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Sample records for activities including anti-tumor

  1. Blocking IDO activity to enhance anti-tumor immunity.

    PubMed

    Munn, David H

    2012-01-01

    Tumors express potentially immunogenic antigens, yet the immune response to these antigens is typically profoundly suppressed. Patients with established tumors behave as if they were functionally tolerant to any antigens associated with the tumor. This tolerance reflects a process of active immune suppression elicited by the tumor, and represents a critical barrier to successful anti-tumor immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is a natural immunoregulatory mechanism contributes to immune suppression and tolerance in a variety of settings. In tumor-bearing hosts, animal models suggest that tumor-induced IDO helps create a tolerogenic milieu within the tumor and the associated tumor-draining lymph nodes. IDO directly suppresses the proliferation and differentiation of effector T cells, and markedly enhances the suppressor activity of regulatory T cells (Tregs). Together, these effects contribute to the inability of the immune system to respond effectively to tumor antigens. Treatment of tumor-bearing animals with IDO-inhibitor drugs enhances anti-tumor immune responses, and IDO-inhibitors are synergistic with a variety of chemotherapeutic drugs, anti-tumor vaccines and other immunotherapy. Strategies to pharmacologically inhibit IDO may thus enhance immune-mediated responses following conventional chemotherapy, and may be synergistic with other forms of immunotherapy.

  2. Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

    PubMed Central

    Qi, Quan; Li, Rui; Li, Hui-ying; Cao, Yu-bing; Bai, Ming; Fan, Xiao-jing; Wang, Shu-yan; Zhang, Bo; Li, Shao

    2016-01-01

    Aim: Nuciferine is an aporphine alkaloid extracted from lotus leaves, which is a raw material in Chinese medicinal herb for weight loss. In this study we used a network pharmacology approach to identify the anti-tumor activity of nuciferine and the underlying mechanisms. Methods: The pharmacological activities and mechanisms of nuciferine were identified through target profile prediction, clustering analysis and functional enrichment analysis using our traditional Chinese medicine (TCM) network pharmacology platform. The anti-tumor activity of nuciferine was validated by in vitro and in vivo experiments. The anti-tumor mechanisms of nuciferine were predicted through network target analysis and verified by in vitro experiments. Results: The nuciferine target profile was enriched with signaling pathways and biological functions, including “regulation of lipase activity”, “response to nicotine” and “regulation of cell proliferation”. Target profile clustering results suggested that nuciferine to exert anti-tumor effect. In experimental validation, nuciferine (0.8 mg/mL) markedly inhibited the viability of human neuroblastoma SY5Y cells and mouse colorectal cancer CT26 cells in vitro, and nuciferine (0.05 mg/mL) significantly suppressed the invasion of 6 cancer cell lines in vitro. Intraperitoneal injection of nuciferine (9.5 mg/mL, ip, 3 times a week for 3 weeks) significantly decreased the weight of SY5Y and CT26 tumor xenografts in nude mice. Network target analysis and experimental validation in SY5Y and CT26 cells showed that the anti-tumor effect of nuciferine was mediated through inhibiting the PI3K-AKT signaling pathway and IL-1 levels in SY5Y and CT26 cells. Conclusion: By using a TCM network pharmacology method, nuciferine is identified as an anti-tumor agent against human neuroblastoma and mouse colorectal cancer in vitro and in vivo, through inhibiting the PI3K-AKT signaling pathways and IL-1 levels. PMID:27180984

  3. Anti-tumor activity of safranal against neuroblastoma cells

    PubMed Central

    Samarghandian, Saeed; Shoshtari, Mohammad Ebrahim; Sargolzaei, Javad; Hossinimoghadam, Hosna; Farahzad, Jabbari Azad

    2014-01-01

    Objective: Safranal (2,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehyde, C10H14O) is an active ingredient in the saffron, which is used in traditional medicine, and also, the biological activity of saffron in anti-cancer is in development. It has been reported to have anti-oxidant effects, but its anti-tumor effects remain uncertain. The aim of this study was to evaluate effects of safranal on anti-tumor on neuroblastoma cells. Materials and Methods: Neuroblastoma cells were cultured and exposed to safranal (0, 10, 15, 20, 50 μg/ml). Cell proliferation was examined using the 3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Apoptotic cells, cell cycle distribution, and sub-G1 fraction were analyzed using flow cytometric analysis after propidium iodide staining. Results: Safranal inhibited the growth of malignant cells in a dose-and time-dependent manner. The IC (50) values against the neuroblastoma cell line were determined as 11.1 and 23.3 μg/ml after 24 and 48 h, respectively. Safranal induced a sub-G1 peak in the flow cytometry histogram of treated cells compared to control cells indicating that apoptotic cell death is involved in safranal toxicity. Conclusions: Our pre-clinical study demonstrated a neuroblastoma cell line to be highly sensitive to safranal-mediated growth inhibition and apoptotic cell death. Although the molecular mechanisms of safranal action are not yet clearly understood, it appears to have potential as a therapeutic agent. PMID:24991121

  4. Anti-tumor activity of a polysaccharide from blueberry.

    PubMed

    Sun, Xiyun; Liu, Ning; Wu, Zhaoxia; Feng, Ying; Meng, Xianjun

    2015-01-01

    Blueberries (Vaccinium spp.) are rich in bioactive compounds. However, the biological activity of polysaccharides from blueberry has not been reported so far. This study evaluated the anti-tumor and immunological activities of a polysaccharide (BBP3-1) from blueberry in S180-bearing mice. The experimental results indicated that BBP3-1 (100 mg·kg-1·d-1) inhibited the tumor growth rate by 73.4%. Moreover, this group, compared with the model control, had shown an effect of increasing both the spleen and thymus indices (p < 0.05), increasing phagocytosis by macrophages (p < 0.05), boosting the proliferation and transformation of lymphocytes (p < 0.01), promoting the secretion of TNF-α, IFN-γ, and IL-2 (p < 0.05) and improving NK cell activity (p < 0.01). From this study, we could easily conclude that BBP3-1 has the ability to inhibit tumor progression and could act as a good immunomodulator.

  5. Anti-tumor activity of a polysaccharide from blueberry.

    PubMed

    Sun, Xiyun; Liu, Ning; Wu, Zhaoxia; Feng, Ying; Meng, Xianjun

    2015-01-01

    Blueberries (Vaccinium spp.) are rich in bioactive compounds. However, the biological activity of polysaccharides from blueberry has not been reported so far. This study evaluated the anti-tumor and immunological activities of a polysaccharide (BBP3-1) from blueberry in S180-bearing mice. The experimental results indicated that BBP3-1 (100 mg·kg-1·d-1) inhibited the tumor growth rate by 73.4%. Moreover, this group, compared with the model control, had shown an effect of increasing both the spleen and thymus indices (p < 0.05), increasing phagocytosis by macrophages (p < 0.05), boosting the proliferation and transformation of lymphocytes (p < 0.01), promoting the secretion of TNF-α, IFN-γ, and IL-2 (p < 0.05) and improving NK cell activity (p < 0.01). From this study, we could easily conclude that BBP3-1 has the ability to inhibit tumor progression and could act as a good immunomodulator. PMID:25734419

  6. Anti-tumor activity of splice-switching oligonucleotides

    PubMed Central

    Bauman, John A.; Li, Shyh-Dar; Yang, Angela; Huang, Leaf; Kole, Ryszard

    2010-01-01

    Alternative splicing has emerged as an important target for molecular therapies. Splice-switching oligonucleotides (SSOs) modulate alternative splicing by hybridizing to pre-mRNA sequences involved in splicing and blocking access to the transcript by splicing factors. Recently, the efficacy of SSOs has been established in various animal disease models; however, the application of SSOs against cancer targets has been hindered by poor in vivo delivery of antisense therapeutics to tumor cells. The apoptotic regulator Bcl-x is alternatively spliced to express anti-apoptotic Bcl-xL and pro-apoptotic Bcl-xS. Bcl-xL is upregulated in many cancers and is associated with chemoresistance, distinguishing it as an important target for cancer therapy. We previously showed that redirection of Bcl-x pre-mRNA splicing from Bcl-xL to -xS induced apoptosis in breast and prostate cancer cells. In this study, the effect of SSO-induced Bcl-x splice-switching on metastatic melanoma was assessed in cell culture and B16F10 tumor xenografts. SSOs were delivered in vivo using lipid nanoparticles. Administration of nanoparticle with Bcl-x SSO resulted in modification of Bcl-x pre-mRNA splicing in lung metastases and reduced tumor load, while nanoparticle alone or formulated with a control SSO had no effect. Our findings demonstrate in vivo anti-tumor activity of SSOs that modulate Bcl-x pre-mRNA splicing. PMID:20719743

  7. [Primary research on anti-tumor activity of panaxadiol fatty acid esters].

    PubMed

    Zhang, Chun-Hong; Zhang, Lian-Xue; Li, Xiang-Gao; Gao, Yu-Gang; Liu, Ya-Jing

    2006-11-01

    For making use of Ginseng resources and finding new anti-tumor drugs, the anti-tumor activity of three kinds of new panaxadiol fatty acid ester derivates: 3beta-acetoxy panaxadiol (I), 3beta-palmitic acid aceloxy panaxadiol (II), 3beta-octadecanoic acid aceloxy panaxadiol (Ill) and panaxaiol were compared through the method of cell stain and counting. Tumor cell was Vero cell line. Positive control was 5-FU. Blank was RPM11640 culture medium. Negative control was RPM11640 culture medium and the solvent for subjected drugs. The result showed that compound I had the strongest anti-tumor activity, second was panaxadiol, II and III had the same and the weakest antitumor activity. Furthermore, the anti-tumor activities of panaxadiol fatty acid ester derivates showed positive correlation with subjects' concentrations, but no relationship with molecular weight of fatty acid. PMID:17228662

  8. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity.

    PubMed

    Geiger, Roger; Rieckmann, Jan C; Wolf, Tobias; Basso, Camilla; Feng, Yuehan; Fuhrer, Tobias; Kogadeeva, Maria; Picotti, Paola; Meissner, Felix; Mann, Matthias; Zamboni, Nicola; Sallusto, Federica; Lanzavecchia, Antonio

    2016-10-20

    Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity. Proteome-wide probing of structural alterations, validated by the analysis of knockout T cell clones, identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells that are crucial for anti-tumor responses.

  9. Anti-tumor activity of benzylideneacetophenone derivatives via proteasomal inhibition in prostate cancer cells.

    PubMed

    Lee, Yun-hee; Yun, Jaesuk; Jung, Jae-Chul; Oh, Seikwan; Jung, Young-Suk

    2016-05-01

    A number of some chalcone derivatives possess promising biological properties including anti-inflammation, anti-oxidant, and anti-tumor activity. Although it has been shown that some derivatives of chalcone induce apoptosis in different kinds of cancer cells, the involved mechanism of action is not well defined. The purpose of this study is to investigate the primary target of a benzylideneacetophenone derivative (JC3), which is a synthetic compound derived from the chalcone family, in human cancer, using prostate cancer cells as a working model. Herein, we show that JC3 inhibits proteasomal activity as indicated by both in vitro and in cell-based assays. Especially, the JC3-dimer was more potent than monomer in the aspect of proteasome inhibition, which induced apoptosis significantly in the prostate cancer cells. Owing to the critical roles of the proteasome in the biology of human tumor progression, invasion, and metastasis, these findings give an important clue for the development of novel anti-tumor agents. PMID:27348972

  10. Anti-microorganism, anti-tumor, and immune activities of a novel polysaccharide isolated from Tricholoma matsutake

    PubMed Central

    Hou, Yiling; Ding, Xiang; Hou, Wanru; Zhong, Jie; Zhu, Hongqing; Ma, Binxiang; Xu, Ting; Li, Junhua

    2013-01-01

    Background: Many more fungal polysaccharides have been reported to exhibit a variety of biological activities, including anti-tumor, immunostimulation, anti-oxidation, and so on. The non-starch polysaccharides have emerged as an important class of bioactive natural products. Objective: To investigate the anti-microorganism, anti-tumor, and immune activities of a novel polysaccharide (TMP-A) isolated from Tricholoma matsutake. Materials and Methods: The anti-microorganism activity of purified polysaccharides (TMP-A) was evaluated by the inhibition zone diameter, the anti-tumor activity was evaluated by the S180 tumor cells that were implanted subcutaneously into the Kunming strain male mice in vivo, and the immune activity was evaluated by lymphocyte proliferation and macrophage stimulation, respectively. Results: In this study, the most susceptible bacteria of TMP-A at a concentration of 20 mg/ml was Micrococcus lysodeikticus (inhibition zone diameter 24.38 ± 1.19 mm) and the TMP-A did not show any antifungal activity for the tested stains of the fungi. In addition, the inhibitory rate in mice treated with 80 mg/kg TMP-A could reach 68.422%, being the highest in the three doses, which might be comparable to mannatide. The anti-tumor activity of the TMP-A was usually believed to be a consequence of the stimulation of the cell-mediated immune response, because it could significantly promote the lymphocyte and macrophage cells in the dose range of 50–200 μg/mL and in the dose range of 100 – 400 μg/mL in vitro, respectively. Discussion and Conclusion: The results obtained in the present study indicate that the purification polysaccharide of Tricholoma matsutake is a potential source of natural broad-spectrum, anti-microorganism, anti-tumor, and immunomodulation. PMID:23930009

  11. Enhancement of anti-tumor activity of natural killer cells by BALL-1, a B cell lymphoma line.

    PubMed

    Hirashima, M; Yoshida, N; Seki, M; Okada, H; Takamura, S; Mihara, Y

    1998-04-01

    The anti-tumor activity of human peripheral blood mononuclear cells (PBMC) against various tumor cell line cells (K562, Daudi, KMG-2, and KATOIII) was enhanced by coculture with irradiated BALL-1, but not with other irradiated B cell line cells (NALM-1, Namalwa, and Daudi). PBMC cocultured with BALL-1, however, failed to exhibit evident cytotoxicity against autologous concanavalin A-induced lymphoblasts. The enhancement of the anti-tumor activity seemed not to be correlated with EBNA and HLA-DR expression on B cell line cells. Monoclonal antibodies (mAbs) against interleukin (IL)-2, interferon-gamma, IL-12, IL-15, tumor necrosis factor-alpha and lymphotoxin showed little or no suppression of the anti-tumor activity of PBMC treated with irradiated BALL-1. Furthermore, the culture supernatants of BALL-1 failed to enhance the anti-tumor activity of PBMC, suggesting no involvement of soluble factors in the induction of the anti-tumor activity. The anti-tumor activity of PBMC treated with BALL-1 was synergistically enhanced by an additional IL-2 stimulation. Periodate-lysine-paraformaldehyde-fixed, but not ethanol- or acetone-fixed, BALL-1 could significantly enhance the anti-tumor activity. Furthermore, BALL-1-derived membrane fraction, but not that of Daudi, enhances the anti-tumor activity. It was thus suggested that some membrane glycoproteins on the cell surface of BALL-1 play a crucial role in the induction of the anti-tumor activity. By analysis using mAbs against human leukocytes, we found that depletion of CD11b, CD16, and CD56-positive cells resulted in decreased anti-tumor activity, suggesting that the main effector cells in the BALL-1-induced anti-tumor activity were natural killer (NK) cells. The present results thus raise the possibility that BALL-1, probably via membrane glycoproteins, modulates NK cell-mediated anti-tumor activity. PMID:9617349

  12. A new cell counting method to evaluate anti-tumor compound activity.

    PubMed

    Wang, Xue-Jian; Zhang, Xiu-Rong; Zhang, Lei; Li, Qing-Hua; Wang, Lin; Shi, Li-Hong; Fang, Chun-Yan

    2014-01-01

    Determining cell quantity is a common problem in cytology research and anti-tumor drug development. A simple and low-cost method was developed to determine monolayer and adherent-growth cell quantities. The cell nucleus is located in the cytoplasm, and is independent. Thus, the nucleus cannot make contact even if the cell density is heavy. This phenomenon is the foundation of accurate cell-nucleus recognition. The cell nucleus is easily recognizable in images after fluorescent staining because it is independent. A one-to-one relationship exists between the nucleus and the cell; therefore, this method can be used to determine the quantity of proliferating cells. Results indicated that the activity of the histone deacetylase inhibitor Z1 was effective after this method was used. The nude-mouse xenograft model also revealed the potent anti-tumor activity of Z1. This research presents a new anti-tumor-drug evaluation method.

  13. Ganoderma lucidum polysaccharide exerts anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells.

    PubMed

    Yang, Guohua; Yang, Lei; Zhuang, Yun; Qian, Xifeng; Shen, Yunfeng

    2016-01-01

    In this study, we investigated the anti-tumor activity both in vitro and in vivo of a polysaccharide obtained from Ganoderma lucidum on HL-60 acute myeloid leukemia cells, and focused on its targeting effect on mitogen-activated protein kinase (MAPK) pathways. It was found by the methods such as western blot and flow cytometry (FCM), that G. lucidum polysaccharide (GLP) blocked the extracellular signal-regulated kinase/MAPK signaling pathway, simultaneously activated p38 and JNK MAPK pathways, and therefore regulated their downstream genes and proteins, including p53, c-myc, c-fos, c-jun, Bcl-2, Bax, cleaved caspase-3 and cyclin D1. As a result, cycle arrest and apoptosis of HL-60 cells were induced. Therefore, GLP exerted anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells.

  14. Anti-tumor activities of triterpenes from Syzygium kusukusense.

    PubMed

    Bai, Li-Yuan; Lin, Wei-Yu; Chiu, Chang-Fang; Weng, Jing-Ru

    2014-11-01

    In this study, we report the isolation from the stem of Syzygium kusukusense of five triterpenes, 2α-hydroxybetulinic acid (1), betulinic acid (2), platanic acid (3), ursolic acid (4), and hyptatic acid A (5). All were identified for the first time from this indigenous plant of Taiwan. Assessment of the cytotoxic activities of these compounds against a panel of human tumor cell lines, including MCF-7 breast, PC-3 prostate, and SCC2095 oral squamous cell cancers, revealed the high potency of compounds 1 (IC50, 5.7 - 7.6 μM) and, especially, 4 (IC50, 1.7 - 3.7 μM) in suppressing cell viability, which warrants further mechanistic investigations.

  15. Gamma-irradiated bacterial preparation having anti-tumor activity

    DOEpatents

    Vass, Arpad A.; Tyndall, Richard L.; Terzaghi-Howe, Peggy

    1999-01-01

    A bacterial preparation from Pseudomonas species isolated #15 ATCC 55638 that has been exposed to gamma radiation exhibits cytotoxicity that is specific for neoplastic carcinoma cells. A method for obtaining a bacterial preparation having antitumor activity consists of suspending a bacterial isolate in media and exposing the suspension to gamma radiation. A bacterial preparation of an aged culture of an amoeba-associated bacteria exhibits anti-reverse transcriptase activity. A method for obtaining a bacterial preparation having anti-reverse transcriptase activity from an amoeba-associated bacterial isolate grown to stationary phase is disclosed.

  16. Gamma-irradiated bacterial preparation having anti-tumor activity

    SciTech Connect

    Vass, A.A.; Tyndall, R.L.; Terzaghi-Howe, P.

    1999-11-16

    This application describes a bacterial preparation from Pseudomonas species isolated {number{underscore}sign}15 ATCC 55638 that has been exposed to gamma radiation exhibits cytotoxicity that is specific for neoplastic carcinoma cells. A method for obtaining a bacterial preparation having antitumor activity consists of suspending a bacterial isolate in media and exposing the suspension to gamma radiation. A bacterial preparation of an aged culture of an amoeba-associated bacteria exhibits anti-reverse transcriptase activity. A method for obtaining a bacterial preparation having anti-reverse transcriptase activity from an amoeba-associated bacterial isolate grown to stationary phase is disclosed.

  17. [Novel derivatives of diosgenin: design, synthesis and anti-tumor activity].

    PubMed

    Ding, Xiao-Yong; He, Gu; Jiang, Hong-Ping; Wan, Jian-Fei; Fan, Ju-Zheng

    2012-04-01

    Diosgenin can inhibit the growth of A375 and K562 cell lines and induce their apoptosis with an effect on pro-apoptotic members of Bcl-2 family. To study the SAR of diosgenin derivatives, and to improve the anti-tumor activity of diosgenin, a series of novel diosgenin derivatives were designed and synthesized. Their anti-tumor activities in vitro were evaluated. The results revealed that most of the new derivatives had potent effects against K562, A375 and A549 (three tumor cell lines) in vitro, and had no or less effect against H293 and L02 (two normal cell lines). Particularly, some compounds (e.g. 1, 6-8) showed excellent activities on K562 with IC50 values ranging from 1.96 to 4.35 micromol x L(-1).

