 4 meals consisting of dry cereal and yogurt with 2 g sprouts, 2 g powder, both, or neither. Blood and urine were analyzed for SF metabolites. The 24 h urinary SF recovery was 74%, 49%, and 19% of the dose ingested from broccoli sprouts, combination, and broccoli powder meals, respectively. Urinary and plasma ITC appearance was delayed from the broccoli powder compared to the sprouts and combination. A liver function panel indicated no toxicity from any treatment at 24 h. These data indicate a delayed appearance in plasma and urine of SF from the broccoli powder relative to SF from myrosinase-rich sprouts. Combining broccoli sprouts with the broccoli powder enhanced SF absorption from broccoli powder, offering the potential for development of foods that modify the health impact of broccoli products. Copyright © 2011, Taylor & Francis Group, LLC

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

    PubMed

    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. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    PubMed Central

    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

  11. 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.

  12. The effect of sulforaphane on histone deacetylase activity in keratinocytes: Differences between in vitro and in vivo analyses.

    PubMed

    Dickinson, Sally E; Rusche, Jadrian J; Bec, Sergiu L; Horn, David J; Janda, Jaroslav; Rim, So Hyun; Smith, Catharine L; Bowden, G Timothy

    2015-11-01

    Sulforaphane is a natural product found in broccoli, which is known to exert many different molecular effects in the cell, including inhibition of histone deacetylase (HDAC) enzymes. Here, we examine for the first time the potential for sulforaphane to inhibit HDACs in HaCaT keratinocytes and compare our results with those found using HCT116 colon cancer cells. Significant inhibition of HDAC activity in HCT116 nuclear extracts required prolonged exposure to sulforaphane in the presence of serum. Under the same conditions HaCaT nuclear extracts did not exhibit reduced HDAC activity with sulforaphane treatment. Both cell types displayed down-regulation of HDAC protein levels by sulforaphane treatment. Despite these reductions in HDAC family member protein levels, acetylation of marker proteins (acetylated Histone H3, H4, and tubulin) was decreased by sulforaphane treatment. Time-course analysis revealed that HDAC6, HDAC3, and acetylated histone H3 protein levels are significantly inhibited as early as 6 h into sulforaphane treatment. Transcript levels of HDAC6 are also suppressed after 48 h of treatment. These results suggest that HDAC activity noted in nuclear extracts is not always translated as expected to target protein acetylation patterns, despite dramatic inhibition of some HDAC protein levels. In addition, our data suggest that keratinocytes are at least partially resistant to the nuclear HDAC inhibitory effects of sulforaphane, which is exhibited in HCT116 and other cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

  13. The effect of sulforaphane on histone deacetylase activity in keratinocytes: differences between in vitro and in vivo analyses

    PubMed Central

    Dickinson, Sally E.; Rusche, Jadrian J.; Bec, Sergiu L.; Horn, David J.; Janda, Jaroslav; Rim, So Hyun; Smith, Catharine L.; Bowden, G. Timothy

    2015-01-01

    Sulforaphane is a natural product found in broccoli which is known to exert many different molecular effects in the cell, including inhibition of histone deacetylase (HDAC) enzymes. Here we examine for the first time the potential for sulforaphane to inhibit HDACs in HaCaT keratinocytes and compare our results with those found using HCT116 colon cancer cells. Significant inhibition of HDAC activity in HCT116 nuclear extracts required prolonged exposure to sulforaphane in the presence of serum. Under the same conditions HaCaT nuclear extracts did not exhibit reduced HDAC activity with sulforaphane treatment. Both cell types displayed down-regulation of HDAC protein levels by sulforaphane treatment. Despite these reductions in HDAC family member protein levels, acetylation of marker proteins (acetylated Histone H3, H4 and tubulin) was decreased by sulforaphane treatment. Timecourse analysis revealed that HDAC6, HDAC3 and acetylated histone H3 protein levels are significantly inhibited as early as 6hr into sulforaphane treatment. Transcript levels of HDAC6 are also suppressed after 48hr of treatment. These results suggest that HDAC activity noted in nuclear extracts is not always translated as expected to target protein acetylation patterns, despite dramatic inhibition of some HDAC protein levels. In addition, our data suggest that keratinocytes are at least partially resistant to the nuclear HDAC inhibitory effects of sulforaphane which is exhibited in HCT116 and other cells. PMID:25307283