  18. The antimicrobial peptide pardaxin exerts potent anti-tumor activity against canine perianal gland adenoma

    PubMed Central

    Pan, Chieh-Yu; Lin, Chao-Nan; Chiou, Ming-Tang; Yu, Chao Yuan; Chen, Jyh-Yih; Chien, Chi-Hsien

    2015-01-01

    Pardaxin is an antimicrobial peptide of 33 amino acids, originally isolated from marine fish. We previously demonstrated that pardaxin has anti-tumor activity against murine fibrosarcoma, both in vitro and in vivo. In this study, we examined the anti-tumor activity, toxicity profile, and maximally-tolerated dose of pardaxin treatment in dogs with different types of refractory tumor. Local injection of pardaxin resulted in a significant reduction of perianal gland adenoma growth between 28 and 38 days post-treatment. Surgical resection of canine histiocytomas revealed large areas of ulceration, suggesting that pardaxin acts like a lytic peptide. Pardaxin treatment was not associated with significant variations in blood biochemical parameters or secretion of immune-related proteins. Our findings indicate that pardaxin has strong therapeutic potential for treating perianal gland adenomas in dogs. These data justify the veterinary application of pardaxin, and also provide invaluable information for veterinary medicine and future human clinical trials. PMID:25544775

  19. Anti-tumor-promoting activities of selected pungent phenolic substances present in ginger.

    PubMed

    Surh, Y J; Park, K K; Chun, K S; Lee, L J; Lee, E; Lee, S S

    1999-01-01

    Ginger (Zingiber officinale Roscoe, Zingiberaceae) has been widely used as a dietary spice, as well as in traditional oriental medicine. The rhizome of ginger contains pungent vanillyl ketones, including [6]-gingerol and [6]-paradol, and has been reported to possess a strong anti-inflammatory activity. These pungent substances have a vanilloid structure found in other chemopreventive phytochemicals, including curcumin. In our study, we found anti-tumor-promoting properties of [6]-gingerol and [6]-paradol. Thus, topical application of [6]-gingerol or [6]-paradol 30 min prior to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) attenuated the skin papillomagenesis initiated by 7,12-dimethylbenz[a]anthracene in female ICR mice. These substances also significantly inhibited the tumor-promoter-stimulated inflammation, TNF-alpha production, and activation of epidermal ornithine decarboxylase in mice. In another study, [6]-gingerol and [6]-paradol suppressed the superoxide production stimulated by TPA in differentiated HL-60 cells. Taken together, these findings suggest that pungent vanilloids found in ginger possess potential chemopreventive activities. PMID:15281225

  20. Saffron and natural carotenoids: Biochemical activities and anti-tumor effects.

    PubMed

    Bolhassani, Azam; Khavari, Afshin; Bathaie, S Zahra

    2014-01-01

    Saffron, a spice derived from the flower of Crocus sativus, is rich in carotenoids. Two main natural carotenoids of saffron, crocin and crocetin, are responsible for its color. Preclinical studies have shown that dietary intake of some carotenoids have potent anti-tumor effects both in vitro and in vivo, suggesting their potential preventive and/or therapeutic roles in several tissues. The reports represent that the use of carotenoids without the potential for conversion to vitamin A may provide further protection and avoid toxicity. The mechanisms underlying cancer chemo-preventive activities of carotenoids include modulation of carcinogen metabolism, regulation of cell growth and cell cycle progression, inhibition of cell proliferation, anti-oxidant activity, immune modulation, enhancement of cell differentiation, stimulation of cell-to-cell gap junction communication, apoptosis and retinoid-dependent signaling. Taken together, different hypotheses for the antitumor actions of saffron and its components have been proposed such as a) the inhibitory effect on cellular DNA and RNA synthesis, but not on protein synthesis; b) the inhibitory effect on free radical chain reactions; c) the metabolic conversion of naturally occurring carotenoids to retinoids; d) the interaction of carotenoids with topoisomerase II, an enzyme involved in cellular DNA-protein interaction. Furthermore, the immunomodulatory activity of saffron was studied on driving toward Th1 and Th2 limbs of the immune system. In this mini-review, we briefly describe biochemical and immunological activities and chemo-preventive properties of saffron and natural carotenoids as an anticancer drug.

  1. Saffron and natural carotenoids: Biochemical activities and anti-tumor effects.

    PubMed

    Bolhassani, Azam; Khavari, Afshin; Bathaie, S Zahra

    2014-01-01

    Saffron, a spice derived from the flower of Crocus sativus, is rich in carotenoids. Two main natural carotenoids of saffron, crocin and crocetin, are responsible for its color. Preclinical studies have shown that dietary intake of some carotenoids have potent anti-tumor effects both in vitro and in vivo, suggesting their potential preventive and/or therapeutic roles in several tissues. The reports represent that the use of carotenoids without the potential for conversion to vitamin A may provide further protection and avoid toxicity. The mechanisms underlying cancer chemo-preventive activities of carotenoids include modulation of carcinogen metabolism, regulation of cell growth and cell cycle progression, inhibition of cell proliferation, anti-oxidant activity, immune modulation, enhancement of cell differentiation, stimulation of cell-to-cell gap junction communication, apoptosis and retinoid-dependent signaling. Taken together, different hypotheses for the antitumor actions of saffron and its components have been proposed such as a) the inhibitory effect on cellular DNA and RNA synthesis, but not on protein synthesis; b) the inhibitory effect on free radical chain reactions; c) the metabolic conversion of naturally occurring carotenoids to retinoids; d) the interaction of carotenoids with topoisomerase II, an enzyme involved in cellular DNA-protein interaction. Furthermore, the immunomodulatory activity of saffron was studied on driving toward Th1 and Th2 limbs of the immune system. In this mini-review, we briefly describe biochemical and immunological activities and chemo-preventive properties of saffron and natural carotenoids as an anticancer drug. PMID:24269582

  2. The anti-tumor activity of pineal melatonin and cancer enhancing life styles in industrialized societies.

    PubMed

    Bartsch, Christian; Bartsch, Hella

    2006-05-01

    This review discusses the potential role of the anti-tumor activity of pineal melatonin for the aetiology and prevention of cancers related to life-styles in industrialized societies, e.g. frequent long-distance flights as well as chronic night shift work leading to circadian disturbances of neuroendocrine parameters including melatonin. Experimental studies show that melatonin controls not only the growth of well-differentiated cancers, but also possesses anti-carcinogenic properties. Therefore, it is plausible that disturbances of circadian melatonin rhythmicity could be functionally involved in elevated cancer risks among aircrew members and nurses frequently working on night shifts. Due to the suppression of melatonin by light it can be assumed that too much artificial light at night could, at least in part, be responsible for generally increasing rates of e.g. breast cancer in industrialized countries. It is discussed under which conditions a transient substitutional therapy with melatonin could be justified or which forms of living could help to physiologically foster melatonin secretion to optimise control over cancerous growth and development.

  3. Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

    SciTech Connect

    Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

    2014-09-01

    We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti-tumor

  4. Models for anti-tumor activity of bisphosphonates using refined topochemical descriptors.

    PubMed

    Goyal, Rakesh K; Singh, G; Madan, A K

    2011-10-01

    An in silico approach comprising of decision tree (DT), random forest (RF) and moving average analysis (MAA) was successfully employed for development of models for prediction of anti-tumor activity of bisphosphonates. A dataset consisting of 65 analogues of both nitrogen-containing and non-nitrogen-containing bisphosphonates was selected for the present study. Four refinements of eccentric distance sum topochemical index termed as augmented eccentric distance sum topochemical indices 1-4 [formula: see text] have been proposed so as to significantly augment discriminating power. Proposed topological indices (TIs) along with the exiting TIs (>1,400) were subsequently utilized for development of models for prediction of anti-tumor activity of bisphosphonates. A total of 43 descriptors of diverse nature, from a large pool of molecular descriptors, calculated through E-Dragon software (version 1.0) and an in-house computer program were selected for development of suitable models by employing DT, RF and MAA. DT identified two TIs as most important and classified the analogues of the dataset with an accuracy of 97% in training set and 90.7% in tenfold cross-validated set. Random forest correctly classified the analogues with an accuracy of 89.2%. Four independent models developed through MAA predicted the activity of analogues of the dataset with an accuracy of 87.6% to 89%. The statistical significance of proposed models was assessed through intercorrelation analysis, specificity, sensitivity and Matthew's correlation coefficient. The proposed models offer a vast potential for providing lead structures for development of potent anti-tumor agents for treatment of cancer that has spread to the bone.

  5. Models for anti-tumor activity of bisphosphonates using refined topochemical descriptors

    NASA Astrophysics Data System (ADS)

    Goyal, Rakesh K.; Singh, G.; Madan, A. K.

    2011-10-01

    An in silico approach comprising of decision tree (DT), random forest (RF) and moving average analysis (MAA) was successfully employed for development of models for prediction of anti-tumor activity of bisphosphonates. A dataset consisting of 65 analogues of both nitrogen-containing and non-nitrogen-containing bisphosphonates was selected for the present study. Four refinements of eccentric distance sum topochemical index termed as augmented eccentric distance sum topochemical indices 1-4 ( {ξ_{{1c}}^{{ADS}},ξ_{{2c}}^{{ADS}},ξ_{{3c}}^{{ADS}},ξ_{{4c}}^{{ADS}}} ) have been proposed so as to significantly augment discriminating power. Proposed topological indices (TIs) along with the exiting TIs (>1,400) were subsequently utilized for development of models for prediction of anti-tumor activity of bisphosphonates. A total of 43 descriptors of diverse nature, from a large pool of molecular descriptors, calculated through E-Dragon software (version 1.0) and an in-house computer program were selected for development of suitable models by employing DT, RF and MAA. DT identified two TIs as most important and classified the analogues of the dataset with an accuracy of 97% in training set and 90.7% in tenfold cross-validated set. Random forest correctly classified the analogues with an accuracy of 89.2%. Four independent models developed through MAA predicted the activity of analogues of the dataset with an accuracy of 87.6% to 89%. The statistical significance of proposed models was assessed through intercorrelation analysis, specificity, sensitivity and Matthew's correlation coefficient. The proposed models offer a vast potential for providing lead structures for development of potent anti-tumor agents for treatment of cancer that has spread to the bone.

  6. Biodegradable nanoassemblies of piperlongumine display enhanced anti-angiogenesis and anti-tumor activities

    NASA Astrophysics Data System (ADS)

    Liu, Yuanyuan; Chang, Ying; Yang, Chao; Sang, Zitai; Yang, Tao; Ang, Wei; Ye, Weiwei; Wei, Yuquan; Gong, Changyang; Luo, Youfu

    2014-03-01

    Piperlongumine (PL) shows an inhibitory effect on tumor growth; however, lipophilicity has restricted its further applications. Nanotechnology provides an effective method to overcome the poor water solubility of lipophilic drugs. Polymeric micelles with small particle size can passively target tumors by the enhanced permeability and retention (EPR) effect, thus improving their anti-tumor effects. In this study, to improve the water solubility and anti-tumor activity of PL, PL encapsulated polymeric micelles (PL micelles) were prepared by a solid dispersion method. The prepared PL micelles showed a small particle size and high encapsulation efficiency, which could be lyophilized into powder, and the re-dissolved PL micelles are homogenous and stable in water. In addition, a sustained release behavior of PL micelles was observed in vitro. Encapsulation of PL into polymeric micelles could increase the cytotoxicity, cellular uptake, reactive oxygen species (ROS) and oxidized glutathione (GSSG), and reduce glutathione (GSH) levels in vitro. Encapsulation of PL into polymeric micelles enhanced its inhibitory effect on neovascularization both in vitro and in vivo. Compared with free PL, PL micelles showed a stronger inhibitory effect on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). Additionally, in a transgenic zebrafish model, embryonic angiogenesis was inhibited by PL micelles. Furthermore, PL micelles were more effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT-26 murine tumor model in vivo. Therefore, our data revealed that the encapsulation of PL into biodegradable polymeric micelles enhanced its anti-angiogenesis and anti-tumor activities both in vitro and in vivo.

  7. The anti-tumor activity and mechanism of alkaloids from Aconitum szechenyianum Gay.

    PubMed

    Fan, Yunpeng; Jiang, Yuede; Liu, Jianjun; Kang, Yongxiang; Li, Ruiqiao; Wang, Jingyu

    2016-01-15

    In the current study, the anti-tumor activity of Aconitum szechenyianum Gay alkaloids (ASA) and its mechanism of action were investigated. The result showed that ASA could induce apoptosis in HepG-2, Hela and A549 cells but not in normal human embryonic kidney 293A cells, and its apoptotic effect on A549 cells was stronger than those of HepG-2 and Hela cells. Moreover, the following study showed that ASA could up-regulate the expression levels of p38 and phosphorylated p38 MAPK, suggesting ASA-induced apoptosis was associated with the p38 MAPK mediated pathway. Furthermore, ASA could up-regulate TNF-R1 and DR5 via activation of p38 MAPK, thereby activating caspase 8, revealing the death receptor pathway was also involved in this process. In addition, ASA could led to a loss in the mitochondrial out membrane potential, up-regulate p53, phosphorylated p53 and Bax, down-regulate Bcl-2, release cytochrome c from the mitochondria to the cytoplasm, and activate caspase-9 and caspase-3 in A549 cells, which revealed that ASA could also induce apoptosis through the mitochondria mediated pathway. These results suggested that ASA played the anti-tumor role through the activation of p38 MAPK-, death receptor-, mitochondria- and caspase-dependent apoptotic pathways.

  8. A natural diterpenoid kamebacetal A with anti-tumor activity: Theoretical and experimental study

    NASA Astrophysics Data System (ADS)

    Wang, Tao; Tang, Fu-ming; Zhang, Yi-Heng; Chen, Zhong

    2010-06-01

    Kamebacetal A ( 1) is an ent-kaurane diterpenoid isolated from Isodon racemosa (Hemsl) Hara. This natural product exhibits significant cytotoxicity against human Bel-7402 and HO-8910 tumor cells. The geometrical conformation of 1 has been optimized at the B3LYP/6-311+G(d) level of theory. The results indicated that the calculated geometric parameters are close to the X-ray crystal structure. The theoretical 13C NMR chemical shifts of 1 were also calculated at the GIAO-B3LYP level of theory with different basis sets. The calculated NMR chemical shifts are in closer agreement with the experimental results. A molecular electrostatic potential (MEP) map was used in an attempt to identify key features of the kamebacetal A to account for its anti-tumor activity. MEP investigations reveal that compound 1, which shows anti-tumor activity, possesses electron-rich regions that extend over the hydroxyl and carbonyl groups of compound 1. The data generated in this study is valuable as it provides an insight into kamebacetal A molecular and structure-activity relationships.

  9. Tivantinib (ARQ-197) exhibits anti-tumor activity with down-regulation of FAK in oral squamous cell carcinoma

    SciTech Connect

    Xi, Wei-Hong; Yang, Li-Yun; Cao, Zhong-Yi; Qian, Yong

    2015-02-20

    Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide and the 5 years survival rate of the patients is about 60% in the USA, due to acquired chemotherapeutic resistance and metastasis of the disease. In this study, we found that tivantinib, a selective MET inhibitor, suppresses OCSS cell proliferation and colony formation, however, anti-tumor activities induced by tivantinib are independent of the inhibition of MET signaling pathway. In addition, tivantinib cause G2/M cell cycle arrest and caspases-dependent apoptosis in OSCC cell lines. We also found that tivantinib dose-dependently suppressed the activation and expression of FAK. In all, these data suggested that tivantinib may be developed as a chemotherapeutic agent to effectively treat certain cancers including OSCC. - Highlights: • Tivantinib suppresses OSCC cell growth independent of the inhibition of HGF/MET signaling pathway. • Tivantinib blocks cell cycle and induces caspases-mediated apoptosis. • Tivantinib elicits its anti-tumor activity with the inhibition of FAK signaling pathway.

  10. Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Chiang, Po-Chang; Gould, Stephen; Nannini, Michelle; Qin, Ann; Deng, Yuzhong; Arrazate, Alfonso; Kam, Kimberly R.; Ran, Yingqing; Wong, Harvey

    2014-04-01

    Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

  11. [Anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes].

    PubMed

    Li, Xiang; Zhang, Jing; Wang, Dong-Kai; Pan, Wei-San

    2013-07-01

    The anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes (FA-PDCT-L) was investigated in vitro and in vivo. FA-PDCT-L was prepared by organic solvent injection method. Transmission electron microscope, dynamic light scattering and electrophoretic light scattering were employed to study the physicochemical parameters of FA-PDCT-L. The inhibitory effects of docetaxel injection (DCT-I), non-modified DCT liposomes (DCT-L) and FA-PDCT-L on the growth of MCF-7 and A-549 cells at different incubation times were detected by CCK-8 assay; and the hemolytic test was employed in vitro. Tumor mice were randomized into 4 groups: DCT-I, DCT-L, FA-PDCT-L and control group (normal saline), and given drugs at 10 mg x kg(-1) x d(-1) through tail vein. The tumor volume, mice weight, inhibition rate of tumor and life span were measured at the end of experiments. The IC50 of the FA-PDCT-L for MCF-7 and A549 cell lines were significantly lower than that of DCT-I and DCT-L, without hemolysis reaction observed. Compared with control group, the weights of tumor in DCT-I, DCT-L and FA-PDCT-L were decreased, especially for FA-PDCT-L, with inhibitory rates at 79.03 % (P < 0.05). The life span and median survival time of FA-PDCT-L treated mice were significantly higher than that of DCT-I and DCT-L. In conclusion, FA-PDCT-L shows a good anti-tumor activity, indicating that it is potential carriers for DCT in the treatment of tumor.

  12. Anti-tumor activity of CpG-ODN aerosol in mouse lung metastases.

    PubMed

    Sfondrini, Lucia; Sommariva, Michele; Tortoreto, Monica; Meini, Alessandra; Piconese, Silvia; Calvaruso, Marco; Van Rooijen, Nick; Bonecchi, Raffaella; Zaffaroni, Nadia; Colombo, Mario P; Tagliabue, Elda; Balsari, Andrea

    2013-07-15

    Studies in preclinical models have demonstrated the superior anti-tumor effect of CpG oligodeoxynucleotides (CpG-ODN) when administered at the tumor site rather than systemically. We evaluated the effect of aerosolized CpG-ODN on lung metastases in mice injected with immunogenic N202.1A mammary carcinoma cells or weakly immunogenic B16 melanoma cells. Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-γ and IL-1β and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice. Treatment with aerosolized CpG-ODN induced an expansion of CD4+ cells in lung and was more efficacious than systemic i.p. administration against experimental lung metastases of immunogenic N202.1A mammary carcinoma cells, whereas only i.p. delivery of CpG-ODN provided anti-tumor activity, which correlated with NK cell expansion in the lung, against lung metastases of the poorly immunogenic B16 melanoma. The inefficacy of aerosol therapy to induce NK expansion was related to the presence of immunosuppressive macrophages in B16 tumor-bearing lungs, as mice depleted of these cells by clodronate treatment responded to aerosol CpG-ODN through expansion of the NK cell population and significantly reduced numbers of lung metastases. Our results indicate that tumor immunogenicity and the tumor-induced immunosuppressive environment are critical factors to the success of CpG therapy in the lung, and point to the value of routine sampling of the lung immune environment in defining an optimal immunotherapeutic strategy. PMID:23319306

  13. Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

    PubMed

    Trump, Donald L; Hershberger, Pamela A; Bernardi, Ronald J; Ahmed, Sharmilla; Muindi, Josephia; Fakih, Marwan; Yu, Wei-Dong; Johnson, Candace S

    2004-05-01

    1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent. PMID:15225831

  14. Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

    PubMed

    Trump, Donald L; Hershberger, Pamela A; Bernardi, Ronald J; Ahmed, Sharmilla; Muindi, Josephia; Fakih, Marwan; Yu, Wei-Dong; Johnson, Candace S

    2004-05-01

    1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.

  15. Anti-tumor activity and cytotoxicity in vitro of novel 4,5-dialkylimidazolium surfactants.

    PubMed

    Wang, Da; Richter, Christian; Rühling, Andreas; Hüwel, Sabine; Glorius, Frank; Galla, Hans-Joachim

    2015-11-27

    Natural monoalkylated imidazolium derivatives exhibit significant anti-tumor activity as well as general cytotoxicity. In the present study, we used a series of newly synthesized imidazolium derivatives bearing two alkyl chains in the backbone of the imidazolium core in 4- and 5-position and either dimethyl- or dibenzyl-substituents at 1- and 3-position. Their anti-tumor activity and cytotoxicity were determined in vitro using the lactate dehydrogenase (LDH) assay. The tumor cell line C6 from rat glioma, the non-tumor MDCK cell line (Madin-Darby canine kidney) as well as the mouse embryonic fibroblast cell line (NIH3T3) were used as cellular targets. Surface activity measurements were performed leading to the determination of their critical micelle concentration (CMC) of these new lipid analogues to evaluate the molecular mechanism of the observed cellular effects. We found that 4,5-dialkylation of the imidazole ring enhances the anti-tumor activity compared to simple 1-alkylated imidazoles. The corresponding C7 homologues are found to be the most potent compounds. Furthermore dibenzyl-substituted imidazolium surfactants exhibit higher surface activity and increased toxicity against tumor cells compared to dimethyl-substituted imidazolium surfactants. In summary the dibenzyl-derivative carrying the two C7 chains was found to exhibit a drastically increased anti-tumor activity especially compared to so far known monoalkylated species.

  16. Anti-tumor and anti-viral activities of Galanthus nivalis agglutinin (GNA)-related lectins.

    PubMed

    Wu, Lei; Bao, Jin-Ku

    2013-04-01

    Galanthus nivalis agglutinin (GNA)-related lectin family, a superfamily of strictly mannose-binding specific lectins widespread among monocotyledonous plants, is well-known to possess a broad range of biological functions such as anti-tumor, anti-viral and anti-fungal activities. Herein, we mainly focused on exploring the precise molecular mechanisms by which GNA-related lectins induce cancer cell apoptotic and autophagic death targeting mitochondria-mediated ROS-p38-p53 apoptotic or autophagic pathway, Ras-Raf and PI3K-Akt anti-apoptotic or anti-autophagic pathways. In addition, we further discussed the molecular mechanisms of GNA-related lectins exerting anti-viral activities by blocking the entry of the virus into its target cells, preventing transmission of the virus as well as forcing virus to delete glycan in its envelope protein and triggering neutralizing antibody. In conclusion, these findings may provide a new perspective of GNA-related lectins as potential drugs for cancer and virus therapeutics in the future.

  17. Canine parvovirus NS1 protein exhibits anti-tumor activity in a mouse mammary tumor model.

    PubMed

    Gupta, Shishir Kumar; Yadav, Pavan Kumar; Gandham, Ravi Kumar; Sahoo, A P; Harish, D R; Singh, Arvind Kumar; Tiwari, A K

    2016-02-01

    Many viral proteins have the ability to kill tumor cells specifically without harming the normal cells. These proteins, on ectopic expression, cause lysis or induction of apoptosis in the target tumor cells. Parvovirus NS1 is one of such proteins, which is known to kill high proliferating tumor cells. In the present study, we assessed the apoptosis inducing ability of canine parvovirus type 2 NS1 protein (CPV2.NS1) in vitro in 4T1 cells, and found it to cause significant cell death due to induction of apoptosis through intrinsic or mitochondrial pathway. Further, we also evaluated the oncolytic activity of CPV2.NS1 protein in a mouse mammary tumor model. The results suggested that CPV2.NS1 was able to inhibit the growth of 4T1 induced mouse mammary tumor as indicated by significantly reduced tumor volume, mitotic, AgNOR and PCNA indices. Further, inhibition of tumor growth was found to be because of induction of apoptosis in the tumor cells, which was evident by a significant increase in the number of TUNEL positive cells. Further, CPV2.NS1 was also able to stimulate the immune cells against the tumor antigens as indicated by the increased CD4+ and CD8+ counts in the blood of CVP2.NS1 treated mice. Further optimization of the delivery of NS1 protein and use of an adjuvant may further enhance its anti-tumor activity.

  18. The effect of stealth liposomes on pharmacokinetics, tissue distribution and anti-tumor activity of oridonin.

    PubMed

    Wang, Chuanjin; Wei, Yunyang; Yu, Li; Zhang, Liang

    2009-01-01

    High-purity oridonin was isolated and identified from Rabdosia rubescens hemsl by preparative high-performance liquid chromatography (HPLC). Stealth liposomes of oridonin were prepared by thin-film ultrasonic dispersion using polyethylene glycol-distearoylphosphatidyleth-anolamine(PEG2000-DSPE) as the surface-coating material. A reversed-phase HPLC method was developed and validated to determine the concentrations of oridonin in the serum and tissues of mice. The tissue distribution and pharmacokinetics of oridonin stealth liposomes and oridonin solution in mice were investigated. The results showed that the distribution and pharmacokinetics of oridonin stealth liposomes in mice were changed as compared to the distribution and pharmacokinetics of oridonin solution. The levels of stealth liposomal oridonin in the heart tissues were reduced, while the levels of stealth liposomal oridonin in the blood were increased. The stealth liposomes were very effective at inhibiting the rate of solid tumor growth. The PEG2000-DSPE of liposomes prolonged the circulation time of oridonin in mouse blood, reduced accumulation in the reticuloendothelial system and increased the anti-tumor activity of oridonin.

  19. Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity.

    PubMed

    Daburon, Sophie; Devaud, Christel; Costet, Pierre; Morello, Aurore; Garrigue-Antar, Laure; Maillasson, Mike; Hargous, Nathalie; Lapaillerie, Delphine; Bonneu, Marc; Dechanet-Merville, Julie; Legembre, Patrick; Capone, Myriam; Moreau, Jean-François; Taupin, Jean-Luc

    2013-01-01

    Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas. PMID:23326557

  20. Liposomes Encapsulating 10-Hydroxycamptothecin-Cyclodextrin Complexes and Their In Vitro Anti-Tumor Activities.

    PubMed

    Chen, Yang; Chen, Cheng; Xiao, Yiyun; Zhang, Xiuzhen; Chen, Yuxiang

    2015-05-01

    Manufacturing and characterizing hydroxycamptothecin inclusion liposomes, establishing their quality standard and testing their in vitro anti-tumor activity is of significance for potential application. The neutralization agitation method was used to prepare hydroxycamptothecin inclusion and film evaporation method was utilized to manufacture hydroxycamptothecin inclusion liposomes. The phase solubility method, differential scanning calorimetry and infrared spectroscopy were used to identify the prepared inclusion complex. The hydroxycamptothecin inclusion liposomes were characterized for particle morphology, size, in vitro release and stability. The hepatoma (HepG-2), lung cancer (A549), and gastric cancer (SGC-7901) cell lines were used as models for preliminary evaluation of anti-cancer effect from the hydroxycamptothecin inclusion liposomes, done by MTT colorimetry, cytometer experiments, and apoptosis staining. The anti-cancer evaluation was compared with commercially available hydroxycamptothecin. The results showed the hydroxycamptothecin inclusion was successfully prepared by neutralization agitation method. Phase solubility method, differential scanning calorimetry and infrared spectroscopy proved the formation of the hydroxycamptothecin inclusion. The hydroxycamptothecin inclusion liposomes were successfully prepared by film evaporation method. (2) The inclusions were found to be spherical, with average particle size of 119.7 nm, zeta potential of - 45.6 mV, average inclusion rate of 70.55%, and drug-loading was 14.60%. The inclusions were also found to have a sustained release effect, when compared to the commercially available hydroxyccamptothecine. The hydroxyccamptothecine inclusion liposomes had better stability at 4 degrees. (3) The hydroxycamptothecin inclusion liposomes also exhibited better inhibition effect for the three kinds of cancer cell lines above, when compared to the commercially available hydroxycamptothecin the anti-cancer effect being

  1. Myeloma cells can corrupt senescent mesenchymal stromal cells and impair their anti-tumor activity

    PubMed Central

    Özcan, Servet; Alessio, Nicola; Acar, Mustafa Burak; Toprak, Güler; Gönen, Zeynep Burcin; Peluso, Gianfranco; Galderisi, Umberto

    2015-01-01

    Senescent cells secrete several molecules that help to prevent the progression of cancer. However, cancer cells can also misuse these secreted elements to survive and grow. Since the molecular and functional bases of these different elements remain poorly understood, we analyzed the effect of senescent mesenchymal stromal cell (MSC) secretome on the biology of ARH-77 myeloma cells. In addition to differentiating in mesodermal derivatives, MSCs have sustained interest among researchers by supporting hematopoiesis, contributing to tissue homeostasis, and modulating inflammatory response, all activities accomplished primarily by the secretion of cytokines and growth factors. Moreover, senescence profoundly affects the composition of MSC secretome. In this study, we induced MSC senescence by oxidative stress, DNA damage, and replicative exhaustion. While the first two are considered to induce acute senescence, extensive proliferation triggers replicative (i.e., chronic) senescence. We cultivated cancer cells in the presence of acute and chronic senescent MSC-conditioned media and evaluated their proliferation, DNA damage, apoptosis, and senescence. Our findings revealed that senescent secretomes induced apoptosis or senescence, if not both, to different extents. This anti-tumor activity became heavily impaired when secretomes were collected from senescent cells previously in contact (i.e., primed) with cancer cells. Our analysis of senescent MSC secretomes with LC-MS/MS followed by Gene Ontology classification further indicated that priming with cancer profoundly affected secretome composition by abrogating the production of pro-senescent and apoptotic factors. We thus showed for the first time that compared with cancer-primed MSCs, naïve senescent MSCs can exert different effects on tumor progression. PMID:26498687

  2. Anti-tumor activity of N-hydroxy-7-(2-naphthylthio) heptanomide, a novel histone deacetylase inhibitor

    SciTech Connect

    Kim, Dong Hoon; Lee, Jiyong; Kim, Kyung Noo; Kim, Hye Jin; Jeung, Hei Cheul; Chung, Hyun Cheol; Kwon, Ho Jeong . E-mail: kwonhj@yonsei.ac.kr

    2007-04-27

    Histone deacetylase (HDAC), a key enzyme in gene expression and carcinogenesis, is considered an attractive target molecule for cancer therapy. Here, we report a new synthetic small molecule, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), as a HDAC inhibitor with anti-tumor activity both in vitro and in vivo. The compound inhibited HDAC enzyme activity as well as proliferation of human fibrosarcoma cells (HT1080) in vitro. Treatment of cells with HNHA elicited histone hyperacetylation leading to an up-regulation of p21 transcription, cell cycle arrest, and an inhibition of HT1080 cell invasion. Moreover, HNHA effectively inhibited the growth of tumor tissue in a mouse xenograph assay in vivo. Together, these data demonstrate that this novel HDAC inhibitor could be developed as a potential anti-tumor agent targeting HDAC.

  3. Effects of extraction methods on the yield, chemical structure and anti-tumor activity of polysaccharides from Cordyceps gunnii mycelia.

    PubMed

    Zhu, Zhen-Yuan; Dong, Fengying; Liu, Xiaocui; Lv, Qian; YingYang; Liu, Fei; Chen, Ling; Wang, Tiantian; Wang, Zheng; Zhang, Yongmin

    2016-04-20

    This study was to investigate the effects of different extraction methods on the yield, chemical structure and antitumor activity of polysaccharides from Cordyceps gunnii (C. gunnii) mycelia. Five extraction methods were used to extract crude polysaccharides (CPS), which include room-temperature water extraction (RWE), hot-water extraction (HWE), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE) and cellulase-assisted extraction (CAE). Then Sephadex G-100 was used for purification of CPS. As a result, the antitumor activities of CPS and PPS on S180 cells were evaluated. Five CPS and purified polysaccharides (PPS) were obtained. The yield of CPS by microwave-assisted extraction (CPSMAE) was the highest and its anti-tumor activity was the best and its macromolecular polysaccharide (3000-1000kDa) ratio was the largest. The PPS had the same monosaccharide composition, but their obvious difference was in the antitumor activity and the physicochemical characteristics, such as intrinsic viscosity, specific rotation, scanning electron microscopy and circular dichroism spectra.

  4. Effects of extraction methods on the yield, chemical structure and anti-tumor activity of polysaccharides from Cordyceps gunnii mycelia.

    PubMed

    Zhu, Zhen-Yuan; Dong, Fengying; Liu, Xiaocui; Lv, Qian; YingYang; Liu, Fei; Chen, Ling; Wang, Tiantian; Wang, Zheng; Zhang, Yongmin

    2016-04-20

    This study was to investigate the effects of different extraction methods on the yield, chemical structure and antitumor activity of polysaccharides from Cordyceps gunnii (C. gunnii) mycelia. Five extraction methods were used to extract crude polysaccharides (CPS), which include room-temperature water extraction (RWE), hot-water extraction (HWE), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE) and cellulase-assisted extraction (CAE). Then Sephadex G-100 was used for purification of CPS. As a result, the antitumor activities of CPS and PPS on S180 cells were evaluated. Five CPS and purified polysaccharides (PPS) were obtained. The yield of CPS by microwave-assisted extraction (CPSMAE) was the highest and its anti-tumor activity was the best and its macromolecular polysaccharide (3000-1000kDa) ratio was the largest. The PPS had the same monosaccharide composition, but their obvious difference was in the antitumor activity and the physicochemical characteristics, such as intrinsic viscosity, specific rotation, scanning electron microscopy and circular dichroism spectra. PMID:26876874

  5. Comparative studies on the anti-tumor activities of high temperature- and pH-modified citrus pectins.

    PubMed

    Hao, Miao; Yuan, Xiaowen; Cheng, Hairong; Xue, Huiting; Zhang, Tao; Zhou, Yifa; Tai, Guihua

    2013-06-01

    High temperature and pH modification could produce functional pectins. In this study, high temperature-modified (HTCP) and pH-modified (MCP) citrus pectins were prepared for studying their anti-tumor activities in eight cancer cell lines and a mouse Sarcoma-180 (S-180) tumor model. HTCP inhibited the proliferation of these cancer cells and induced a caspase-3-dependent cell apoptosis and cell cycle arrest at G2/M phase. It also inhibited the growth of S-180 tumor to 49% of the control at the dose of 200 mg kg(-1) d(-1) and extended the survival time of the tumor-bearing mice. MCP had no anti-proliferative effects on these cancer cells and no anti-tumor effect in the mouse model. The anti-tumor activity of HTCP in the mouse tumor model was not correlated with immunomodulation and galectin-3 inhibition, but correlated well with proliferation inhibition. HTCP might be exploited as a functional food for cancer prevention and/or treatment.

  6. Evaluation and structure-activity relationship analysis of a new series of arylnaphthalene lignans as potential anti-tumor agents.

    PubMed

    Luo, Jiaoyang; Hu, Yichen; Kong, Weijun; Yang, Meihua

    2014-01-01

    Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6'-hydroxy justicidin A (HJA), 6'-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6' significantly increased the antiproliferative activity of

  7. A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

    PubMed Central

    Arlia-Ciommo, Anthony; Svistkova, Veronika; Mohtashami, Sadaf; Titorenko, Vladimir I.

    2016-01-01

    A recently conducted chemical genetic screen for pharmaceuticals that can extend longevity of the yeast Saccharomyces cerevisiae has identified lithocholic acid as a potent anti-aging molecule. It was found that this hydrophobic bile acid is also a selective anti-tumor chemical compound; it kills different types of cultured cancer cells if used at concentrations that do not compromise the viability of non-cancerous cells. These studies have revealed that yeast can be successfully used as a model organism for high-throughput screens aimed at the discovery of selectively acting anti-tumor small molecules. Two metabolic traits of rapidly proliferating fermenting yeast, namely aerobic glycolysis and lipogenesis, are known to be similar to those of cancer cells. The mechanisms underlying these key metabolic features of cancer cells and fermenting yeast have been established; such mechanisms are discussed in this review. We also suggest how a yeast-based chemical genetic screen can be used for the high-throughput development of selective anti-tumor pharmaceuticals that kill only cancer cells. This screen consists of searching for chemical compounds capable of increasing the abundance of membrane lipids enriched in unsaturated fatty acids that would therefore be toxic only to rapidly proliferating cells, such as cancer cells and fermenting yeast. PMID:26636650

  8. Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.

    PubMed

    Peng, Sheng-Bin; Henry, James R; Kaufman, Michael D; Lu, Wei-Ping; Smith, Bryan D; Vogeti, Subha; Rutkoski, Thomas J; Wise, Scott; Chun, Lawrence; Zhang, Youyan; Van Horn, Robert D; Yin, Tinggui; Zhang, Xiaoyi; Yadav, Vipin; Chen, Shih-Hsun; Gong, Xueqian; Ma, Xiwen; Webster, Yue; Buchanan, Sean; Mochalkin, Igor; Huber, Lysiane; Kays, Lisa; Donoho, Gregory P; Walgren, Jennie; McCann, Denis; Patel, Phenil; Conti, Ilaria; Plowman, Gregory D; Starling, James J; Flynn, Daniel L

    2015-09-14

    LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation. PMID:26343583

  9. Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.

    PubMed

    Peng, Sheng-Bin; Henry, James R; Kaufman, Michael D; Lu, Wei-Ping; Smith, Bryan D; Vogeti, Subha; Rutkoski, Thomas J; Wise, Scott; Chun, Lawrence; Zhang, Youyan; Van Horn, Robert D; Yin, Tinggui; Zhang, Xiaoyi; Yadav, Vipin; Chen, Shih-Hsun; Gong, Xueqian; Ma, Xiwen; Webster, Yue; Buchanan, Sean; Mochalkin, Igor; Huber, Lysiane; Kays, Lisa; Donoho, Gregory P; Walgren, Jennie; McCann, Denis; Patel, Phenil; Conti, Ilaria; Plowman, Gregory D; Starling, James J; Flynn, Daniel L

    2015-09-14

    LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.

  10. Structure elucidation and anti-tumor activities of water-soluble oligosaccharides from Lactarius deliciosus (L. ex Fr.) Gray

    PubMed Central

    Ding, Xiang; Hou, Yiling; Hou, Wanru; Zhu, Yuanxiu; Fu, Lei; Zhu, Hongqing

    2015-01-01

    Background: Oligosaccharides are composed of a variable number of monosaccharide units and very important in the biologically diverse of biological systems. Materials and Methods: Crude water-soluble oligosaccharide was extracted from the fruiting bodies with water and then successively purified by DEAE–cellulose 52 and Sephadex G-100 column chromatography, yielding one major oligosaccharides fractions: LES-A. Structural features of Lactarius deliciosus (L. ex Fr.) Gray oligosaccharide (LDGO-A) were investigated by a combination of monosaccharide component analysis by thin layer chromatography, infrared spectra, nuclear magnetic resonance spectroscopy, scanning electron microscopy, and high-performance gel permeation chromatography analysis. Result: The results indicated that LDGO-A was composed of D-glucose and D-xylose, and the average molecular sizes was approximately 945 Da. The anti-tumor activity of LDGO-A was evaluated in vivo. The inhibitory rate in mice treated with 40 mg/kg LDGO-A can reach 40.02%, being the highest in the three doses, which may be comparable to mannatide. Histology of immune organs shows that the tissues arranged more regular and firmer, but the tumor tissue arranged looser in LDGO-A group than those in the control group. Meanwhile, there is no obvious damage to other organs, such as heart. The anti-tumor activity of the LDGO-A was usually believed to be a consequence of the stimulation of the cell-mediated immune response because it can significantly promote the lymphocyte and macrophage cells in the dose range of 100–400 μg/mL in vitro. LDGO-A also effected the expression of some housekeeping genes mRNA in S180 tumor. Conclusion: Accordingly, the LDGO-A might serve as an effective healthcare food and source of natural anti-tumor compounds. PMID:26600715

  11. In Vitro and in Vivo Anti-tumor Activity of miR-221/222 Inhibitors in Multiple Myeloma

    PubMed Central

    Di Martino, Maria Teresa; Gullà, Annamaria; Cantafio, Maria Eugenia Gallo; Lionetti, Marta; Leone, Emanuela; Amodio, Nicola; Guzzi, Pietro Hiram; Foresta, Umberto; Conforti, Francesco; Cannataro, Mario; Neri, Antonino; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2013-01-01

    A rising body of evidence suggests that silencing microRNAs (miRNAs) with oncogenic potential may represent a successful therapeutic strategy for human cancer. We investigated the therapeutic activity of miR-221/222 inhibitors against human multiple myeloma (MM) cells. Enforced expression of miR-221/222 inhibitors triggered in vitro anti-proliferative effects and up-regulation of canonic miR-221/222 targets, including p27Kip1, PUMA, PTEN and p57Kip2, in MM cells highly expressing miR-221/222. Conversely, transfection of miR-221/222 mimics increased S-phase and down-regulated p27Kip1 protein expression in MM with low basal miR-221/222 levels. The effects of miR-221/222 inhibitors was also evaluated in MM xenografts in SCID/NOD mice. Significant anti-tumor activity was achieved in xenografted mice by the treatment with miR-221/222 inhibitors, together with up-regulation of canonic protein targets in tumors retrieved from animals. These findings provide proof of principle that silencing the miR-221/222 cluster exerts significant therapeutic activity in MM cells with high miR-221/222 level of expression, which mostly occurs in TC2 and TC4 MM groups. These findings suggest that MM genotyping may predict the therapeutic response. All together our results support a framework for clinical development of miR-221/222 inhibitors-based therapeutic strategy in this still incurable disease. PMID:23479461

  12. COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma.

    PubMed

    Qi, Huan; Zuo, Dai-Ying; Bai, Zhao-Shi; Xu, Jing-Wen; Li, Zeng-Qiang; Shen, Qi-Rong; Wang, Zhi-Wei; Zhang, Wei-Ge; Wu, Ying-Liang

    2014-12-12

    5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti-hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal liver cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL-7402 cells led to mitotic slippage followed by senescence via the p14(Arf)-p53-p21 and p16(INK4α)-Rb pathways. Furthermore, suppression of p53 via pifithrin-α (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL-7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent.