  14. 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

  15. 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

  16. Brain mitochondria from rats treated with sulforaphane are resistant to redox-regulated permeability transition.

    PubMed

    Greco, Tiffany; Fiskum, Gary

    2010-12-01

    Oxidative stress promotes Ca2+-dependent opening of the mitochondrial inner membrane permeability transition pore (PTP), causing bioenergetic failure and subsequent cell death in many paradigms, including those related to acute brain injury. One approach to pre-conditioning against oxidative stress is pharmacologic activation of the Nrf2/ARE pathway of antioxidant gene expression by agents such as sulforaphane (SFP). This study tested the hypothesis that administration of SFP to normal rats increases resistance of isolated brain mitochondria to redox-sensitive PTP opening. SFP or DMSO vehicle was administered intraperitoneally to adult male rats at 10 mg/kg 40 h prior to isolation of non-synaptic brain mitochondria. Mitochondria were suspended in medium containing a respiratory substrate and were exposed to an addition of Ca2+ below the threshold for PTP opening. Subsequent addition of tert-butyl hydroperoxide (tBOOH) resulted in a cyclosporin A-inhibitable release of accumulated Ca2+ into the medium, as monitored by an increase in fluorescence of Calcium Green 5N within the medium, and was preceded by a decrease in the autofluorescence of mitochondrial NAD(P)H. SFP treatment significantly reduced the rate of tBOOH-induced Ca2+ release but did not affect NAD(P)H oxidation or inhibit PTP opening induced by the addition of phenylarsine oxide, a direct sulfhydryl oxidizing agent. SFP treatment had no effect on respiration by brain mitochondria and had no effect on PTP opening or respiration when added directly to isolated mitochondria. We conclude that SFP confers resistance of brain mitochondria to redox-regulated PTP opening, which could contribute to neuroprotection observed with SFP.

  17. Chemoprevention of Colorectal Cancer by Artocarpin, a Dietary Phytochemical from Artocarpus heterophyllus.

    PubMed

    Sun, Guochuan; Zheng, Zongping; Lee, Mee-Hyun; Xu, Yijuan; Kang, Soouk; Dong, Zigang; Wang, Mingfu; Gu, Zhennan; Li, Haitao; Chen, Wei

    2017-05-03

    Artocarpus heterophyllus is an evergreen tree distributed in tropical regions, and its fruit (jackfruit) is well-known as the world's largest tree-borne fruit. Although A. heterophyllus has been widely used in folk medicines against inflammation, its potential in cancer chemoprevention remains unclear. Herein we identified artocarpin from A. heterophyllus as a promising colorectal cancer chemopreventive agent by targeting Akt kinase. Phenotypically, artocarpin exhibited selective cytotoxicity against human colon cancer cells. Artocarpin impaired the anchorage-independent growth capability, suppressed colon cancer cell growth, and induced a G1 phase cell cycle arrest which was followed by apoptotic as well as autophagic cell death. Mechanistic studies revealed that artocarpin directly targeted Akt 1 and 2 kinase activity evidenced by in vitro kinase assay, ex vivo binding assay as well as Akt downstream cellular signal transduction. Importantly, oral administration of artocarpin attenuated colitis-associated colorectal tumorigenesis in mice. Taken together, artocarpin, a bioactive component of A. heterophyllus, might merit investigation as a potential colorectal cancer chemopreventive agent.

  18. 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.

  19. Luteolin nanoparticle in chemoprevention – in vitro and in vivo anticancer activity

    PubMed Central

    Majumdar, Debatosh; Jung, Kyung-Ho; Zhang, Hongzheng; Nannapaneni, Sreenivas; Wang, Xu; Amin, A.R.M Ruhul; Chen, Zhengjia; Chen, Zhuo (G).; Shin, Dong M.

    2013-01-01

    Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest due to the broad safety window of these compounds. However, many of these compounds are hydrophobic and poorly soluble in water. They frequently display low bioavailability, poor systemic delivery, and low efficacy. To circumvent this problem, we explored a novel approach towards chemoprevention using nanotechnology to deliver luteolin, a natural compound present in green vegetables. We formulated water soluble polymer-encapsulated Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, like luteolin, Nano-Luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50 value of Nano-Luteolin was 4.13μM, and that of luteolin was 6.96μM. In H292 cells, the IC50 of luteolin was 15.56μM, and Nano-Luteolin was 14.96μM. In vivo studies using a tumor xenograft mouse model demonstrated that Nano-Luteolin has a significant inhibitory effect on the tumor growth of SCCHN in comparison to luteolin. Our results suggest that nanoparticle delivery of naturally occurring dietary agents like luteolin has many advantages and may have potential application in chemoprevention in clinical settings. PMID:24403290

  20. Novel gram-scale production of enantiopure R-sulforaphane from Tuscan black kale seeds.

    PubMed

    De Nicola, Gina Rosalinda; Rollin, Patrick; Mazzon, Emanuela; Iori, Renato

    2014-05-27

    Dietary R-sulforaphane is a highly potent inducer of the Keap1/Nrf2/ARE pathway. Furthermore, sulforaphane is currently being used in clinical trials to assess its effects against different tumour processes. This study reports an efficient preparation of enantiopure R-sulforaphane based on the enzymatic hydrolysis of its natural precursor glucoraphanin. As an alternative to broccoli seeds, we have exploited Tuscan black kale seeds as a suitable source for gram-scale production of glucoraphanin. The defatted seed meal contained 5.1% (w/w) of glucoraphanin that was first isolated through an anion exchange chromatographic process, and then purified by gel filtration. The availability of glucoraphanin (purity≈95%, weight basis) has allowed us to develop a novel simple hydrolytic process involving myrosinase (EC 3.2.1.147) in a biphasic system to directly produce R-sulforaphane. In a typical experiment, 1.09 g of enantiopure R-sulforaphane was obtained from 150 g of defatted Tuscan black kale seed meal.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Biotransformation of the chemopreventive agent isoliquiritigenin by UDP-glucuronosyltransferases

    PubMed Central

    Guo, Jian; Liu, Ang; Cao, Hongmei; Luo, Yan; Pezzuto, John M.; van Breemen, Richard B.

    2008-01-01

    Isoliquiritigenin (2’,4’,4-trihydroxychalcone), a chalcone found in licorice root and shallots, exhibits antioxidant, estrogenic, and anti-tumor 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 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 LC-MS. 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 µM and 3.15 ± 0.24 µM, 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 µM and 25.8 ± 1.3 µM, 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 human liver microsomes, 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

  6. 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.

  7. 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

  8. 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.

  9. Sulforaphane inhibits damage-induced poly (ADP-ribosyl)ation via direct interaction of its cellular metabolites with PARP-1.

    PubMed

    Piberger, Ann Liza; Keil, Claudia; Platz, Stefanie; Rohn, Sascha; Hartwig, Andrea

    2015-11-01

    The isothiocyanate sulforaphane, a major breakdown product of the broccoli glucosinolate glucoraphanin, has frequently been proposed to exert anticarcinogenic properties. Potential underlying mechanisms include a zinc release from Kelch-like ECH-associated protein 1 followed by the induction of detoxifying enzymes. This suggests that sulforaphane may also interfere with other zinc-binding proteins, e.g. those essential for DNA repair. Therefore, we explored the impact of sulforaphane on poly (ADP-ribose)polymerase-1 (PARP-1), poly (ADP-ribosyl)ation (PARylation), and DNA single-strand break repair (SSBR) in cell culture. Immunofluorescence analyses showed that sulforaphane diminished H2 O2 -induced PARylation in HeLa S3 cells starting from 15 μM despite increased lesion induction under these conditions. Subcellular experiments quantifying the damage-induced incorporation of (32) P-ADP-ribose by PARP-1 displayed no direct impact of sulforaphane itself, but cellular metabolites, namely the glutathione conjugates of sulforaphane and its interconversion product erucin, reduced PARP-1 activity concentration dependently. Interestingly, this sulforaphane metabolite-induced PARP-1 inhibition was prevented by thiol compounds. PARP-1 is a stimulating factor for DNA SSBR-rate and we further demonstrated that 25 μM sulforaphane also delayed the rejoining of H2 O2 -induced DNA strand breaks, although this might be partly due to increased lesion frequencies. Sulforaphane interferes with damage-induced PARylation and SSBR, which implies a sulforaphane-dependent impairment of genomic stability. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Sulforaphane improves outcomes and slows cerebral ischemic/reperfusion injury via inhibition of NLRP3 inflammasome activation in rats.