  13. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice.

    PubMed

    Wang, Zili; Celis, Esteban

    2015-08-01

    Therapeutic vaccines to induce anti-tumor CD8 T cells have been used in clinical trials for advanced melanoma patients, but the clinical response rate and overall survival time have not improved much. We believe that these dismal outcomes are caused by inadequate number of antigen-specific CD8 T cells generated by most vaccines. In contrast, huge CD8 T cell responses readily occur during acute viral infections. High levels of type-I interferon (IFN-I) are produced during these infections, and this cytokine not only exhibits anti-viral activity but also promotes CD8 T cell responses. The studies described here were performed to determine whether promoting the production of IFN-I could enhance the potency of a peptide vaccine. We report that cyclic diguanylate monophosphate (c-di-GMP), which activates the stimulator of interferon genes, potentiated the immunogenicity and anti-tumor effects of a peptide vaccine against mouse B16 melanoma. The synergistic effects of c-di-GMP required co-administration of costimulatory anti-CD40 antibody, the adjuvant poly-IC, and were mediated in part by IFN-I. These findings demonstrate that peptides representing CD8 T cell epitopes can be effective inducers of large CD8 T cell responses in vaccination strategies that mimic acute viral infections.

  14. Anti-tumor activities of active ingredients in Compound Kushen Injection

    PubMed Central

    Wang, Wei; You, Rong-li; Qin, Wen-jie; Hai, Li-na; Fang, Ming-jing; Huang, Guo-hua; Kang, Rui-xia; Li, Ming-hua; Qiao, Yu-feng; Li, Jian-wei; Li, An-ping

    2015-01-01

    Kushen (Radix Sophorae Flavescentis) has a long history of use for the treatment of tumors, inflammation and other diseases in traditional Chinese medicine. Compound Kushen Injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling (Rhizoma Smilacis Glabrae). The main principles of CKI are matrine (MT) and oxymatrine (OMT) that exhibit a variety of pharmacological activities, including anti-inflammatory, anti-allergic, anti-viral, anti-fibrotic and cardiovascular protective effects. Recent evidence shows that these compounds also produce anti-cancer actions, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- and/or radiotherapy-induced toxicity when combined with chemotherapeutic drugs. In this review, we summarize recent progress in studying the anti-cancer activities of MT, OMT and CKI and their potential molecular targets, which provide clues and references for further study. PMID:25982630

  15. Anti-tumor activities of active ingredients in Compound Kushen Injection.

    PubMed

    Wang, Wei; You, Rong-li; Qin, Wen-jie; Hai, Li-na; Fang, Ming-jing; Huang, Guo-hua; Kang, Rui-xia; Li, Ming-hua; Qiao, Yu-feng; Li, Jian-wei; Li, An-ping

    2015-06-01

    Kushen (Radix Sophorae Flavescentis) has a long history of use for the treatment of tumors, inflammation and other diseases in traditional Chinese medicine. Compound Kushen Injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling (Rhizoma Smilacis Glabrae). The main principles of CKI are matrine (MT) and oxymatrine (OMT) that exhibit a variety of pharmacological activities, including anti-inflammatory, anti-allergic, anti-viral, anti-fibrotic and cardiovascular protective effects. Recent evidence shows that these compounds also produce anti-cancer actions, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- and/or radiotherapy-induced toxicity when combined with chemotherapeutic drugs. In this review, we summarize recent progress in studying the anti-cancer activities of MT, OMT and CKI and their potential molecular targets, which provide clues and references for further study. PMID:25982630

  16. Extension of the in vivo half-life of endostatin and its improved anti-tumor activities upon fusion to a humanized antibody against tumor-associated glycoprotein 72 in a mouse model of human colorectal carcinoma.

    PubMed

    Lee, Sang-Hyun; Jeung, In Cheul; Park, Tae Woo; Lee, Kyungmin; Lee, Dong Gwang; Cho, Young-Lai; Lee, Tae Sup; Na, Hee-Jun; Park, Young-Jun; Lee, Hee Gu; Jeong, Mun Sik; Bae, Kwang-Hee; Lee, Sang Chul; Lee, Hyo Jin; Kwon, Young-Guen; Hong, Hyo Jeong; Kim, Jang-Seong; Min, Jeong-Ki

    2015-03-30

    Endostatin is an endogenous angiogenesis inhibitor that exhibits potential anti-tumor efficacy in various preclinical animal models. However, its relatively short in vivo half-life and the long-term, frequent administration of high doses limit its widespread clinical use. In this study, we evaluated whether a fusion protein of murine endostatin (mEndo) to a humanized antibody against tumor-associated glycoprotein 72 (TAG-72), which is highly expressed in several human tumor tissues including colon cancer, can extend the serum half-life and improve the anti-tumor efficacy of endostatin by targeted delivery to the tumor mass. The fusion protein (3E8-mEndo) and mEndo showed improved anti-angiogenic activity in vitro and in vivo, predominantly by interfering with pro-angiogenic signaling triggered by vascular endothelial growth factor (VEGF). Moreover, in mice treated with 3E8-mEndo, we observed a markedly prolonged serum half-life and significantly inhibited tumor growth. The improved anti-tumor activity of 3E8-mEndo can be partially explained by increased local concentration in the tumor mass due to targeted delivery of 3E8-mEndo to implanted colon tumors. Collectively, our data clearly indicate that tumor-targeting antibody fusions to endostatin are a powerful strategy that improves the poor pharmacokinetic profile and anti-tumor efficacy of endostatin.

  17. Curcumin Inhibits Glyoxalase 1—A Possible Link to Its Anti-Inflammatory and Anti-Tumor Activity

    PubMed Central

    Santel, Thore; Pflug, Gabi; Hemdan, Nasr Y. A.; Schäfer, Angelika; Hollenbach, Marcus; Buchold, Martin; Hintersdorf, Anja; Lindner, Inge; Otto, Andreas; Bigl, Marina; Oerlecke, Ilka; Hutschenreuter, Antje; Sack, Ulrich; Huse, Klaus; Groth, Marco; Birkemeyer, Claudia; Schellenberger, Wolfgang; Gebhardt, Rolf; Platzer, Mathias; Weiss, Thomas; Vijayalakshmi, Mookambeswaran A.; Krüger, Monika; Birkenmeier, Gerd

    2008-01-01

    Background Glyoxalases (Glo1 and Glo2) are involved in the glycolytic pathway by detoxifying the reactive methylglyoxal (MGO) into D-lactate in a two-step reaction using glutathione (GSH) as cofactor. Inhibitors of glyoxalases are considered as anti-inflammatory and anti-carcinogenic agents. The recent finding that various polyphenols modulate Glo1 activity has prompted us to assess curcumin's potency as an Glo1 inhibitor. Methodology/Principal Findings Cultures of whole blood cells and tumor cell lines (PC-3, JIM-1, MDA-MD 231 and 1321N1) were set up to investigate the effect of selected polyphenols, including curcumin, on the LPS-induced cytokine production (cytometric bead-based array), cell proliferation (WST-1 assay), cytosolic Glo1 and Glo2 enzymatic activity, apoptosis/necrosis (annexin V-FITC/propidium iodide staining; flow cytometric analysis) as well as GSH and ATP content. Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (Ki = 5.1±1.4 µM). Applying a whole blood assay, IC50 values of pro-inflammatory cytokine release (TNF-α, IL-6, IL-8, IL-1β) were found to be positively correlated with the Ki-values of the aforementioned polyphenols. Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231), prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated. Curcumin decreased D-lactate release by tumor cells, another clue for inhibition of intracellular Glo1. Conclusions/Significance The results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content. This may account

  18. Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity

    PubMed Central

    Dahlberg, Carin I. M.; Sarhan, Dhifaf; Chrobok, Michael; Duru, Adil D.; Alici, Evren

    2015-01-01

    Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells

  19. Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity.

    PubMed

    Dahlberg, Carin I M; Sarhan, Dhifaf; Chrobok, Michael; Duru, Adil D; Alici, Evren

    2015-01-01

    Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells

  20. A novel immunomodulatory hemocyanin from the limpet Fissurella latimarginata promotes potent anti-tumor activity in melanoma.

    PubMed

    Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabián; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C; Manubens, Augusto; De Ioannes, Alfredo E; Becker, María Inés

    2014-01-01

    Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-γ production and higher numbers of tumor-infiltrating CD4(+) lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-α) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy.

  1. A Novel Immunomodulatory Hemocyanin from the Limpet Fissurella latimarginata Promotes Potent Anti-Tumor Activity in Melanoma

    PubMed Central

    Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabián; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C.; Manubens, Augusto; De Ioannes, Alfredo E.; Becker, María Inés

    2014-01-01

    Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-γ production and higher numbers of tumor-infiltrating CD4+ lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-α) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy. PMID

  2. Enhanced anti-tumor activity of a new curcumin-related compound against melanoma and neuroblastoma cells

    PubMed Central

    2010-01-01

    Background Sharing the common neuroectodermal origin, melanoma and neuroblastoma are tumors widely diffused among adult and children, respectively. Clinical prognosis of aggressive neuroectodermal cancers remains dismal, therefore the search for novel therapies against such tumors is warranted. Curcumin is a phytochemical compound widely studied for its antioxidant, anti-inflammatory and anti-cancer properties. Recently, we have synthesized and tested in vitro various curcumin-related compounds in order to select new anti-tumor agents displaying stronger and selective growth inhibition activity on neuroectodermal tumors. Results In this work, we have demonstrated that the new α,β-unsaturated ketone D6 was more effective in inhibiting tumor cells growth when compared to curcumin. Normal fibroblasts proliferation was not affected by this treatment. Clonogenic assay showed a significant dose-dependent reduction in both melanoma and neuroblastoma colony formation only after D6 treatment. TUNEL assay, Annexin-V staining, caspases activation and PARP cleavage unveiled the ability of D6 to cause tumor cell death by triggering apoptosis, similarly to curcumin, but with a stronger and quicker extent. These apoptotic features appear to be associated with loss of mitochondrial membrane potential and cytochrome c release. In vivo anti-tumor activity of curcumin and D6 was surveyed using sub-cutaneous melanoma and orthotopic neuroblastoma xenograft models. D6 treated mice exhibited significantly reduced tumor growth compared to both control and curcumin treated ones (Melanoma: D6 vs control: P < 0.001 and D6 vs curcumin P < 0.01; Neuroblastoma: D6 vs both control and curcumin: P < 0.001). Conclusions Our data indicate D6 as a good candidate to develop new therapies against neural crest-derived tumors. PMID:20525240

  3. A New Activity of Anti-HIV and Anti-tumor Protein GAP31: DNA Adenosine Glycosidase – Structural and Modeling Insight into its Functions

    SciTech Connect

    Li, H.; Huang, P; Zhang, D; Sun, Y; Chen, H; Zhang, J; Huang, P; Kong, X; Lee-Huang, S

    2010-01-01

    We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

  4. A new activity of anti-HIV and anti-tumor protein GAP31: DNA adenosine glycosidase - Structural and modeling insight into its functions

    SciTech Connect

    Li, Hui-Guang; Huang, Philip L.; Zhang, Dawei; Sun, Yongtao; Chen, Hao-Chia; Zhang, John; Huang, Paul L.; Kong, Xiang-Peng; Lee-Huang, Sylvia

    2010-01-01

    We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

  5. COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma

    SciTech Connect

    Qi, Huan; Zuo, Dai-Ying; Bai, Zhao-Shi; Xu, Jing-Wen; Li, Zeng-Qiang; Shen, Qi-Rong; Wang, Zhi-Wei; Zhang, Wei-Ge; Wu, Ying-Liang

    2014-12-12

    Highlights: • COH-203 exhibits anti-hepatoma effects in vitro and in vivo with low toxicity. • COH-203 inhibits tubulin polymerization. • COH-203 induces mitotic arrest followed by mitotic slippage in BEL-7402 cells. • COH-203 induces p53-dependent senescence in BEL-7402 cells. - Abstract: 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1, 2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti-hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal liver cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL-7402 cells led to mitotic slippage followed by senescence via the p14{sup Arf}–p53–p21 and p16{sup INK4α}–Rb pathways. Furthermore, suppression of p53 via pifithrin-α (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL-7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent.

  6. Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance.

    PubMed

    Kareva, Irina; Waxman, David J; Lakka Klement, Giannoula

    2015-03-28

    The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.

  7. Synthesis of selenium-containing Artemisia sphaerocephala polysaccharides: Solution conformation and anti-tumor activities in vitro.

    PubMed

    Wang, Junlong; Li, Qingyao; Bao, Aijuan; Liu, Xiurong; Zeng, Junyuan; Yang, Xiaopin; Yao, Jian; Zhang, Ji; Lei, Ziqiang

    2016-11-01

    It has been reported in our previous work that selenized Artemisia sphaerocephala polysaccharides (SeASPs) with the Se content range of 168-1703μg/g were synthesized by using Na2SeO3/HNO3/BaCl2 system. In the present work, the solution property of SeASP was studied by using size exclusion chromatography combined with multi angle laser light scattering (SEC-MALLS). A decrease in df values indicated that SeASPs with different conformational features that were highly dependent on MW. SeASPs exhibited a more rigid conformation (df value of 1.29-1.52) in low molecular weight range (MW of 1.026-1.426×10(4)g/mol) and compact spherical conformation in high molecular weight range (MW of 2.268-4.363×10(4)g/mol). It could be due to the degradation of polysaccharide chains in HNO3, which was supported in monosaccharide composition analysis. Congo red (CR) spectrophotometric method and atomic force microscopy (AFM) results also confirmed the conformational transition and the evidence on the shape of the rigid chains. In vitro anti-tumor assays, SeASP2 displayed greater anti-proliferative effects against three tumor cell lines (hepatocellular carcinoma HepG-2 cells, lung adenocarcinom A549 cells and cervical squamous carcinoma Hela cells) in a dose-dependent manner. This suggested that selenylation could significantly enhance the anti-tumor activities of polysaccharide derivatives in vitro. PMID:27516251

  8. Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells.

    PubMed

    Yuan, Chun-Hui; Sun, Xiao-Ming; Zhu, Cheng-Liang; Liu, Shao-Ping; Wu, Long; Chen, Hao; Feng, Mao-Hui; Wu, Ke; Wang, Fu-Bing

    2015-10-13

    CD8+ T cell-mediated immune response plays an important role in inhibiting progression of hepatocellular carcinoma (HCC). For strategic immunotherapy, it is critical to understand why some of the tumor cells escape from this immune attack. In this study, we investigated how HCC cells alter endogenous anti-tumor immunity and their related signaling pathways. We found that HCC cells, both in vitro and in vivo, substantially secret and express amphiregulin (AR). AR in turn activates immunosuppressive function of intratumoral CD4+Foxp3+ regulatory T cells (Tregs), a major inhibitor of CD8+ T cells. Using either lentiviral siRNA, or AR neutralizing antibody, we blocked the expression and function of AR to test the specificity of AR mediated activation of Tregs, Biochemical and cell biology studies were followed and confirmed that blocking of AR inhibited Tregs activation. In addition, we found that AR can trigger the activation of rapamycin complex 1(mTORC1) signaling in Tregs. The mTORC1 inhibitor rapamycin treatment led to compromise Treg function and resulted in enhancing anti-tumor function of CD8+ T cells. Blocking AR/EGFR signaling in Tregs with Gefitinib also enhanced anti-tumor immunity and decreased tumor size in a mouse xenograft tumor model. Taken together, our study suggested a novel mechanism of functional interaction between HCC and Tregs for regulating anti-tumor function of CD8+ T cells. PMID:26451607

  9. A review on plant-derived natural products and their analogs with anti-tumor activity

    PubMed Central

    Dholwani, K.K.; Saluja, A.K.; Gupta, A.R.; Shah, D.R.

    2008-01-01

    Traditional medicines, including Chinese herbal formulations, can serve as the source of potential new drugs, and initial research focuses on the isolation of bioactive lead compound(s). The development of novel plant-derived natural products and their analogs for anticancer activity details efforts to synthesize new derivatives based on bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design - based modification. Also, the anticancer activity of certain natural products and their analogs can be enhanced by synthesizing new derivatives based on active pharmacophore models; drug resistance and solubility and metabolic limitations can be overcome by appropriate molecular modifications; and new biological properties or mechanisms of action can be added by combining other functional groups or molecules. Preclinical screening for in vitro human cell line panels and selected in vivo xenograft testing then identifies the most promising drug development targets. PMID:21279166

  10. Immune-system-dependent anti-tumor activity of a plant-derived polyphenol rich fraction in a melanoma mouse model.

    PubMed

    Gomez-Cadena, A; Urueña, C; Prieto, K; Martinez-Usatorre, A; Donda, A; Barreto, A; Romero, P; Fiorentino, S

    2016-06-02

    Recent findings suggest that part of the anti-tumor effects of several chemotherapeutic agents require an intact immune system. This is in part due to the induction of immunogenic cell death. We have identified a gallotannin-rich fraction, obtained from Caesalpinia spinosa (P2Et) as an anti-tumor agent in both breast carcinoma and melanoma. Here, we report that P2Et treatment results in activation of caspase 3 and 9, mobilization of cytochrome c and externalization of annexin V in tumor cells, thus suggesting the induction of apoptosis. This was preceded by the onset of autophagy and the expression of immunogenic cell death markers. We further demonstrate that P2Et-treated tumor cells are highly immunogenic in vaccinated mice and induce immune system activation, clearly shown by the generation of interferon gamma (IFN-γ) producing tyrosine-related protein 2 antigen-specific CD8+ T cells. Moreover, the tumor protective effects of P2Et treatment were abolished in immunodeficient mice, and partially lost after CD4 and CD8 depletion, indicating that P2Et's anti-tumor activity is highly dependent on immune system and at least in part of T cells. Altogether, these results support the hypothesis that the gallotannin-rich fraction P2Et's anti-tumor effects are mediated to a great extent by the endogenous immune response following to the exposure to immunogenic dying tumor cells.

  11. Colloidally stable surface-modified iron oxide nanoparticles: Preparation, characterization and anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Macková, Hana; Horák, Daniel; Donchenko, Georgiy Viktorovich; Andriyaka, Vadim Ivanovich; Palyvoda, Olga Mikhailovna; Chernishov, Vladimir Ivanovich; Chekhun, Vasyl Fedorovich; Todor, Igor Nikolaevich; Kuzmenko, Oleksandr Ivanovich

    2015-04-01

    Maghemite (γ-Fe2O3) nanoparticles were obtained by co-precipitation of Fe(II) and Fe(III) chlorides and subsequent oxidation with sodium hypochlorite and coated with poly(N,N-dimethylacrylamide-co-acrylic acid) [P(DMAAm-AA)]. They were characterized by a range of methods including transmission electron microscopy (TEM), elemental analysis, dynamic light scattering (DLS) and zeta potential measurements. The effect of superparamagnetic P(DMAAm-AA)-γ-Fe2O3 nanoparticles on oxidation of blood lipids, glutathione and proteins in blood serum was detected using 2-thiobarbituric acid and the ThioGlo fluorophore. Finally, mice received magnetic nanoparticles administered per os and the antitumor activity of the particles was tested on Lewis lung carcinoma (LLC) in male mice line C57BL/6 as an experimental in vivo metastatic tumor model; the tumor size was measured and the number of metastases in lungs was determined. Surface-modified γ-Fe2O3 nanoparticles showed higher antitumor and antimetastatic activities than commercial CuFe2O4 particles and the conventional antitumor agent cisplatin.