    PubMed

    Yu, Chang; He, Qi; Zheng, Jing; Li, Ling Yu; Hou, Yang Hao; Song, Fang Zhou

    2017-04-01

    Ischemia/reperfusion (I/R) injury has been correlated with systemic inflammatory response. In addition, NLRP3 has been suggested as a cause in many inflammatory processes. Sulforaphane (SFN) is a naturally occurring isothiocyanate found in cruciferous vegetables, such as broccoli and cabbage. While recent studies have demonstrated that Sulforaphane has protective effects against cerebral ischemia/reperfusion injury, little is known about how those protective effects work. In this study, we focus our investigation on the role and process of Sulforaphane in the inhibition of NLRP3 inflammasome activation, as well as its effect on brain ischemia/reperfusion injury. Adult male Sprague-Dawley rats were injected with Sulforaphane (5 or 10mg/kg) intraperitoneally at the beginning of reperfusion, after a 60min period of occlusion. A neurological score and infarct volume were assessed at 24h after the administration of Sulforaphane. Myeloperoxidase (MPO) activity was measured at 24h to assess neutrophil infiltration in brain tissue. ELISA, RT-PCR and Western blot analyses were used to measure any inflammatory reaction. Sulforaphane treatment significantly reduced infarct volume and improved neurological scores when compared to a vehicle-treated group. Neutrophil infiltration was significantly higher in the vehicle-treated group than in the Sulforaphane treatment group. Sulforaphane treatment inhibits NLRP3 inflammasome activation and the downregulation of cleaved caspase-1, while reducing IL-1β and IL-18 expression. The inhibition of inflammatory response with Sulforaphane treatment improves outcomes after focal cerebral ischemia. This neuroprotective effect is likely exerted by Sulforaphane inhibited NLRP3 inflammasome activation caused by the downregulation of NLRP3, the induction of cleaved caspase-1, and thus the reduction of IL-1β and IL-18. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Chemopreventive effects of honokiol on UVB-induced skin cancer development.

    PubMed

    Chilampalli, Shivani; Zhang, Xiaoying; Fahmy, Hesham; Kaushik, Radhey S; Zeman, David; Hildreth, Michael B; Dwivedi, Chandradhar

    2010-03-01

    Skin cancer is the most prevalent of all cancer types and its incidence is expected to increase substantially. Chemoprevention involves the administration of chemical agents to prevent initiation, promotion and/or progression that occurs during neoplastic development. Honokiol, a plant lignan isolated from bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically induced skin cancer development. The objective of this investigation was to study the chemopreventive effects of honokiol on UVB-induced skin tumor development in SKH-1 mice, a model relevant to humans, and to elucidate the possible role of apoptotic proteins involved in the prevention of skin tumor development. Female SKH-1 mice were divided into two groups. Group 1 received acetone (0.2 ml, topical) and Group 2 received honokiol (30 microg in 0.2 ml acetone, topical) one hour before UVB treatment. Tumor initiation and promotion were carried out by UVB radiation (30 mJ/cm(2)/day), 5 days a week for 30 weeks. Tumor counts and mouse weights were taken weekly. The honokiol-pretreated group exhibited a 45% reduction in tumor multiplicity as compared to the control group. Mechanistic studies showed the possible involvement of caspase-3, caspase-8, caspase-9, poly (ADP-ribose) polymerase (PARP) and p53 activation (p<0.05) leading to the induction of DNA fragmentation and apoptosis. Pretreatment with honokiol, at concentrations in micrograms per application compared with milligram applications of other potential chemopreventive agents, prevents UVB-induced skin cancer development, possibly by activating proapoptotic proteins through both intrinsic and extrinsic pathways.

  12. DNA Microarray Profiling Highlights Nrf2-Mediated Chemoprevention Targeted by Wasabi-Derived Isothiocyanates in HepG2 Cells.

    PubMed

    Trio, Phoebe Zapanta; Kawahara, Atsuyoshi; Tanigawa, Shunsuke; Sakao, Kozue; Hou, De-Xing

    2017-01-01

    6-MSITC and 6-MTITC are sulforaphane (SFN) analogs found in Japanese Wasabi. As we reported previously, Wasabi isothiocyanates (ITCs) are activators of Nrf2-antioxidant response element pathway, and also inhibitors of pro-inflammatory cyclooxygenase-2. This study is the first to assess the global changes in transcript levels by Wasabi ITCs, comparing with SFN, in HepG2 cells. We performed comparative gene expression profiling by treating HepG2 cells with ITCs, followed by DNA microarray analyses using HG-U133 plus 2.0 oligonucleotide array. Partial array data on selected gene products were confirmed by RT-PCR and Western blotting. Ingenuity Pathway Analysis (IPA) was used to identify functional subsets of genes and biologically significant network pathways. 6-MTITC showed the highest number of differentially altered (≥2 folds) gene expression, of which 114 genes were upregulated and 75 were downregulated. IPA revealed that Nrf2-mediated pathway, together with glutamate metabolism, is the common significantly modulated pathway across treatments. Interestingly, 6-MSITC exhibited the most potent effect toward Nrf2-mediated pathway. Our data suggest that 6-MSITC could exert chemopreventive role against cancer through its underlying antioxidant activity via the activation of Nrf2-mediated subsequent induction of cytoprotective genes.