  12. The pseudoginsenoside F11 ameliorates cisplatin-induced nephrotoxicity without compromising its anti-tumor activity in vivo

    PubMed Central

    Wang, Hongbo; Kong, Liang; Zhang, Jianqiao; Yu, Guohua; Lv, Guangyao; Zhang, Fangxi; Chen, Xiaoguang; Tian, Jingwei; Fu, Fenghua

    2014-01-01

    The clinical use of cisplatin was severely limited by its associated nephrotoxicity. In this study, we investigated whether the pseudoginsenoside F11 had protective effects against cisplatin-induced nephrotoxicity. To clarify it, one in vivo model of cisplatin-induced acute renal failure was performed. The results showed that pretreatment with F11 reduced cisplatin-elevated blood urea nitrogen and creatinine levels, as well as ameliorated the histophathological damage. Further studies showed that F11 could suppress P53 activation, inverse the ratio of Bax/Bcl2 and the anti-oxidative and free radical levels induced by cisplatin, which in turn inhibited tubular cell apoptosis. Importantly, F11 enhanced rather than inhibited the anti-tumor activity of cispaltin in murine melanoma and Lewis lung cancer xenograft tumor models. Our findings suggested that administering F11 with cisplatin might alleviate the associated nephrotoxicity without compromising its therapeutic efficiency. This finding provides a novel potential strategy in the clinical treatment of cancer. PMID:24832194

  13. Ancient Chinese Formula Qiong-Yu-Gao Protects Against Cisplatin-Induced Nephrotoxicity Without Reducing Anti-tumor Activity

    PubMed Central

    Teng, Zhi-Ying; Cheng, Xiao-Lan; Cai, Xue-Ting; Yang, Yang; Sun, Xiao-Yan; Xu, Jin-Di; Lu, Wu-Guang; Chen, Jiao; Hu, Chun-Ping; Zhou, Qian; Wang, Xiao-Ning; Li, Song-Lin; Cao, Peng

    2015-01-01

    Cisplatin is a highly effective anti-cancer chemotherapeutic agent; however, its clinical use is severely limited by serious side effects, of which nephrotoxicity is the most important. In this study, we investigated whether Qiong-Yu-Gao (QYG), a popular traditional Chinese medicinal formula described 840 years ago, exhibits protective effects against cisplatin-induced renal toxicity. Using a mouse model of cisplatin-induced renal dysfunction, we observed that pretreatment with QYG attenuated cisplatin-induced elevations in blood urea nitrogen and creatinine levels, ameliorated renal tubular lesions, reduced apoptosis, and accelerated tubular cell regeneration. Cisplatin-mediated elevations in tumor necrosis factor alpha (TNF-α) mRNA, interleukin-1 beta (IL-1β) mRNA, and cyclooxygenase-2 (COX-2) protein in the kidney were also significantly suppressed by QYG treatment. Furthermore, QYG reduced platinum accumulation in the kidney by decreasing the expression of copper transporter 1 and organic cation transporter 2. An in vivo study using implanted Lewis lung cancer cells revealed that concurrent administration of QYG and cisplatin did not alter the anti-tumor activity of cisplatin. Our findings suggest that the traditional Chinese medicinal formula QYG inhibits cisplatin toxicity by several mechanisms that act simultaneously, without compromising its therapeutic efficacy. Therefore, QYG may be useful in the clinic as a protective agent to prevent cisplatin-induced nephrotoxicity. PMID:26510880

  14. Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma.

    PubMed

    Qi, Wenqing; Cooke, Laurence S; Liu, Xiaobing; Rimsza, Lisa; Roe, Denise J; Manziolli, Ann; Persky, Daniel O; Miller, Thomas P; Mahadevan, Daruka

    2011-04-01

    Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC(50) of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237+docetaxel enhanced apoptosis by ~3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL. PMID:21291867

  15. F14512, a polyamine-vectorized inhibitor of topoisomerase II, exhibits a marked anti-tumor activity in ovarian cancer.

    PubMed

    Thibault, Benoît; Clement, Emily; Zorza, Grégoire; Meignan, Samuel; Delord, Jean-Pierre; Couderc, Bettina; Bailly, Christian; Narducci, Fabrice; Vandenberghe, Isabelle; Kruczynski, Anna; Guilbaud, Nicolas; Ferré, Pierre; Annereau, Jean-Philippe

    2016-01-01

    Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women and frequently associated with carboplatin resistance, underlining the need for more efficient and targeted therapies. F14512 is an epipodophylotoxin-core linked to a spermine chain which enters cells via the polyamine transport system (PTS). Here, we investigate this novel concept of vectorization in ovarian cancer. We compared the effects of etoposide and F14512 on a panel of five carboplatin-sensitive or resistant ovarian cancer models. We assessed the incorporation of F17073, a spermine-linked fluorescent probe, in these cells and in 18 clinical samples. We then showed that F14512 exhibits a high anti-proliferative and pro-apoptotic activity, particularly in cells with high levels of F17073 incorporation. Consistently, F14512 significantly inhibited tumor growth compared to etoposide, in a cisplatin-resistant A2780R subcutaneous model, at a dose of 1.25 mg/kg. In addition, ex vivo analysis indicated that 15 out of 18 patients presented a higher F17073 incorporation into tumor cells compared to normal cells. Overall, our data suggest that F14512, a targeted drug with a potent anti-tumor efficacy, constitutes a potential new therapy for highly PTS-positive and platinum-resistant ovarian cancer-bearing patients.

  16. Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma.

    PubMed

    Qi, Wenqing; Cooke, Laurence S; Liu, Xiaobing; Rimsza, Lisa; Roe, Denise J; Manziolli, Ann; Persky, Daniel O; Miller, Thomas P; Mahadevan, Daruka

    2011-04-01

    Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC(50) of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237+docetaxel enhanced apoptosis by ~3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL.

  17. Anti-Tumor and Immune Enhancing Activities of Rice Bran Gramisterol on Acute Myelogenous Leukemia

    PubMed Central

    Somintara, Somsuda; Leardkamolkarn, Vijittra; Suttiarporn, Panawan; Mahatheeranont, Sugunya

    2016-01-01

    Background Acute myelogenous leukemia (AML) is a cancer of the blood that most commonly affects human adults. The specific cause of AML is unclear, but it induces abnormality of white blood cells that grow rapidly and accumulate in bone marrow interfering with the production and functions of the normal blood cells. AML patients face poor prognosis and low quality of life during chemotherapy or transplantation of hematopoietic stem cells due to the progressive impairment of their immune system. The goal of this study is to find natural products that have the potential to delay growth or eliminate the abnormal leukemic cells but cause less harmful effect to the body’s immune system. Methods and Findings The unsaponified fraction of Riceberry rice bran (RBDS) and the main pure compound, gramisterol, were studied for cytotoxicity and biological activities in WEHI-3 cells and in the leukemic mouse model induced by transplantation of WEHI-3 cells intraperitoneally. In the in vitro assay, RBDS and gramisterol exerted sub-G1 phase cell cycle arrest with a potent induction of apoptosis. Both of them effectively decreased cell cycle controlling proteins (cyclin D1 and cyclin E), suppressed cellular DNA synthesis and mitotic division, and reduced anti-apoptosis Bcl-2 protein, but increased apoptotic proteins (p53 and Bax) and activated caspase-3 enzyme in the intrinsic cell death stimulation pathway. In leukemic mice, daily feeding of RBDS significantly increased the amount of immune function-related cells including CD3+, CD19+, and CD11b+, and elevated the serum levels of IFN-γ, TNF-α, IL-2, and IL-12β cytokines, but suppressed IL-10 level. At the tumor sites, CD11b+ cells were polarized and became active phagocytotic cells. Treatment of mice normal immune cells with gramisterol alone or a combination of gramisterol with cytokines released from RBDS-treated leukemic mice splenocytes culture synergistically increased pSTAT1 transcriptional factor that up-regulated the

  18. DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma

    PubMed Central

    Amodio, Nicola; Leotta, Marzia; Bellizzi, Dina; Di Martino, Maria Teresa; D'Aquila, Patrizia; Lionetti, Marta; Fabiani, Fernanda; Leone, Emanuela; Gullà, Anna Maria; Passarino, Giuseppe; Caraglia, Michele; Negrini, Massimo; Neri, Antonino; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2012-01-01

    Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs (miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene expression by targeting protein-coding mRNAs. However, miRNAs involvement in the regulation of the epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here, we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in MM cells. Moreover, we show that miR-29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA methylation in MM cells. In vitro transfection of MM cells with synthetic miR-29b mimics significantly impairs cell cycle progression and also potentiates the growth-inhibitory effects induced by the demethylating agent 5-azacitidine. Most importantly, in vivo intratumor or systemic delivery of synthetic miR-29b mimics, in two clinically relevant murine models of human MM, including the SCID-synth-hu system, induces significant anti-tumor effects. All together, our findings demonstrate that aberrant DNMTs expression is efficiently modulated by tumor suppressive synthetic miR-29b mimics, indicating that methyloma modulation is a novel matter of investigation in miRNA-based therapy of MM. PMID:23100393

  19. Cytotoxic and anti-tumor activities of lignans from the seeds of Vietnamese nutmeg Myristica fragrans.

    PubMed

    Thuong, Phuong Thien; Hung, Tran Manh; Khoi, Nguyen Minh; Nhung, Hoang Thi My; Chinh, Nguyen Thi; Quy, Nguyen Thi; Jang, Tae Su; Na, Minkyun

    2014-03-01

    Four lignans, meso-dihydroguaiaretic acid (DHGA), macelignan, fragransin A2 and nectandrin B, were isolated from the seeds of Myristica fragrans (Vietnamese nutmeg) and investigated for their cytotoxic activity against eight cancer cell lines. Of these, DHGA exhibited potent cytotoxicity against H358 with IC50 value of 10.1 μM. In addition, DHGA showed antitumor activity in allogeneic tumor-bearing mice model.

  20. Cytotoxic and anti-tumor activities of lignans from the seeds of Vietnamese nutmeg Myristica fragrans.

    PubMed

    Thuong, Phuong Thien; Hung, Tran Manh; Khoi, Nguyen Minh; Nhung, Hoang Thi My; Chinh, Nguyen Thi; Quy, Nguyen Thi; Jang, Tae Su; Na, Minkyun

    2014-03-01

    Four lignans, meso-dihydroguaiaretic acid (DHGA), macelignan, fragransin A2 and nectandrin B, were isolated from the seeds of Myristica fragrans (Vietnamese nutmeg) and investigated for their cytotoxic activity against eight cancer cell lines. Of these, DHGA exhibited potent cytotoxicity against H358 with IC50 value of 10.1 μM. In addition, DHGA showed antitumor activity in allogeneic tumor-bearing mice model. PMID:23877238

  1. Anti-tumor and immunomodulatory activity of iron hepta-tungsten phosphate oxygen clusters complex.

    PubMed

    Zhang, Bisong; Qiu, Jianping; Wu, Changsheng; Li, Yunxia; Liu, Zhenxiang

    2015-12-01

    Polyoxometalates (POMs) have attracted a considerable attention due to their unique structural characteristics, physicochemical properties and biological activities. In this study, iron hepta-tungsten phosphate oxygen clusters complex Na12H[Fe(HPW7O28)2]·44H2O (IHTPO) was synthesized and evaluated for in vitro cytotoxic activities on human hepatoma HepG2, leukemia K562, lung carcinoma A549, and large cell lung cancer NCI-H460 cells, therapeutic efficacies on mice transplantable tumor, and immunomodulatory potentials on the immune response in tumor-bearing mice. IHTPO exhibited lower in vitro cytotoxic activities against four human tumor cell lines, with the IC50 values being higher than 62.5μM (ca. 300μg/ml). IHTPO, however, significantly inhibited the growth of S180 sarcoma transplanted in mice. It was further showed that IHTPO could not only significantly promote splenocytes proliferation, NK cell and CTL activity from splenocytes, but remarkably enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. IHTPO also significantly promoted Th1 cytokines IFN-γ and IL-2 production, and up-regulated the mRNA expression levels of IFN-γ, IL-2 and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. These results suggested that IHTPO significantly inhibited the growth of mice transplantable tumor, and that its in vivo antitumor activity might be achieved by improving Th1 protective cell-mediated immunity. IHTPO could act as antitumor agent with immunomodulatory activity.

  2. Anti-tumor and anti-virus activity of polysaccharides extracted from Sipunculus nudus(SNP) on Hepg2.2.15.

    PubMed

    Su, Jie; Jiang, Linlin; Wu, Jingna; Liu, Zhiyu; Wu, Yuping

    2016-06-01

    Many polysaccharides have biological activities and have been investigated for their antitumor effects. In this study, we investigated the anti-tumor activity and anti-virus activity of SNP-the water-soluble polysaccharides extracted from Sipunculus nudus on Hepg2.2.15. Flow cytometry analysis demonstrated that SNP induced dose-dependent cell apoptosis on Hepg2.2.15. Real-time PCR and Western Blot analysis showed that SNP down-regulated the synthesis of HBsAg, HBV-DNA and enhanced the expression of pro-apoptosis proteins TNF-α, caspase-3, and Bax, while decreasing the expression of the anti-apoptosis proteins survivin, Bcl-2, and VEGF. These results suggested that SNP suppressed cell viability of Hepg2.2.15 and that could be a novel anti-tumor and anti-HBV agent.

  3. Anti-tumor activity of obinutuzumab and rituximab in a follicular lymphoma 3D model

    PubMed Central

    Decaup, E; Jean, C; Laurent, C; Gravelle, P; Fruchon, S; Capilla, F; Marrot, A; Al Saati, T; Frenois, F-X; Laurent, G; Klein, C; Varoqueaux, N; Savina, A; Fournié, J-J; Bezombes, C

    2013-01-01

    Follicular lymphomas (FLs) account for 35–40% of all adult lymphomas. Treatment typically involves chemotherapy combined with the anti-CD20 monoclonal antibody (MAb) rituximab (RTX). The development of the type II anti-CD20 MAb obinutuzumab (GA101) aims to further improve treatment. Here, using FL cells we show that RTX and GA101 display a similar activity on RL cells cultured in 2D. However, 2D culture cannot mimic tumor spatial organization and conventional 2D models may not reflect the effects of antibodies as they occur in vivo. Thus, we created a non-Hodgkin's lymphoma (NHL) 3D culture system, termed multicellular aggregates of lymphoma cells (MALC), and used it to compare RTX and GA101 activity. Our results show that both antibodies display greater activity towards FL cells in 3D culture compared with 2D culture. Moreover, we observed that in the 3D model GA101 was more effective than RTX both in inhibiting MALC growth through induction of (lysosomal) cell death and senescence and in inhibiting intracellular signaling pathways, such as mammalian target of rapamycin, Akt, PLCgamma (Phospholipase C gamma) and Syk. Altogether, our study demonstrates that spatial organization strongly influences the response to antibody treatment, supporting the use of 3D models for the testing of therapeutic agents in NHL. PMID:23933705

  4. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma

    PubMed Central

    Zhu, Yongxia; Ye, Tinghong; Yu, Xi; Lei, Qian; Yang, Fangfang; Xia, Yong; Song, Xuejiao; Liu, Li; Deng, Hongxia; Gao, Tiantao; Peng, Cuiting; Zuo, Weiqiong; Xiong, Ying; Zhang, Lidan; Wang, Ningyu; Zhao, Lifeng; Xie, Yongmei; Yu, Luoting; Wei, Yuquan

    2016-01-01

    Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK, and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma. PMID:26830149

  5. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma.

    PubMed

    Zhu, Yongxia; Ye, Tinghong; Yu, Xi; Lei, Qian; Yang, Fangfang; Xia, Yong; Song, Xuejiao; Liu, Li; Deng, Hongxia; Gao, Tiantao; Peng, Cuiting; Zuo, Weiqiong; Xiong, Ying; Zhang, Lidan; Wang, Ningyu; Zhao, Lifeng; Xie, Yongmei; Yu, Luoting; Wei, Yuquan

    2016-01-01

    Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK, and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma. PMID:26830149

  6. Carboxyl-terminal fusion of E7 into Flagellin shifts TLR5 activation to NLRC4/NAIP5 activation and induces TLR5-independent anti-tumor immunity

    PubMed Central

    Lin, Kuo-Hsing; Chang, Li-Sheng; Tian, Chun-Yuan; Yeh, Yi-Chen; Chen, Yu-Jie; Chuang, Tsung-Hsien; Liu, Shih-Jen; Leng, Chih-Hsiang

    2016-01-01

    Flagellin has the capacity to activate both Toll-like receptor 5 (TLR5) and Nod-like receptor C4 (NLRC4)/neuronal apoptosis inhibitory protein 5 (NAIP5) inflammasome signaling. We fused E7m (the inactivated E7 of human papillomavirus) to either end of the flagellin protein, and the resulting recombinant flagellin-E7m proteins (rFliCE7m and rE7mFliC) were used as immunogens. Both fusion proteins activated receptor signaling to different degrees. rE7mFliC-induced TLR5 activity was 10-fold higher than that of rFliCE7m, whereas rFliCE7m activated the NLRC4/NAIP5 pathway more strongly. Therefore, these recombinant proteins provided a tool to investigate which signaling pathway is critical for the induction of antigen-specific T cell responses and anti-tumor immunity. We demonstrated that rFliCE7m induced higher levels of E7-specific IFN-gamma-secreting cells and cytotoxic T lymphocytes (CTLs) than rE7mFliC, and a single injection with rFliCE7m but not rE7mFliC inhibited E7-expressing tumor growth in vivo. Furthermore, we confirmed that CD8+ T cells played a major role in the anti-tumor immunity induced by rFliCE7m. These findings suggested that the NLRC4/NAIP5 intracellular signaling pathway was critical for the induction of anti-tumor immunity. These observations provide important information for the rational design of flagellin-based immunotherapy. PMID:27063435

  7. Isolation and characterization of muscle fatigue substance with anti-tumor activities.

    PubMed

    Munoz, Ruben M; Han, Haiyong; Tegeler, Tony; Petritis, Konstantinos; Von Hoff, Daniel D; Hoffman, Stanley A

    2013-01-01

    Research during the 1950's indicated that exercise played a role in the reduction of tumor growth. In the 1960's our studies confirmed that tumor-bearing rats, exercised to fatigue, demonstrated tumor inhibition. Our further studies isolated an extract (Fatigue Substance, or F-Substance) from rectus femoris muscles of rats which had been electrically stimulated to fatigue. This extract significantly inhibited growth of transplanted rat tumors. Research continued until 1978 when it became apparent the methodology at that time was not able to further identify the substance's active components. Using current technology, we now report on the further isolation and characterization of F-Substance. In cell proliferation assays, extracts from electrically stimulated rat rectus femoris muscles had more significant inhibitory effect on the breast cancer cell line MCF-7 than those isolated from unstimulated muscles. To identify the molecule(s) responsible for the antitumor activity, a rat cytokine antibody array was used to profile the cytokines in the substances. Among the 29 different cytokines contained on the array, 3 showed greater than 3-fold difference between the substances isolated from the stimulated and unstimulated muscles. LIX (also known as CXCL5) is 6-fold higher in the substances isolated from stimulated muscles than those from the unstimulated muscles. TIMP-1 is 4.6 fold higher and sICAM is 3.6 fold higher in the substances from the stimulated muscles. Our results indicated that cytokines released from contracting muscles might be responsible for the antitumor effect of F-Substance.