  13. Prostate cancer chemoprevention: Strategies for designing efficient clinical trials.

    PubMed

    Lieberman, R

    2001-04-01

    A chemoprevention (CP) strategy has evolved for conducting efficient clinical trials for prostate cancer (PCa) prevention. It integrates five key components, including agents, biomarkers, cohorts, designs, and endpoints. The rationale for the CP strategy relates to the natural history of prostate cancer. There is a wide array of natural and synthetic agents that hold promise for inhibiting, reversing, or modulating the transition from normal to precancer and from precancer to cancer. These agent classes include antiandrogens, antiestrogens, phytoestrogens, antioxidants, anti-inflammatory (proapoptotic) agents, antiproliferation/antidifferentiation agents, signal transduction modulators of receptor tyrosine kinase and ras farnesylation, antiangiogenesis agents, insulinlike growth factor (IGF)-1, peroxisome proliferator-activator receptor modulators (-gamma and -delta), and gene-based interventions. Biomarkers and endpoints are guided by the level of evidence required (eg, phase 1, 2, 3). Two candidate surrogate endpoints (SE) based on histology are high-grade prostatic intraepithelial neoplasia (HGPIN) and computer-assisted image analysis of dysplastic lesions. Phase 1 trials use standard endpoints of safety, pharmacokinetics and limited pharmacodynamics. Phase 2 trials use endpoints of modulation of biomarkers and correlation with histology. Phase 3 trials use endpoints of clinical benefit, such as cancer incidence reduction and quality of life. Validation of a biomarker as a SE involves correlation of the biomarker with clinical benefit. Cohorts (target populations) for phase 2/3 trials include the general population of men over age 50 with a normal prostate-specific antigen (PSA), subjects with a strong family history of PCa, subjects with elevated PSA/negative biopsy, and subjects with HGPIN/negative biopsy. These at-risk populations reflect key individual risk factors (age, race, serum PSA [free/total]; serum IGF-1/IGF binding protein (IGFBP)-3; 1, 25(OH)(2) D3

  14. Anticancer and Cancer Chemopreventive Potential of Grape Seed Extract and Other Grape-Based Products1–3

    PubMed Central

    Kaur, Manjinder; Agarwal, Chapla; Agarwal, Rajesh

    2009-01-01

    With emerging trends in the incidence of cancer of various organ sites, additional approaches are needed to control human malignancies. Intervention or prevention of cancer by dietary constituents, a strategy defined as chemoprevention, holds great promise in our conquest to control cancer, because it can be implemented on a broader population base with less economic burden. Consistent with this, several epidemiological studies have shown that populations that consume diets rich in fruits and vegetables have an overall lower cancer incidence. Based on these encouraging observations, research efforts from across the globe have focused on identifying, characterizing, and providing scientific basis to the efficacy of various phytonutrients in an effort to develop effective strategy to control various human malignancies. Cancer induction, growth, and progression are multi-step events and numerous studies have demonstrated that various dietary agents interfere with these stages of cancer, thus blocking malignancy. Fruits and vegetables represent untapped reservoir of various nutritive and nonnutritive phytochemicals with potential cancer chemopreventive activity. Grapes and grape-based products are one such class of dietary products that have shown cancer chemopreventive potential and are also known to improve overall human health. This review focuses on recent advancements in cancer chemopreventive and anticancer efficacy of grape seed extract and other grape-based products. Overall, completed studies from various scientific groups conclude that both grapes and grape-based products are excellent sources of various anticancer agents and their regular consumption should thus be beneficial to the general population. PMID:19640973

  15. Sulforaphane and related mustard oils in focus of cancer prevention and therapy.

    PubMed

    Herr, Ingrid; Lozanovski, Vladimir; Houben, Philipp; Schemmer, Peter; Büchler, Markus W

    2013-02-01

    The plant family Brassicaceae, formerly Cruciferae, contains mustard oil glycosides, from which mustard oils are enzymatically hydrolyzed. Mustard oils offer protection from pests, microorganisms and fungi. More than 120 different mustard oils with various biological functions are known. Since ancient times, these substances are used as natural antibiotics, antiviral drugs and antimycotics. The antioxidative effect of mustard oils contributes to protection from DNA damage. Epidemiological and experimental studies have shown preventive and therapeutic effects of crucifers or isolated substances thereof. Particularly well studied is the mustard oil sulforaphane, which is contained in high concentrations in broccoli and its sprouts. As has been shown in mice recently, sulforaphane also targets the most malignant cancer stem cells, which are not affected by conventional cancer treatments. Based on these promising results, the first prospective clinical studies with cancer patients and sulforaphane-enriched broccoli sprouts have now been initiated in the United States.

  16. Chemoprevention of Colon Cancer in a Rat Carcinogenesis Model Using a Novel Nanotechnology-based Combined Treatment System

    PubMed Central

    Chaudhary, Abhishek; Sutaria, Dhruvitkumar; Huang, Ying; Wang, Jeffrey; Prabhu, Sunil

    2011-01-01

    Colorectal cancer (CRC) is the third most common cause of cancer death in the US, accounting for ~51,000 deaths each year. We have previously shown in vitro chemopreventive effects of mixtures of aspirin, folic acid and calcium (AFAC) on colon cancer cell lines. The objective of the present study was to evaluate the in vivo effects of orally administered, colon targeted chemopreventive combination regimens on the inhibition of aberrant crypt foci (ACF) in a rat model of colon carcinogenesis using (1) unmodified (free drug) combinations of AFAC, and (2) nanoparticle-encapsulated combinations of the same agents. A 14-week animal study was conducted in three phases to determine an optimal effective dose from AFAC combinations and evaluate the efficacy of nanotechnology-based chemopreventive regimens administered in combined (mixtures), and individual (single entity) forms. ACF inhibition when compared to azoxymethane (AOM)-treated rat control group was significant in both, the unmodified and the modified nanoparticle-mediated chemopreventive regimens, demonstrating a range of 31 – 38% (p < 0.05) and 50 – 75% (p < 0.001) reduction respectively, in the number of ACFs. In addition, the nanoparticulate combination regimens of AFAC demonstrated a 2-fold increase in suppression of ACF compared to free drug mixtures. Individual administration of nanoparticle encapsulated drugs showed no significant effect on the reduction of ACF. Histochemical analysis provided further confirmation of chemopreventive effects, demonstrating a significant reduction in cell nuclear proliferation. Overall, our results provide a strong proof-of-concept using nanoparticle-mediated combination treatment in the chemoprevention of colon cancer. PMID:21914855

  17. Chemoprevention by grape seed extract and genistein in carcinogen-induced mammary cancer in rats is diet dependent.

    PubMed

    Kim, Helen; Hall, Patti; Smith, Michelle; Kirk, Marion; Prasain, Jeevan K; Barnes, Stephen; Grubbs, Clinton

    2004-12-01

    Many popular dietary supplements are enriched in polyphenols such as the soy isoflavones, tea catechins, and resveratrol (from grape skins), each of which has been shown to have chemopreventive activity in cellular models of cancer. The proanthocyanidins, which are oligomers of the catechins, are enriched in grape seeds and form the basis of the dietary supplement grape seed extract (GSE). Evidence suggests that the proanthocyanidins may be metabolized to the monomeric catechins. This study was carried out to determine whether GSE added to rodent diets protected against carcinogen-induced mammary tumorigenesis in rats and whether this was affected by the composition of the whole diet. Female rats were begun on 5%, 1.25%, or 0% (control) GSE-supplemented diets at age 35 d. At age 50 d they were administered 7,12-dimethylbenz[a]anthracene (DMBA) in sesame oil at 80 mg/kg body weight. They were weighed and monitored weekly for tumor development until 120 d after DMBA administration. Administration of GSE in AIN-76A diet did not show any protective activity of GSE against DMBA-induced breast cancer. However, administration of GSE in a laboratory dry food diet (Teklad 4% rodent diet) resulted in a 50% reduction in tumor multiplicity. In similar experiments, genistein administered in AIN-76A diet also failed to show chemopreventive activity against the carcinogen N-methyl-N-nitrosourea; however, when administered at the same dose in the Teklad 4% rodent diet, genistein exhibited significant chemopreventive activity (44-61%). These results demonstrate that GSE is chemopreventive in an animal model of breast cancer; moreover, the diet dependency of the chemopreventive activity for both GSE and genistein suggests that whether or not a compound is chemopreventive may depend on the diet in which the agent is administered.

  18. Biomarkers of Selenium Chemoprevention of Prostate Cancer

    DTIC Science & Technology

    2003-01-01

    C 134 2.1 MCM6 0.5 receptor of retinoic acid 5.0 Ki67a 0.2 dual spec ificity phosphatase MKP-S 6.4 DNA prisnose 0.4 caltnodulin-dependent protein...to impaired function of the endoplasmic reticulum, Genes Dev., 12: 982-995, 1998. methylseleninic acid : evidence that a monomethylated selenium ...AD_____ Award Number: DAMD17-02-1-0134 TITLE: Biomarkers of Selenium Chemoprevention of Prostate Cancer PRINCIPAL INVESTIGATOR: Yan Dong, Ph.D