  8. Anti-tumor activity of ESX1 on cancer cells harboring oncogenic K-ras mutation

    SciTech Connect

    Nakajima, Junta; Ishikawa, Susumu; Hamada, Jun-Ichi; Yanagihara, Masatomo; Koike, Takao; Hatakeyama, Masanori

    2008-05-23

    Human ESX1 is a 65-kilodalton (kDa) paired-like homeoprotein that is proteolytically processed into N-terminal 45-kDa and C-terminal 20-kDa fragments. The N-terminal ESX1 fragment, which contains the homeodomain, localizes to the nucleus and represses mRNA transcription from the K-ras gene. When we inoculated human colorectal carcinoma HCT116 constitutive expressing N-terminal region of ESX1 (N-ESX1) into nude mice, transfectant cells uniformly showed decreased tumor-forming activity compared with that of the parental cells. Furthermore, pretreatment of HCT116 carcinoma cells with a fusion protein consisting of N-ESX1 and the protein-transduction domain derived from the human immunodeficiency virus type-1 TAT protein gave rise to a dramatic reduction in the tumorigenicity of HCT116 cells in nude mice. Our results provide first in vivo evidence for the molecular targeting therapeutic application of the K-ras repressor ESX1, especially TAT-mediated transduction of N-ESX1, in the treatment of human cancers having oncogenic K-ras mutations.

  9. Chemically and Biologically Synthesized CPP-Modified Gelonin for Enhanced Anti-tumor Activity

    PubMed Central

    Shin, Meong Cheol; Zhang, Jian; David, Allan E.; Trommer, Wolfgang E.; Kwon, Young Min; Min, Kyoung Ah; Kim, Jin H.; Yang, Victor C.

    2013-01-01

    The ineffectiveness of small molecule drugs against cancer has generated significant interest in more potent macromolecular agents. Gelonin, a plant-derived toxin that inhibits protein translation, has attracted much attention in this regard. Due to its inability to internalize into cells, however, gelonin exerts only limited tumoricidal effect. To overcome this cell membrane barrier, we modified gelonin, via both chemical conjugation and genetic recombination methods, with low molecular weight protamine (LMWP), a cell-penetrating peptide (CPP) which was shown to efficiently ferry various cargos into cells. Results confirmed that gelonin-LMWP chemical conjugate (cG-L) and recombinant gelonin-LMWP chimera (rG-L) possessed N-glycosidase activity equivalent to that of unmodified recombinant gelonin (rGel); however, unlike rGel, both gelonin-LMWPs were able to internalize into cells. Cytotoxicity studies further demonstrated that cG-L and rG-L exhibited significantly improved tumoricidal effects, with IC50 values being 120-fold lower than that of rGel. Moreover, when tested against a CT26 s.c. xenograft tumor mouse model, significant inhibition of tumor growth was observed with rG-L doses as low as 2 μg/tumor, while no detectable therapeutic effects were seen with rGel at 10-fold higher doses. Overall, this study demonstrated the potential of utilizing CPP-modified gelonin as a highly potent anticancer drug to overcome limitations of current chemotherapeutic agents. PMID:23973813

  10. The anti-tumor drug bleomycin preferentially cleaves at the transcription start sites of actively transcribed genes in human cells.

    PubMed

    Murray, Vincent; Chen, Jon K; Galea, Anne M

    2014-04-01

    The genome-wide pattern of DNA cleavage at transcription start sites (TSSs) for the anti-tumor drug bleomycin was examined in human HeLa cells using next-generation DNA sequencing. It was found that actively transcribed genes were preferentially cleaved compared with non-transcribed genes. The 143,600 identified human TSSs were split into non-transcribed genes (82,596) and transcribed genes (61,004) for HeLa cells. These transcribed genes were further split into quintiles of 12,201 genes comprising the top 20, 20-40, 40-60, 60-80, and 80-100 % of expressed genes. The bleomycin cleavage pattern at highly transcribed gene TSSs was greatly enhanced compared with purified DNA and non-transcribed gene TSSs. The top 20 and 20-40 % quintiles had a very similar enhanced cleavage pattern, the 40-60 % quintile was intermediate, while the 60-80 and 80-100 % quintiles were close to the non-transcribed and purified DNA profiles. The pattern of bleomycin enhanced cleavage had peaks that were approximately 200 bp apart, and this indicated that bleomycin was identifying the presence of phased nucleosomes at TSSs. Hence bleomycin can be utilized to detect chromatin structures that are present at actively transcribed genes. In this study, for the first time, the pattern of DNA damage by a clinically utilized cancer chemotherapeutic agent was performed on a human genome-wide scale at the nucleotide level.

  11. Synthesis, anti-hypertensive effect of a novel angiotensin II AT1 receptor antagonist and its anti-tumor activity in prostate cancer.

    PubMed

    Da, Y-J; Yuan, W-D; Zhu, L-F; Chen, Z-L

    2012-12-01

    Since the first non-peptide Ang II receptor antagonist was originally reported, it has become the most common target in the development of new treatments for hypertension. In recent years, all components of the classical RAS have been reported in the prostate, these results suggest the possibility that ARB is a novel therapeutic class of agents for prostate cancer. In this study, a new compound 2-(4-((2-propyl-5-nitro-1H-benzo[d]imidazol-1-yl) methyl)-1H-indol-1-yl) benzoic acid was synthesized and evaluated as a novel angiotensin II AT1 receptor antagonist by radioligand binding assays, anti-hypertensive assays in vivo and oral acute toxicity test. MTT assays and tests in nude mice were used to demonstrate its anti-tumor activity. This new compound showed high affinity to AT1 receptor and anti-hypertensive activity in spontaneously hypertensive rats and renal hypertensive rats. Moreover, in human prostate cancer cells and in athymic nude mice bearing human prostate cancer cells, we observed this new compound had an efficient antiproliferative activity in vitro and anti-tumor activity in vivo. The preliminary pharmacological characteristics with oral acute toxicity test suggested that this new compound can be considered as a candidate for both anti-hypertensive and anti-tumor drug. PMID:23203543

  12. Research progress of ursolic acid's anti-tumor actions.

    PubMed

    Zang, Li-li; Wu, Bao-ning; Lin, Yuan; Wang, Jun; Fu, Lei; Tang, Ze-yao

    2014-01-01

    Ursolic acid (UA) is a sort of pentacyclic triterpenoid carboxylic acid purified from natural plant. UA has a series of biological effects such as sedative, anti-inflammatory, anti-bacterial, anti-diabetic, antiulcer, etc. It is discovered that UA has a broad-spectrum anti-tumor effect in recent years, which has attracted more and more scholars' attention. This review explained anti-tumor actions of UA, including (1) the protection of cells' DNA from different damages; (2) the anti-tumor cell proliferation by the inhibition of epidermal growth factor receptor/mitogen-activated protein kinase signal or of FoxM1 transcription factors, respectively; (3) antiangiogenesis, (4) the immunological surveillance to tumors; (5) the inhibition of tumor cell migration and invasion; (6) the effect of UA on caspase, cytochromes C, nuclear factor kappa B, cyclooxygenase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or mammalian target of rapamycin signal to induce tumor cell apoptosis respectively, and etc. Moreover, UA has selective toxicity to tumor cells, basically no effect on normal cells. With further studies, UA would be one of the potential anti-tumor agents. PMID:24374755

  13. Enhanced anti-angiogenesis and anti-tumor activity of endostatin by chemical modification with polyethylene glycol and low molecular weight heparin.

    PubMed

    Tan, Haining; Yang, Shenglin; Liu, Chunhui; Cao, Jichao; Mu, Guoying; Wang, Fengshan

    2012-12-01

    Endostatin (ES), a potent endogenous angiogenesis inhibitor found in 1997 by O'Reilly, can effectively inhibit angiogenesis, inhibit the growth and metastasis of tumors. ES can also decrease drug resistance in long term and repeated treatment when it is used in combination with other chemotherapeutic agents. But there are still lots of obstacles on its clinical application, such as the need of a high dose to maintain its efficacy short half-life, poor stability, expensive, and some other shortcomings just like other protein drugs. Chemical modification on ES by polyethylene glycol (PEG) and low molecular weight heparin (LMWH) were successfully carried out in order to obtain a better ES derivative. Several classic experimental models were employed to study the bioactivity of ES and modified ES, including chicken chorioallantoic membrane (CAM) assay, corneal neovascularization (CNV) assay and Sarcoma 180 tumor bearing mice assay. The results showed that PEG-ES and LMWH-ES had better anti-angiogenesis and anti-tumor activity than ES, which indicates that LMWH was also a good protein modifier.

  14. Physalin A exerts anti-tumor activity in non-small cell lung cancer cell lines by suppressing JAK/STAT3 signaling

    PubMed Central

    Loo, Jacky F.C.; Xia, Dajin; Gao, Sizhi P.; Ma, Zhongjun; Chen, Zhe

    2016-01-01

    The signal transducers and activators of transcription 3 (STAT3) signaling pathway plays critical roles in the pathogenesis and progression of various human cancers, including non-small cell lung cancer (NSCLC). In this study, we aimed to evaluate the therapeutic potential of physalin A, a bioactive withanolide derived from Physalis alkekengi var. francheti used in traditional Chinese medicine, was evaluated in human NSCLC cells. Its and determined whether it effect oninhibited both constitutive and induced STAT3 activity, through repressing the phosphorylation levels of JAK2 and JAK3, resulting in anti-proliferation and pro-apoptotic effects on NSCLC cells was also determined, and. theThe antitumor effects of physalin A were also validated usingin an in vivo mouse xenograft models of NSCLC cells. Physalin A had anti-proliferative and pro-apoptotic effects in NSCLC cells with constitutively activated STAT3; it also suppressed both constitutive and induced STAT3 activity by modulating the phosphorylation of JAK2 and JAK3. Furthermore, physalin A abrogated the nuclear translocation and transcriptional activity of STAT3, thereby decreasing the expression levels of STAT3, its target genes, such as Bcl-2 and XIAP. Knockdown of STAT3 expression by small interfering RNA (siRNA) significantly enhanced the pro-apoptotic effects of physalin A in NSCLC cells. Moreover, physalin A significantly suppressed tumor xenograft growth. Thus, as an inhibitor of JAK2/3-STAT3 signaling, physalin A, has potent anti-tumor activities, which may facilitate the development of a therapeutic strategy for treating NSCLC. PMID:26843613

  15. Inhibition of protein kinase CK2 reduces CYP24A1 expression and enhances 1,25-dihydroxyvitamin D3 anti-tumor activity in human prostate cancer cells

    PubMed Central

    Luo, Wei; Yu, Wei-Dong; Ma, Yingyu; Chernov, Mikhail; Trump, Donald L.; Johnson, Candace S.

    2013-01-01

    Vitamin D has broad range of physiological functions and anti-tumor effects. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 anti-tumor activity. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3 induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3 mediated target gene expression. Lastly, inhibition of CK2 by TBBz or CK2 siRNA significantly enhanced 1,25D3 mediated anti-proliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3 mediated anti-tumor effect. PMID:23358686

  16. EBI-907, a novel BRAF(V600E) inhibitor, has potent oral anti-tumor activity and a broad kinase selectivity profile.

    PubMed

    Zhang, Jiayin; Lu, Biao; Liu, Dong; Shen, Ru; Yan, Yinfa; Yang, Liuqing; Zhang, Minsheng; Zhang, Lei; Cao, Guoqing; Cao, Hu; Fu, Beibei; Gong, Aishen; Sun, Qiming; Wan, Hong; Zhang, Lianshan; Tao, Weikang; Cao, Jingsong

    2016-01-01

    The oncogenic mutation of BRAF(V600E) has been found in approximately 8% of all human cancers, including more than 60% of melanoma and 10% of colorectal cancers. The clinical proof of concept in treating BRAF(V600E)-driving melanoma patients with the BRAF inhibitors has been well established. We have sought to identify and develop novel BRAF(V600E) inhibitors with more favorable profiles. Our chemistry effort has led to the discovery of EBI-907 as a novel BRAF(V600E) inhibitor with potent anti-tumor activity in vitro and in vivo. In a LanthaScreen BRAF(V600E) kinase assay, EBI-907 showed an IC50 of 4.8 nM, which is >10 -fold more potent than Vemurafenib (IC50 = 58.5 nM). In addition, EBI-907 showed a broader kinase selectivity profile, with potent activity against a number of important oncogenic kinases including FGFR1-3, RET, c-Kit, and PDGFRb. Concomitant with such properties, EBI-907 exhibits potent and selective cytotoxicity against a broader range of BRAF(V600E)-dependent cell lines including certain colorectal cancer cell lines with innate resistance to Vemurafenib. In BRAF(V600E)-dependent human Colo-205 and A375 tumor xenograft mouse models, EBI-907 caused a marked tumor regression in a dose-dependent manner, with superior efficacy to Vemurafenib. Our results also showed that combination with EGFR or MEK inhibitor enhanced the potency of EBI-907 in cell lines with innate or acquired resistance to BRAF inhibition alone. Our findings present EBI-907 as a potent and promising BRAF inhibitor, which might be useful in broader indications. PMID:26810733

  17. EBI-907, a novel BRAF(V600E) inhibitor, has potent oral anti-tumor activity and a broad kinase selectivity profile.

    PubMed

    Zhang, Jiayin; Lu, Biao; Liu, Dong; Shen, Ru; Yan, Yinfa; Yang, Liuqing; Zhang, Minsheng; Zhang, Lei; Cao, Guoqing; Cao, Hu; Fu, Beibei; Gong, Aishen; Sun, Qiming; Wan, Hong; Zhang, Lianshan; Tao, Weikang; Cao, Jingsong

    2016-01-01

    The oncogenic mutation of BRAF(V600E) has been found in approximately 8% of all human cancers, including more than 60% of melanoma and 10% of colorectal cancers. The clinical proof of concept in treating BRAF(V600E)-driving melanoma patients with the BRAF inhibitors has been well established. We have sought to identify and develop novel BRAF(V600E) inhibitors with more favorable profiles. Our chemistry effort has led to the discovery of EBI-907 as a novel BRAF(V600E) inhibitor with potent anti-tumor activity in vitro and in vivo. In a LanthaScreen BRAF(V600E) kinase assay, EBI-907 showed an IC50 of 4.8 nM, which is >10 -fold more potent than Vemurafenib (IC50 = 58.5 nM). In addition, EBI-907 showed a broader kinase selectivity profile, with potent activity against a number of important oncogenic kinases including FGFR1-3, RET, c-Kit, and PDGFRb. Concomitant with such properties, EBI-907 exhibits potent and selective cytotoxicity against a broader range of BRAF(V600E)-dependent cell lines including certain colorectal cancer cell lines with innate resistance to Vemurafenib. In BRAF(V600E)-dependent human Colo-205 and A375 tumor xenograft mouse models, EBI-907 caused a marked tumor regression in a dose-dependent manner, with superior efficacy to Vemurafenib. Our results also showed that combination with EGFR or MEK inhibitor enhanced the potency of EBI-907 in cell lines with innate or acquired resistance to BRAF inhibition alone. Our findings present EBI-907 as a potent and promising BRAF inhibitor, which might be useful in broader indications.

  18. Akbu-LAAO exhibits potent anti-tumor activity to HepG2 cells partially through produced H2O2 via TGF-β signal pathway

    PubMed Central

    Guo, Chunmei; Liu, Shuqing; Dong, Panpan; Zhao, Dongting; Wang, Chengyi; Tao, Zhiwei; Sun, Ming-Zhong

    2015-01-01

    Previously, we characterized the biological properties of Akbu-LAAO, a novel L-amino acid oxidase from Agkistrodon blomhoffii ussurensis snake venom (SV). Current work investigated its in vitro anti-tumor activity and underlying mechanism on HepG2 cells. Akbu-LAAO inhibited HepG2 growth time and dose-dependently with an IC50 of ~38.82 μg/mL. It could induce the apoptosis of HepG2 cells. Akbu-LAAO exhibited cytotoxicity by inhibiting growth and inducing apoptosis of HepG2 as it showed no effect on its cell cycle. The inhibition of Akbu-LAAO to HepG2 growth partially relied on enzymatic-released H2O2 as catalase only partially antagonized this effect. cDNA microarray results indicated TGF-β signaling pathway was linked to the cytotoxicity of Akbu-LAAO on HepG2. TGF-β pathway related molecules CYR61, p53, GDF15, TOB1, BTG2, BMP2, BMP6, SMAD9, JUN, JUNB, LOX, CCND1, CDK6, GADD45A, CDKN1A were deregulated in HepG2 following Akbu-LAAO stimulation. The presence of catalase only slightly restored the mRNA changes induced by Akbu-LAAO for differentially expressed genes. Meanwhile, LDN-193189, a TGF-β pathway inhibitor reduced Akbu-LAAO cytotoxicity on HepG2. Collectively, we reported, for the first time, SV-LAAO showed anti-tumor cell activity via TGF-β pathway. It provides new insight of SV-LAAO exhibiting anti-tumor effect via a novel signaling pathway. PMID:26655928

  19. Akbu-LAAO exhibits potent anti-tumor activity to HepG2 cells partially through produced H2O2 via TGF-β signal pathway.

    PubMed

    Guo, Chunmei; Liu, Shuqing; Dong, Panpan; Zhao, Dongting; Wang, Chengyi; Tao, Zhiwei; Sun, Ming-Zhong

    2015-01-01

    Previously, we characterized the biological properties of Akbu-LAAO, a novel L-amino acid oxidase from Agkistrodon blomhoffii ussurensis snake venom (SV). Current work investigated its in vitro anti-tumor activity and underlying mechanism on HepG2 cells. Akbu-LAAO inhibited HepG2 growth time and dose-dependently with an IC50 of ~38.82 μg/mL. It could induce the apoptosis of HepG2 cells. Akbu-LAAO exhibited cytotoxicity by inhibiting growth and inducing apoptosis of HepG2 as it showed no effect on its cell cycle. The inhibition of Akbu-LAAO to HepG2 growth partially relied on enzymatic-released H2O2 as catalase only partially antagonized this effect. cDNA microarray results indicated TGF-β signaling pathway was linked to the cytotoxicity of Akbu-LAAO on HepG2. TGF-β pathway related molecules CYR61, p53, GDF15, TOB1, BTG2, BMP2, BMP6, SMAD9, JUN, JUNB, LOX, CCND1, CDK6, GADD45A, CDKN1A were deregulated in HepG2 following Akbu-LAAO stimulation. The presence of catalase only slightly restored the mRNA changes induced by Akbu-LAAO for differentially expressed genes. Meanwhile, LDN-193189, a TGF-β pathway inhibitor reduced Akbu-LAAO cytotoxicity on HepG2. Collectively, we reported, for the first time, SV-LAAO showed anti-tumor cell activity via TGF-β pathway. It provides new insight of SV-LAAO exhibiting anti-tumor effect via a novel signaling pathway. PMID:26655928

  20. Bystander Activation and Anti-Tumor Effects of CD8+ T Cells Following Interleukin-2 Based Immunotherapy Is Independent of CD4+ T Cell Help

    PubMed Central

    Grossenbacher, Steven K.; Hsiao, Hui-Hua; Zamora, Anthony E.; Mirsoian, Annie; Koehn, Brent; Blazar, Bruce R.; Weiss, Jonathan M.; Wiltrout, Robert H.; Sckisel, Gail D.; Murphy, William J.

    2014-01-01

    We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent “bystander-activated” (CD8+CD44high) T cells displaying a CD25−NKG2D+ phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4+ T cell help for antigen-specific CD8+ T cell expansion, little is known regarding the role of CD4+ T cells in antigen-nonspecific bystander-memory CD8+ T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8+ T cells upregulated PD-1 in the absence of CD4+ T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8+ T cells. Interestingly, compared to CD8+ T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8+ response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8+ T cell expansion, CD4+ T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8+ T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion. PMID:25119341

  1. Neutrophil lymphocyte ratio can be a valuable marker in defining disease activity in patients who have started anti-tumor necrosis factor (TNF) drugs for ankylosing spondylitis

    PubMed Central

    Coşkun, Belkıs Nihan; Öksüz, Mustafa Ferhat; Ermurat, Selime; Tufan, Ayşe Nur; Oruçoğlu, Nurdan; Doğan, Akif; Dalkılıç, Ediz; Pehlivan, Yavuz

    2014-01-01

    Objective Neutrophil lymphocyte ratio (NLR) has emerged as a valuable and reliable method for follow-up of systemic inflammatory disease. We herein aimed to evaluate the role of NLR in the clinical follow-up of inflammation and also to compare its relationship with other measures, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Material and Methods A total of 35 active ankylosing spondylitis (AS) and 38 healthy volunteers were included in the study. The patient group was enrolled for treatment with one anti-tumor necrosis factor (TNF) drug. Total blood count, ESR, CRP, and BASDAI score were obtained before and 3 months following the treatment. NLR was found with a mathematical calculation of the ratio of neutrophils with lymphocytes. Results The mean NLR value of the control group and patients was 1.90±0.89 and 2.67±1.17, respectively (p<0.05). After a 3-month course of treatment, the patient group had a mean NLR value of 1.8±0.7, which was significantly lower than pretreatment values (p<0.001). The post-treatment mean ESR, CRP, and BASDAI scores were significantly lower than mean baseline scores (p<0.001, p=0.007, p<0.001, respectively). Also, NLR was found to be correlated with BASDAI, ESR, and CRP (r=0.388, p<0.001; r=0.455, p<0.0001; and r=0.3389, p<0.005, respectively). Conclusion Neutrophil lymphocyte ratio could be a reliable and easily accessible method for follow-up of patients with AS. PMID:27708888

  2. Anti-CCR7 therapy exerts a potent anti-tumor activity in a xenograft model of human mantle cell lymphoma

    PubMed Central

    2013-01-01

    Background The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model. Methods NOD/SCID mice were either subcutaneously or intravenously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. The anti-CCR7 mAb treatment (3 × 200 μg) was started on day 2 or 7 to target lymphoma cells in either a peri-implantation or a post-implantation stage, respectively. Results The anti-CCR7 therapy significantly delayed the tumor appearance and also reduced the volumes of tumors in the subcutaneous model. Moreover, an increased number of apoptotic tumor cells was detected in mice treated with the anti-CCR7 mAb compared to the untreated animals. In addition, significantly reduced number of Granta-519 cells migrated from subcutaneous tumors to distant lymphoid organs, such as bone marrow and spleen in the anti-CCR7 treated mice. In the intravenous models, the anti-CCR7 mAb drastically increased survival of the mice. Accordingly, dissemination and infiltration of tumor cells in lymphoid and non-lymphoid organs, including lungs and central nervous system, was almost abrogated. Conclusions The anti-CCR7 mAb exerts a potent anti-tumor activity and might represent an interesting therapeutic alternative to conventional therapies. PMID:24305507

  3. PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment.

    PubMed

    Lam, Wing; Jiang, Zaoli; Guan, Fulan; Huang, Xiu; Hu, Rong; Wang, Jing; Bussom, Scott; Liu, Shwu-Huey; Zhao, Hongyu; Yen, Yun; Cheng, Yung-Chi

    2015-01-01

    PHY906 (KD018) is a four-herb Chinese Medicine Formula. It has been shown to potentially enhance the therapeutic indices of different class anticancer agents in vivo. Here, PHY906 is reported to enhance the anti-tumor activity of Sorafenib in nude mice bearing HepG2 xenografts. Among the four herbal ingredients of PHY906, Scutellaria baicalensis Georgi (S) and Paeonia lactiflora Pall (P) are required; however, S plays a more important role than P in increasing tumor apoptosis induced by Sorafenib with an increase of mouse(m)FasL and human(h)FasR expression. PHY906 may potentiate Sorafenib action by increasing hMCP1 expression and enhancing infiltration of macrophages into tumors with a higher M1/M2 (tumor rejection) signature expression pattern, as well as affect autophagy by increasing AMPKα-P and ULK1-S555-P of tumors. Depletion of macrophage could counteract PHY906 to potentiate the anti-tumor activity of Sorafenib. It was reported that tumor cells with higher levels of ERK1/2-P are more susceptible to Sorafenib, and the S component of PHY906 may increase ERK1/2-P via inhibition of ERK1/2 phosphatase in HepG2 tumors. PHY906 may potentiate the anti-hepatoma activity of Sorafenib by multiple mechanisms targeting on the inflammatory state of microenvironment of tumor tissue through two major ingredients (P and S) of PHY906. PMID:25819872

  4. VEGFR2 targeted antibody fused with MICA stimulates NKG2D mediated immunosurveillance and exhibits potent anti-tumor activity against breast cancer.

    PubMed

    Xie, Wei; Liu, Fang; Wang, Youfu; Ren, Xueyan; Wang, Tong; Chen, Zhiguo; Tang, Mingying; Sun, Fumou; Li, Zhaoting; Wang, Min; Zhang, Juan

    2016-03-29

    Binding of MHC class I-related chain molecules A and B (MICA/B) to the natural killer (NK) cell receptor NK group 2, member D (NKG2D) is thought critical for activating NK-mediated immunosurveillance. Angiogenesis is important for tumor growth and interfering with angiogenesis using the fully human IgG1 anti-VEGFR2 (vascular endothelial growth factor receptor 2) antibody (mAb04) can be effective in treating malignancy. In an effort to make mAb04 more effective we have generated a novel antibody fusion protein (mAb04-MICA) consisting of mAb04 and MICA. We found that mAb04-MICA maintained the anti-angiogenic and antineoplastic activities of mAb04, and also enhanced immunosurveillance activated by the NKG2D pathway. Moreover, in human breast tumor-bearing nude mice, mAb04-MICA demonstrated superior anti-tumor efficacy compared to combination therapy of mAb04 + Docetaxel or Avastin + Docetaxel, highlighting the immunostimulatory effect of MICA. In conclusion, mAb04-MICA provided new inspiration for anti-tumor treatment and had prospects for clinical application.

  5. [Discovery of Novel Biologically Active Compounds of Natural Origin, with a Focus on Anti-tumor Activity].

    PubMed

    Yokosuka, Akihito

    2015-01-01

    Numerous clinically valuable medicines, including anticancer drugs, have been developed from biologically active natural compounds and their structurally related derivatives. This review discusses novel natural compounds with promising biological activities and those with novel chemical structures. Glaziovianin A, an isoflavone isolated from the leaves of Ateleia glazioviana (Legminosae), inhibited cell cycle progression at the M-phase with an abnormal spindle structure. AU-1 and YG-1, 5β-steroidal glycosides isolated from the whole plants of Agave utahensis and the underground parts of Yucca glauca (Agavaceae), induced apoptosis of HL-60 cells via caspase-3 activation. Lycolicidinol, an alkaloid isolated from the bulbs of Lycoris albiflora (Amaryllidaceae), induced transient autophagy and morphological changes in mitochondria in the early stage of the apoptotic cell death process in HSC-2 cells. Taccasterosides isolated from the rhizomes of Tacca chantrieri (Taccaceae) and stryphnosides isolated from the pericarps of Stryphnodendron fissuratum (Legminosae) are steroidal and triterpene glycosides with unique chemical structures having novel sugar sequences.

  6. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity.

    PubMed

    Fisher, Timothy S; Kamperschroer, Cris; Oliphant, Theodore; Love, Victoria A; Lira, Paul D; Doyonnas, Regis; Bergqvist, Simon; Baxi, Sangita M; Rohner, Allison; Shen, Amy C; Huang, Chunli; Sokolowski, Sharon A; Sharp, Leslie L

    2012-10-01

    4-1BB (CD137, TNFRSF9) is a costimulatory receptor expressed on several subsets of activated immune cells. Numerous studies of mouse and human T cells indicate that 4-1BB promotes cellular proliferation, survival, and cytokine production. 4-1BB agonist mAbs have demonstrated efficacy in prophylactic and therapeutic settings in both monotherapy and combination therapy tumor models and have established durable anti-tumor protective T-cell memory responses. PF-05082566 is a fully human IgG2 that binds to the extracellular domain of human 4-1BB with high affinity and specificity. In preclinical studies, this agonist antibody demonstrated its ability to activate NF-κB and induce downstream cytokine production, promote leukocyte proliferation, and inhibit tumor growth in a human PBMC xenograft tumor model. The mechanism of action and robust anti-tumor efficacy of PF-05082566 support its clinical development for the treatment of a broad spectrum of human malignancies. PMID:22406983

  7. Anti-tumor activity of heat-killed Lactobacillus plantarum BF-LP284 on Meth-A tumor cells in BALB/c mice.

    PubMed

    Shin, Ryoichi; Itoh, Yukie; Kataoka, Motoyuki; Iino-Miura, Shiori; Miura, Ryosuke; Mizutani, Takeo; Fujisawa, Tomohiko

    2016-09-01

    Probiotics exert numerous effects on human well-being. Here, heat-killed Lactobacillus plantarum BF-LP284 (H-Lp) was isolated as a potent immuno-modulator among 15 strains of lactobacilli in terms of TNF-α induction ability in peritoneal macrophages. In vitro TNF-α and IFN-γ induction in Peyer's patch (PP) cells was higher when incubated with H-Lp than with live L. plantarum BF-LP284 (L-Lp). Suppression of syngeneic Meth-A tumors in a murine model by oral administration of H-Lp was also greater than that of L-Lp and of controls. H-Lp stimulated IFN-γ production in spleen cells, which displayed inhibited tumor growth in Winn assays when treated with H-Lp. Moreover, H-Lp increased the ratio of CD3(+ )cells among peripheral blood mononuclear cells in Meth-A tumor-bearing mice, suggesting an H-Lp-mediated anti-tumor mechanism whereby immune cells that are activated by H-Lp in PP and acquire anti-tumor activity in the spleen migrate to tumor sites through lymphocyte homing to inhibit tumor growth. PMID:27198983

  8. The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions

    PubMed Central

    Wu, Shaowei; Fu, Xiong; Brennan, Margaret A.; Brennan, Charles S.; Chun, Chen

    2016-01-01

    Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L). Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography (GC) were used to characterize these Abrus polysaccharides fractions (APF). In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR) method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%), arabinose (8.9%), fructose (3.0%), galactose (9.9%), glucose (4.3%), galacturonic acid (3.0%) and glucuronic acid (61.1%) with a molecular weight of 4.4 × 104 Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO) production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent. PMID:27058538

  9. A Monoclonal Antibody to O-Acetyl-GD2 Ganglioside and Not to GD2 Shows Potent Anti-Tumor Activity without Peripheral Nervous System Cross-Reactivity

    PubMed Central

    Cochonneau, Denis; Chaumette, Tanguy; Clemenceau, Béatrice; Leprieur, Stéphanie; Bougras, Gwenola; Supiot, Stéphane; Mussini, Jean-Marie; Barbet, Jacques; Saba, Julie; Paris, François; Aubry, Jacques; Birklé, Stéphane

    2011-01-01

    Background Monoclonal antibodies (mAb) against GD2 ganglioside have been shown to be effective for the treatment of neuroblastoma. Beneficial actions are, however, associated with generalized pain due to the binding of anti- GD2 mAbs to peripheral nerve fibers followed by complement activation. Neuroblastoma cells that express GD2 also express its O-acetyl derivative, O-acetyl- GD2 ganglioside (OAcGD2). Hence, we investigated the distribution of OAcGD2 in human tissues using mAb 8B6 to study the cross-reactivity of mAb 8B6 with human tissues. Methodology/Principal Findings The distribution of OAcGD2 was performed in normal and malignant tissues using an immunoperoxydase technique. Anti-tumor properties of mAb 8B6 were studied in vitro and in vivo in a transplanted tumor model in mice. We found that OAcGD2 is not expressed by peripheral nerve fibers. Furthermore, we demonstrated that mAb 8B6 was very effective in the in vitro and in vivo suppression of the growth of tumor cells. Importantly, mAb 8B6 anti-tumor efficacy was comparable to that of mAb 14G2a specific to GD2. Conclusion/Significance Development of therapeutic antibodies specific to OAcGD2 may offer treatment options with reduced adverse side effects, thereby allowing dose escalation of antibodies. PMID:21966461

  10. The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions.

    PubMed

    Wu, Shaowei; Fu, Xiong; Brennan, Margaret A; Brennan, Charles S; Chun, Chen

    2016-01-01

    Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L). Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography (GC) were used to characterize these Abrus polysaccharides fractions (APF). In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR) method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%), arabinose (8.9%), fructose (3.0%), galactose (9.9%), glucose (4.3%), galacturonic acid (3.0%) and glucuronic acid (61.1%) with a molecular weight of 4.4 × 10⁴ Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO) production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent. PMID:27058538

  11. [Discovery of Novel Biologically Active Compounds of Natural Origin, with a Focus on Anti-tumor Activity].

    PubMed

    Yokosuka, Akihito

    2015-01-01

    Numerous clinically valuable medicines, including anticancer drugs, have been developed from biologically active natural compounds and their structurally related derivatives. This review discusses novel natural compounds with promising biological activities and those with novel chemical structures. Glaziovianin A, an isoflavone isolated from the leaves of Ateleia glazioviana (Legminosae), inhibited cell cycle progression at the M-phase with an abnormal spindle structure. AU-1 and YG-1, 5β-steroidal glycosides isolated from the whole plants of Agave utahensis and the underground parts of Yucca glauca (Agavaceae), induced apoptosis of HL-60 cells via caspase-3 activation. Lycolicidinol, an alkaloid isolated from the bulbs of Lycoris albiflora (Amaryllidaceae), induced transient autophagy and morphological changes in mitochondria in the early stage of the apoptotic cell death process in HSC-2 cells. Taccasterosides isolated from the rhizomes of Tacca chantrieri (Taccaceae) and stryphnosides isolated from the pericarps of Stryphnodendron fissuratum (Legminosae) are steroidal and triterpene glycosides with unique chemical structures having novel sugar sequences. PMID:26423865

  12. Arctigenin anti-tumor activity in bladder cancer T24 cell line through induction of cell-cycle arrest and apoptosis.

    PubMed

    Yang, Shucai; Ma, Jing; Xiao, Jianbing; Lv, Xiaohong; Li, Xinlei; Yang, Huike; Liu, Ying; Feng, Sijia; Zhang, Yafang

    2012-08-01

    Bladder cancer is the most common neoplasm in the urinary system. This study assesses arctigenin anti-tumor activity in human bladder cancer T24 cells in vitro and the underlying molecular events. The flow cytometry analysis was used to detect cell-cycle distribution and apoptosis. Western blotting was used to detect changes in protein expression. The data showed that arctigenin treatment reduced viability of bladder cancer T24 cells in a dose- and time-dependent manner after treatment with arctigenin (10, 20, 40, 80, and 100 μmol/L) for 24 hr and 48 hr. Arctigenin treatment clearly arrested tumor cells in the G1 phase of the cell cycle. Apoptosis was detected by hoechst stain and flow cytometry after Annexin-V-FITC/PI double staining. Early and late apoptotic cells were accounted for 2.32-7.01% and 3.07-7.35%, respectively. At the molecular level, arctigenin treatment decreased cyclin D1 expression, whereas CDK4 and CDK6 expression levels were unaffected. Moreover, arctigenin selectively altered the phosphorylation of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 and activated phosphorylation of p38 significantly in a dose-dependent manner. These results suggest that arctigenin may inhibit cell viability and induce apoptosis by direct activation of the mitochondrial pathway, and the mitogen-activated protein kinase pathway may play an important role in the anti-tumor effect of arctigenin. The data from the current study demonstrate the usefulness of arctigenin in bladder cancer T24 cells, which should further be evaluated in vivo before translation into clinical trials for the chemoprevention of bladder cancer.

  13. [The anti-tumor mechanisms in long-lived rodents].

    PubMed

    Dong, Yanjiao; Pang, Yue; Li, Qingwei

    2016-05-01

    Rodents, including the nude mice with congenital aplasia of the thymus, cancer-resistant naked mole rat (Heterocephalus glaber) and blind mole rat (Spalax galili), are important model organisms that are widely used in biomedical research. The aging process is closely related to cancer incidence in mammals and the aging degree is positively correlated with the risk of cancer. Since rodents account for 40% of mammals, study of the unique antitumor mechanism in long-lived rodents is very important. Replicative senescence is anti-tumor mechanism that prevalently exist in rodents, however, unique anti-tumor mechanisms have been found in naked mole-rats and blind mole-rats. The cancer resistance of Spalax galili is mediated by cell-released IFN-β which activates p53 and Rb signaling pathway and the cells undergoes concerted cell death while that of Heterocephalus glaber is mediated by high molecular weight hyaluronan (HMW-HA) which causes contact inhibition. In addition, highly expressed pro-cell-death and anti-inflammation related genes are found in the genome of both naked mole-rats and blind mole-rats. In this review, we summarize the anti-tumor mechanisms in both Heterocephalus glaber and Spalax galili, which may provide information for related research. PMID:27232489

  14. [Halophilous microbial groups in saline lake of Qinghai and the growth characteristics and anti-microbial and anti-tumor activities of F16].

    PubMed

    Ye, Yanfang; Yan, Xiaojun; Huang, Xiaochun; Chen, Ye; Chen, Haimin; Zhu, Shihua

    2006-10-01

    A total of forty-five halophilous microorganisms were isolated from the sediment of saline lake in Qinghai Province, among which, filamentous fungus F16 showed the highest activity of anti-microorganism and anti-tumor. The ethyl acetate extract of F16 culture filtrate showed a strong cytotoxicity, and could inhibit the growth of four kinds of bacteria, especially Escherichia coli. When the concentration of the crude extract was 50 microg x ml(-1), the inhibition rate to liver cancer cell BEL7402 reached 76. 91%. The optimal temperature for F16 growth was 15 degrees C , and the increase of salt concentration in media would inhibit its growth. When the concentration of salt surpassed 15% , F16 could not survive. F16 grew well when the pH value ranged from 5 to 9.

  15. Anti-tumor activity and safety evaluation of fisetin-loaded methoxy poly(ethylene glycol)-poly(epsilon-caprolactone) nanoparticles.

    PubMed

    Yang, Qian; Liao, Jinfeng; Deng, Xin; Liang, Jian; Long, Chaofeng; Xie, Chengshi; Chen, Xiaoxin; Zhang, Lan; Sun, Jinxin; Peng, Jinrong; Chu, Bingyang; Guo, Gang; Luo, Feng; Qian, Zhiyong

    2014-04-01

    Fisetin (3,3',4',7-tetrahydroxyflavone) is a potential anti-tumor agent but poor water solubility hinders its application and complicates direct parenteral administration. Nanoparticle encapsulation is an efficient way to enhance the solubility of some hydrophobic drugs. In this study, methoxy poly(ethylene glycol)-polycaprolactone (MPEG-PCL) nanoparticles were successfully prepared for fisetin delivery in vitro and in vivo. Narrow distribution fisetin-loaded MPEG-PCL NPs (aproximately100 nm) were obtained via emulsification (O/W) and displayed a sustained release behavior in vitro. Moreover, hemolysis and cell cytotoxicity testing showed that MPEG-PCL is biocompatible and safe for intravenous injection. Most importantly, NPs encapsulation enhanced the anti-cancer activity of fisetin as shown in a subcutaneous LL/2 tumor model, and reduced the hepatotoxicity of fisetin. Therefore, our data demonstrate that fisetin-loaded MPEG-PCL NPs have potential application in cancer chemotherapy.

  16. Improvement of anti-tumor activity of photodynamic therapy through inhibition of cytoprotective mechanism in tumor cells

    NASA Astrophysics Data System (ADS)

    Nowis, Dominika; Szokalska, Angelika; Makowski, Marcin; Winiarska, Magdalena; Golab, Jakub

    2009-06-01

    Photodynamic therapy (PDT) leads to oxidative damage of cellular macromolecules, including numerous proteins that undergo multiple modifications such as fragmentation, cross-linking and carbonylation that result in protein unfolding and aggregation. Several mechanisms are involved in the protective responses to PDT that include activation of transcription factors, heat shock proteins, antioxidant enzymes and antiapoptotic pathways. Identification of these cytoprotective mechanisms might result in the design of more effective combination strategies to improve the antitumor efficacy of PDT. By using various molecular biology approaches, including microarray-based technologies we have identified genes that are up-regulated following PDT. Subsequent experiments revealed that some of these gene products can become targets for the combined therapeutic regimens encompassing PDT and selective small-molecule inhibitors. These include superoxide dismutase (SOD-2), cyclooxygenase 2 (COX-2), heme oxygenase 1 (HO-1), and proteins engaged in signaling endoplasmatic reticulum (ER) stress and unfolded protein response (UPR). Since a major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in ER, aggravated ER stress and potentiated cytotoxicity towards tumor cells. Indeed, we observed that incubation of tumor cells with three different proteasome inhibitors, including bortezomib, MG132 and PSI gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells to PDT-mediated cytotoxicity and augmented antitumor effects of PDT in vivo.

  17. Anti-inflammatory, anti-tumor-promoting, and cytotoxic activities of constituents of marigold (Calendula officinalis) flowers.