  19. Sulforaphane prevents quinolinic acid-induced mitochondrial dysfunction in rat striatum.

    PubMed

    Luis-García, Erika Rubí; Limón-Pacheco, Jorge Humberto; Serrano-García, Norma; Hernández-Pérez, Alma Delia; Pedraza-Chaverri, José; Orozco-Ibarra, Marisol

    2017-02-01

    Quinolinic acid (QA) triggers striatal neuronal death by an excitotoxic cascade that involves oxidative stress, which in turns is tightly linked to mitochondria. Mitochondrial dysfunction is a molecular feature described in several brain pathologies. In this work, we determined whether the sulforaphane-neuroprotective effect in the rodent experimental model of Huntington's disease induced by QA is associated with mitochondrial function preservation. We found that QA impaired mitochondrial function within 24 h post-lesion. Sulforaphane effectively disrupted the mitochondrial dysfunction by preventing the decrease in respiratory control ratio, transmembrane potential, ability to synthetize ATP, and the activity of mitochondrial complexes I, II, and IV. © 2016 Wiley Periodicals, Inc.

  20. 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

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

    PubMed

    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.

  2. Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor, which disrupts tubulin polymerization.

    PubMed

    Jackson, Steven J T; Singletary, Keith W

    2004-02-01

    Sulforaphane (SUL), an isothiocyanate found in broccoli and other cruciferous vegetables, has been shown to induce phase II detoxification enzymes, inhibit chemically induced mammary tumors in rats, and more recently to induce cell cycle arrest and apoptosis in cancer cells of the colon. Here, we provide evidence that SUL also acts as a breast cancer anti-proliferative agent. The BALB/c mouse mammary carcinoma cell line F3II was treated with SUL at concentrations up to 15 microM and examined for markers of cell cycle arrest and apoptosis. Treatment of asynchronous F3II cells with 15 microM SUL resulted in G2/M cell cycle arrest, elevated p34cdc2 (cdc2) kinase activity, Bcl-2 down-regulation, evidence of caspase activation, and aggregation of condensed nuclear chromatin. Subsequent exposure of synchronized cells to 15 microM SUL resulted in elevated numbers of prophase/prometaphase mitotic figures, indicating cell cycle progression beyond G2 and arrest early within mitosis. Moreover, cells treated with 15 microM SUL displayed aberrant mitotic spindles, and higher doses of SUL inhibited tubulin polymerization in vitro. In addition, BALB/c mice injected s.c. with F3II cells and subsequently injected daily i.v. with SUL (15 nmol/day for 13 days) developed significantly smaller tumors (approximately 60% less in mass) than vehicle-treated controls. Western blot analysis of tumor proteins demonstrated significantly (P<0.05) reduced PCNA and elevated PARP fragmentation in samples from animals dosed with SUL. Taken together, these results indicate that SUL has mammary cancer suppressive actions both in cell culture and in the whole animal. Inhibition of mammary carcinogenesis appears in part to involve perturbation of mitotic microtubules and early M-phase block associated with cdc2 kinase activation, indicating that cells arrest prior to metaphase exit.

  3. Photothrombosis-induced infarction of the mouse cerebral cortex is not affected by the Nrf2-activator sulforaphane.

    PubMed

    Porritt, Michelle J; Andersson, Helene C; Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

    2012-01-01

    Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage.

  4. Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells

    PubMed Central

    LI, BO; KIM, DO SUNG; YADAV, RAJ KUMAR; KIM, HYUNG RYONG; CHAE, HAN JUNG

    2015-01-01

    Sulforaphane, a natural isothiocyanate compound found in cruciferous vegetables, has been shown to exert cardioprotective effects during ischemic heart injury. However, the effects of sulforaphane on cardiotoxicity induced by doxorubicin are unknown. Thus, in the present study, H9c2 rat myoblasts were pre-treated with sulforaphane and its effects on cardiotoxicity were then examined. The results revealed that the pre-treatment of H9c2 rat myoblasts with sulforaphane decreased the apoptotic cell number (as shown by trypan blue exclusion assay) and the expression of pro-apoptotic proteins (Bax, caspase-3 and cytochrome c; as shown by western blot analysis and immunostaining), as well as the doxorubicin-induced increase in mitochondrial membrane potential (measured by JC-1 assay). Furthermore, sulforaphane increased the mRNA and protein expression of heme oxygenase-1 (HO-1, measured by RT-qPCR), which consequently reduced the levels of reactive oxygen species (ROS, measured using MitoSOX Red reagent) in the mitochondria which were induced by doxorubicin. The cardioprotective effects of sulforaphane were found to be mediated by the activation of the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor-2 (Nrf2)/antioxidant-responsive element (ARE) pathway, which in turn mediates the induction of HO-1. Taken together, the findings of this study demonstrate that sulforaphane prevents doxorubicin-induced oxidative stress and cell death in H9c2 cells through the induction of HO-1 expression. PMID:25936432

  5. Photothrombosis-Induced Infarction of the Mouse Cerebral Cortex Is Not Affected by the Nrf2-Activator Sulforaphane

    PubMed Central

    Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

    2012-01-01

    Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage. PMID:22911746

  6. Sulforaphane Potentiates the Efficacy of 17-Allylamino 17-Demethoxygeldanamycin Against Pancreatic Cancer Through Enhanced Abrogation of Hsp90 Chaperone Function

    PubMed Central

    Li, Yanyan; Zhang, Tao; Schwartz, Steven J.; Sun, Duxin

    2013-01-01

    Heat shock protein 90 (Hsp90), an essential molecular chaperone that regulates the stability of a wide range of oncogenic proteins, is a promising target for cancer therapeutics. We investigated the combination efficacy and potential mechanisms of sulforaphane, a dietary component from broccoli and broccoli sprouts, and 17-allylamino 17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, in pancreatic cancer. MTS assay demonstrated that sulforaphane sensitized pancreatic cancer cells to 17-AAG in vitro. Caspase-3 was activated to 6.4-fold in response to simultaneous treatment with sulforaphane and 17-AAG, whereas 17-AAG alone induced caspase-3 activity to 2-fold compared to control. ATP binding assay and coimmunoprecipitation revealed that sulforaphane disrupted Hsp90-p50Cdc37 interaction, whereas 17-AAG inhibited ATP binding to Hsp90. Concomitant use of sulforaphane and 17-AAG synergistically downregulated Hsp90 client proteins in Mia Paca-2 cells. Co-administration of sulforaphane and 17-AAG in pancreatic cancer xenograft model led to more than 70% inhibition of the tumor growth, whereas 17-AAG alone only suppressed the tumor growth by 50%. Our data suggest that sulforaphane potentiates the efficacy of 17-AAG against pancreatic cancer through enhanced abrogation of Hsp90 function. These findings provide a rationale for further evaluation of broccoli/broccoli sprout preparations combined with 17-AAG for better efficacy and lower dose-limiting toxicity in pancreatic cancer. PMID:21875325

  7. Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells.

    PubMed

    Li, Bo; Kim, Do Sung; Yadav, Raj Kumar; Kim, Hyung Ryong; Chae, Han Jung

    2015-07-01

    Sulforaphane, a natural isothiocyanate compound found in cruciferous vegetables, has been shown to exert cardioprotective effects during ischemic heart injury. However, the effects of sulforaphane on cardiotoxicity induced by doxorubicin are unknown. Thus, in the present study, H9c2 rat myoblasts were pre-treated with sulforaphane and its effects on cardiotoxicity were then examined. The results revealed that the pre-treatment of H9c2 rat myoblasts with sulforaphane decreased the apoptotic cell number (as shown by trypan blue exclusion assay) and the expression of pro-apoptotic proteins (Bax, caspase-3 and cytochrome c; as shown by western blot analysis and immunostaining), as well as the doxorubicin-induced increase in mitochondrial membrane potential (measured by JC-1 assay). Furthermore, sulforaphane increased the mRNA and protein expression of heme oxygenase-1 (HO-1, measured by RT-qPCR), which consequently reduced the levels of reactive oxygen species (ROS, measured using MitoSOX Red reagent) in the mitochondria which were induced by doxorubicin. The cardioprotective effects of sulforaphane were found to be mediated by the activation of the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor-2 (Nrf2)/antioxidant-responsive element (ARE) pathway, which in turn mediates the induction of HO-1. Taken together, the findings of this study demonstrate that sulforaphane prevents doxorubicin-induced oxidative stress and cell death in H9c2 cells through the induction of HO-1 expression.

  8. Sulforaphane induces adipocyte browning and promotes glucose and lipid utilization

    PubMed Central

    Zhang, Hui Q.; Chen, Shi Y.; Wang, An S.; Yao, An J.; Fu, Jian F.; Zhao, Jin S.; Chen, Fen; Zou, Zu Q.; Shan, Yu J.; Bao, Yong P.

    2016-01-01

    1 Scope Obesity is closely related to the imbalance of white adipose tissue storing excess calories, and brown adipose tissue dissipating energy to produce heat in mammals. Recent studies revealed that acquisition of brown characteristics by white adipocytes, termed “browning,” may positively contribute to cellular bioenergetics and metabolism homeos