    PubMed

    Ukiya, Motohiko; Akihisa, Toshihiro; Yasukawa, Ken; Tokuda, Harukuni; Suzuki, Takashi; Kimura, Yumiko

    2006-12-01

    Ten oleanane-type triterpene glycosides, 1-10, including four new compounds, calendulaglycoside A 6'-O-methyl ester (2), calendulaglycoside A 6'-O-n-butyl ester (3), calendulaglycoside B 6'-O-n-butyl ester (5), and calendulaglycoside C 6'-O-n-butyl ester (8), along with five known flavonol glycosides, 11-15, were isolated from the flowers of marigold (Calendula officinalis). Upon evaluation of compounds 1-9 for inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, all of the compounds, except for 1, exhibited marked anti-inflammatory activity, with ID50 values of 0.05-0.20 mg per ear. In addition, when 1-15 were evaluated against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA, compounds 1-10 exhibited moderate inhibitory effects (IC50 values of 471-487 mol ratio/32 pmol TPA). Furthermore, upon evaluation of the cytotoxic activity against human cancer cell lines in vitro in the NCI Developmental Therapeutics Program, two triterpene glycosides, 9 and 10, exhibited their most potent cytotoxic effects against colon cancer, leukemia, and melanoma cells. PMID:17190444

  18. Novel biotransformation process of podophyllotoxin to 4 β-sulfur-substituted podophyllum derivates with anti-tumor activity by Penicillium purpurogenum Y.J. Tang.

    PubMed

    Bai, J-K; Zhao, W; Li, H-M; Tang, Y-J

    2012-01-01

    According to the structure-function relationship of podophyllotoxin (PTOX) and its analogue of 4'- demethylepipodophyllotoxin (DMEP), the 4 β-substitution of sulfur-containing heterocyclic compounds with a carbon-sulfur bond at 4 position of PTOX or DMEP is an essential modification direction for improving the anti-tumor activity. So, four novel 4 β-sulfursubstituted podophyllum derivatives (i.e., 4β -(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MT-PTOX), 4β-(1,3,4- thiadiazole-2-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MTD-PTOX), 4β-(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-4' -demethylepipodophyllotoxin (4-MT-DMEP), and 4β-(1,3,4-thiadiazole-2-yl)sulfanyl-4-deoxy-4'-demethylepipodophyllotoxin (4-MTD-DMEP)) were designed and then successfully biosynthesized in this work. In the novel sulfur-substituted biotransformation processes, PTOX and DMEP was linked with sulfur-containing compounds (i.e., 3-mercapto-1,2,4-triazole (MT) and 2-mercapto-1,3,4-thiadiazole (MTD)) at 4 position of cycloparaffin to produce 4-MT-PTOX (1), 4-MTD-PTOX (2), 4-MT-DMEP (3), and 4-MTD-DMEP (4) by Penicillium purpurogenum Y.J. Tang, respectively, which was screened out from Diphylleia sinensis Li (Hubei, China). All the novel compounds exhibited promising in vitro bioactivity, especially 4-MT-PTOX (1). Compared with etoposide (i.e., a 50 % effective concentration [EC(50)] of 25.72, 167.97, and 1.15 M), the EC(50) values of 4-MT-PTOX (1) against tumor cell line BGC-823, A549 and HepG2 (i.e., 0.28, 0.76, and 0.42 M) were significantly improved by 91, 221 and 2.73 times, respectively. Moreover, the EC(50) value of 4-MT-PTOX (1) against the normal human cell line HK-2 (i.e., 182.4 μM) was 19 times higher than that of etoposide (i.e., 9.17 μM). Based on the rational design, four novel 4 β-sulfur-substituted podophyllum derivatives with superior in vitro anti-tumor activity were obtained for the first time. The correctness of structure-function relationship and rational drug

  19. Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

    PubMed

    Chakrabarti, Mrinmay; Ray, Swapan K

    2016-03-01

    Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo. PMID:26573275

  20. Anti-tumor activity of the novel hexahydrocannabinol analog LYR-8 in Human colorectal tumor xenograft is mediated through the inhibition of Akt and hypoxia-inducible factor-1α activation.

    PubMed

    Thapa, Dinesh; Kang, Youra; Park, Pil-Hoon; Noh, Seok Kyun; Lee, Yong Rok; Han, Sung Soo; Ku, Sae Kwang; Jung, Yunjin; Kim, Jung-Ae

    2012-01-01

    Cannabinoid compounds have been shown to exert anti-tumor effects by affecting angiogenesis, invasion, and metastasis. In the present study, we examined the action mechanism by which LYR-8, a novel hexahydrocannabinol analog, exerts anti-angiogenic and anti-tumor activity in human cancer xenografts. In the xenografted tumor tissues, LYR-8 significantly reduced the expression of hypoxia-inducible factor-1 alpha (HIF-1α), a transcription factor responsible for induction of angiogenesis-promoting factors, and its target genes, vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). In HT-29 human colon cancer cells treated with a hypoxia-inducing agent (CoCl(2)), LYR-8 dose-dependently suppressed the induction of HIF-1α and subsequently its targets, VEGF and COX-2. In addition, highly elevated prostaglandin E(2) (PGE(2)) concentrations in CoCl(2)-treated HT-29 cells were also significantly suppressed by LYR-8. However, LYR-8 alone in the absence of CoCl(2) did not alter the basal expression of VEGF and COX-2, or PGE(2) production. Furthermore, LYR-8 effectively suppressed Akt signaling, which corresponded to the suppression of CoCl(2)-induced HIF-1α accumulation. Taken together, LYR-8 exerts anti-tumor effects through the inhibition of Akt and HIF-1α activation, and subsequently suppressing factors regulating tumor microenvironment, such as VEGF and COX-2. These results indicate a novel function of cannabinoid-like compound LYR-8 as an anti-tumor agent with a HIF-1α inhibitory activity.

  1. Purification of Lectin from Larvae of the fly, Musca domestica, and in Vitro Anti-Tumor Activity in MCF-7 Cells

    PubMed Central

    Cao, X.; Huo, Z.; Lu, M.; Mao, D.; Zhao, Q.; Xu, C.; Wang, C.; Zeng, B.

    2010-01-01

    A new lectin was purified from larvae of the fly, Musca domestica L. (Diptera: Muscidae) (MLL-2, 38 kDa) using affinity chromatography and HPLC. Anti-tumor activity of MLL-2 was demonstrated by its inhibition of proliferation of human breast cancer (MCF-7) cells in a time-and dose-dependent manner. The results of acridine orange staining indicated that MLL-2 caused apoptosis in MCF-7 cells. DNA fragmentation in MCF-7 cells has been detected by TUNEL. Flow cytometric analysis also demonstrated that MLL-2 caused dose-dependent apoptosis of MCF-7 cells through cell arrest at G2/M phase. The MLL-2 induced a sustained increase in concentration of intracellular free calcium. Western blot revealed that MLL-2 induced apoptosis in MCF-7 cells was associated with typical apoptosis proteins in the mitochondrial pathway. In addition, the caspase-3 activity in MCF-7 cells treated with MLL-2 for 48 hours was significantly increased compared to controls (407.4 ± 3.0 vs. 1749.2 ± 6.0, P <0.01). Since MLL-2 induced apoptosis in MCF-7cells the mitochondrial pathway may be the main pathway of antitumor activity. PMID:21067415

  2. Enhanced Anti-Tumoral Activity of Methotrexate-Human Serum Albumin Conjugated Nanoparticles by Targeting with Luteinizing Hormone-Releasing Hormone (LHRH) Peptide

    PubMed Central

    Taheri, Azade; Dinarvand, Rassoul; Atyabi, Fatemeh; Ahadi, Fatemeh; Nouri, Farank Salman; Ghahremani, Mohammad Hossein; Ostad, Seyed Nasser; Borougeni, Atefeh Taheri; Mansoori, Pooria

    2011-01-01

    Active targeting could increase the efficacy of anticancer drugs. Methotrexate-human serum albumin (MTX-HSA) conjugates, functionalized by luteinizing hormone-releasing hormone (LHRH) as targeting moieties, with the aim of specifically targeting the cancer cells, were prepared. Owing to the high expression of LHRH receptors in many cancer cells as compared to normal cells, LHRH was used as the targeting ligand in this study. LHRH was conjugated to MTX-HSA nanoparticles via a cross-linker. Three types of LHRH targeted nanoparticles with a mean particle size between 120–138 nm were prepared. The cytotoxicity of LHRH targeted and non-targeted nanoparticles were determined on the LHRH positive and negative cell lines. The internalization of the targeted and non-targeted nanoparticles in LHRH receptor positive and negative cells was investigated using flow cytometry analysis and fluorescence microscopy. The cytotoxicity of the LHRH targeted nanoparticles on the LHRH receptor positive cells were significantly more than non-targeted nanoparticles. LHRH targeted nanoparticles were also internalized by LHRH receptor positive cells significantly more than non-targeted nanoparticles. There were no significant differences between the uptake of targeted and non-targeted nanoparticles to the LHRH receptor negative cells. The active targeting procedure using LHRH targeted MTX-HSA nanoparticles could increase the anti-tumoral activity of MTX. PMID:21845098

  3. The anti-tumor effect and biological activities of the extract JMM6 from the stem-barks of the Chinese Juglans mandshurica Maxim on human hepatoma cell line BEL-7402.

    PubMed

    Zhang, Yongli; Cui, Yuqiang; Zhu, Jiayong; Li, Hongzhi; Mao, Jianwen; Jin, Xiaobao; Wang, Xiangsheng; Du, Yifan; Lu, Jiazheng

    2013-01-01

    Juglans mandshurica Maxim is a traditional herbal medicines in China, and its anti-tumor bioactivities are of research interest. Bioassay-guided fractionation method was employed to isolate anti-tumor compounds from the stem barks of the Juglans mandshurica Maxim. The anti-tumor effect and biological activities of the extracted compound JMM6 were studied in BEL-7402 cells by MTT, Cell cycle analysis, Hoechst 33342 staining, Annexin V-FITC/PI assay and Detection of mitochondrial membrane potential (ΔΨm). After treatment with the JMM6, the growth of BEL-7402 cells was inhibited and cells displayed typical morphological apoptotic characteristics. Further investigations revealed that treatment with JMM6 mainly caused G2/M cell cycle arrest and induced apoptosis in BEL-7402 cells. To evaluate the alteration of mitochondria in JMM6 induced apoptosis. The data showed that JMM6 decreased significantly the ΔΨm, causing the depolarization of the mitochondrial membrane. Our results show that the JMM6 will have a potential advantage of anti-tumor, less harmful to normal cells. This paper not only summarized the JMM6 pick-up technology from Juglans mandshurica Maxim and biological characteristic, but also may provide further evidence to exploit the potential medicine compounds from the stem-barks of the Chinese Juglans mandshurica Maxim.

  4. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma

    PubMed Central

    Ma, Jiao; Xing, Wei; Coffey, Greg; Dresser, Karen; Lu, Kellie; Guo, Ailin; Raca, Gordana; Pandey, Anjali; Conley, Pamela; Yu, Hongbo; Wang, Y. Lynn

    2015-01-01

    B-cell receptor (BCR) and JAK/STAT pathways play critical roles in diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the anti-lymphoma activity of cerdulatinib, a novel compound that dually targets SYK and JAK/STAT pathways. On a tissue microarray of 62 primary DLBCL tumors, 58% expressed either phosphorylated SYK or STAT3 or both. SYK and STAT3 are also phosphorylated in a panel of eleven DLBCL cell lines although ABC and GCB subtypes exhibited different JAK/STAT and BCR signaling profiles. In both ABC and GCB cell lines, cerdulatinib induced apoptosis that was associated with caspase-3 and PARP cleavage. The compound also blocked G1/S transition and caused cell cycle arrest, accompanied by inhibition of RB phosphorylation and down-regulation of cyclin E. Phosphorylation of BCR components and STAT3 was sensitive to cerdulatinib in both ABC and GCB cell lines under stimulated conditions. Importantly, JAK/STAT and BCR signaling can be blocked by cerdulatinib in primary GCB and non-GCB DLBCL tumor cells that were accompanied by cell death. Our work provides mechanistic insights into the actions of cerdulatinib, suggesting that the drug has a broad anti-tumor activity in both ABC and GCB DLBCL, at least in part by inhibiting SYK and JAK pathways. PMID:26575169

  5. Arsenic Trioxide Overcomes Rapamycin-Induced Feedback Activation of AKT and ERK Signaling to Enhance the Anti-Tumor Effects in Breast Cancer

    PubMed Central

    Guilbert, Cynthia; Annis, Matthew G.; Dong, Zhifeng; Siegel, Peter M.; Miller, Wilson H.; Mann, Koren K.

    2013-01-01

    Inhibitors of the mammalian target of rapamycin (mTORi) have clinical activity; however, the benefits of mTOR inhibition by rapamycin and rapamycin-derivatives (rapalogs) may be limited by a feedback mechanism that results in AKT activation. Increased AKT activity resulting from mTOR inhibition can be a result of increased signaling via the mTOR complex, TORC2. Previously, we published that arsenic trioxide (ATO) inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and rapamycin may circumvent the AKT feedback loop and increase the anti-tumor effects. Using a panel of breast cancer cell lines, we find that ATO, at clinically-achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus. In all cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in those cell lines where ATO enhanced growth inhibition. Treatment with rapalog also results in activated ERK signaling, which is decreased with ATO co-treatment in all cell lines tested. We next tested the toxicity and efficacy of rapamycin plus ATO combination therapy in a MDA-MB-468 breast cancer xenograft model. The drug combination was well-tolerated, and rapamycin did not increase ATO-induced liver enzyme levels. In addition, combination of these drugs was significantly more effective at inhibiting tumor growth compared to individual drug treatments, which corresponded with diminished phospho-Akt and phospho-ERK levels when compared with rapamycin-treated tumors. Therefore, we propose that combining ATO and mTORi may overcome the feedback loop by decreasing activation of the MAPK and AKT signaling pathways. PMID:24392034

  6. Anti-Tumor Effects of Novel 5-O-Acyl Plumbagins Based on the Inhibition of Mammalian DNA Replicative Polymerase Activity

    PubMed Central

    Kawamura, Moe; Kuriyama, Isoko; Maruo, Sayako; Kuramochi, Kouji; Tsubaki, Kazunori; Yoshida, Hiromi; Mizushina, Yoshiyuki

    2014-01-01

    We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins enhanced mammalian pol inhibition and their cytotoxic activity. Plumbagin conjugated with chains consisting of more than C18-unsaturated fatty acids strongly inhibited the activities of calf pol α and human pol γ. Plumbagin conjugated with oleic acid (C18:1-acyl plumbagin) showed the strongest suppression of human colon carcinoma (HCT116) cell proliferation among the ten synthesized 5-O-acyl plumbagins. The inhibitory activity on pol α, a DNA replicative pol, by these compounds showed high correlation with their cancer cell proliferation suppressive activity. C18:1-Acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. This compound inhibited the proliferation of various human cancer cell lines, and was the cytotoxic inhibitor showing strongest inhibition towards HT-29 colon cancer cells (LD50 = 2.9 µM) among the nine cell lines tested. In an in vivo anti-tumor assay conducted on nude mice bearing solid tumors of HT-29 cells, C18:1-acyl plumbagin was shown to be a promising tumor suppressor. These data indicate that novel 5-O-acyl plumbagins act as anti-cancer agents based on mammalian DNA replicative pol α inhibition. Moreover, the results suggest that acylation of plumbagin is an effective chemical modification to improve the anti-cancer activity of vitamin K3 derivatives, such as plumbagin. PMID:24520419

  7. A modified spontaneous emulsification solvent diffusion method for the preparation of curcumin-loaded PLGA nanoparticles with enhanced in vitro anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Chen, Cen; Yang, Wei; Wang, Dan-Tong; Chen, Chao-Long; Zhuang, Qing-Ye; Kong, Xiang-Dong

    2014-12-01

    To improve the anti-tumor activity of hydrophobic drug curcumin, we prepared curcumin-loaded PLGA nanoparticles (PLGA-Cur NPs) through a modified spontaneous emulsification solvent diffusion (modified-SESD) method. The influence of main preparation parameters was investigated, such as the volume ratio of binary organic solvents and the concentration of surfactant. Results indicated that the synthesized regular spherical PLGA NPs with the average diameter of 189.7 nm exhibited relatively higher yield (58.9%), drug loading (11.0% (w/w)) and encapsulation efficiency (33.5%), and also a controllable drug release profile. In order to evaluate the in vitro cytotoxicity of the prepared NPs, MTT assay was conducted, and results showed that the NPs could effectively inhibit HL60 and HepG2 cells with lower IC50 values compared with free curcumin. Furthermore, confocal microscopy together with flow cytometry analysis proved the enhanced apoptosis-inducing ability of PLGA-Cur NPs. Polymeric NP formulations are potential to be used for hydrophobic drug delivery systems in cancer therapy.

  8. Microwave-assisted extraction and purification of chlorogenic acid from by-products of Eucommia Ulmoides Oliver and its potential anti-tumor activity.

    PubMed

    Shao, P; Zhang, J F; Chen, X X; Sun, P L

    2015-08-01

    An efficient method for the rapid extraction, separation and purification of chlorogenic acid (CGA) from by-products of Eucommia Ulmoides Oliver (E. ulmoides) by microwave-assisted extraction (MAE) coupled with high-speed counter-current chromatography (HSCCC) was developed. The optimal MAE parameters were evaluated by response surface methodology (RSM), and they were extraction time of 12 min, microwave power of 420 W, ethanol concentration of 75 %, solvent/sample ratio of 30:1 (mL/g), yield of CGA reached 3.59 %. The crude extract was separated and purified directly by HSCCC using ethyl acetate-butyl alcohol-water (3:1:4, v/v) as the two-phase solvent system. The 14.5 mg of CGA with the purity of 98.7 % was obtained in one-step separation from 400 mg of crude extract. The chemical structure of CGA was verified with IR, ESI-MS analysis. Meanwhile, the purified CGA extract was evaluated by MTT assay and results indicate that CGA extract exhibited potential anti-tumor activity for AGS gastric cancer cell.

  9. Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models.

    PubMed

    Cicatiello, Valeria; Apicella, Ivana; Tudisco, Laura; Tarallo, Valeria; Formisano, Luigi; Sandomenico, Annamaria; Kim, Younghee; Bastos-Carvalho, Ana; Orlandi, Augusto; Ambati, Jayakrishna; Ruvo, Menotti; Bianco, Roberto; De Falco, Sandro

    2015-04-30

    To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts. PMID:25868854

  10. Lebecin, a new C-type lectin like protein from Macrovipera lebetina venom with anti-tumor activity against the breast cancer cell line MDA-MB231.

    PubMed

    Jebali, Jed; Fakhfekh, Emna; Morgen, Maram; Srairi-Abid, Najet; Majdoub, Hafedh; Gargouri, Ali; El Ayeb, Mohamed; Luis, José; Marrakchi, Naziha; Sarray, Sameh

    2014-08-01

    C-type lectins like proteins display various biological activities and are known to affect especially platelet aggregation. Few of them have been reported to have anti-tumor effects. In this study, we have identified and characterized a new C-type lectin like protein, named lebecin. Lebecin is a heterodimeric protein of 30 kDa. The N-terminal amino acid sequences of both subunits were determined by Edman degradation and the entire amino acid sequences were deduced from cDNAs. The precursors of both lebecin subunits contain a 23-amino acid residue signal peptide and the mature α and β subunits are composed of 129 and 131 amino acids, respectively. Lebecin is shown to be a potent inhibitor of MDA-MB231 human breast cancer cells proliferation. Furthermore, lebecin dose-dependently inhibited the integrin-mediated attachment of these cells to different adhesion substrata. This novel C-type lectin also completely blocked MDA-MB231 cells migration towards fibronectin and fibrinogen in haptotaxis assays.

  11. Allorestricted T lymphocytes with a high avidity T-cell receptor towards NY-ESO-1 have potent anti-tumor activity.

    PubMed

    Krönig, Holger; Hofer, Kathrin; Conrad, Heinke; Guilaume, Philippe; Müller, Julia; Schiemann, Matthias; Lennerz, Volker; Cosma, Antonio; Peschel, Christian; Busch, Dirk H; Romero, Pedro; Bernhard, Helga

    2009-08-01

    The cancer-testis antigen NY-ESO-1 has been targeted as a tumor-associated antigen by immunotherapeutical strategies, such as cancer vaccines. The prerequisite for a T-cell-based therapy is the induction of T cells capable of recognizing the NY-ESO-1-expressing tumor cells. In this study, we generated human T lymphocytes directed against the immunodominant NY-ESO-1(157-165) epitope known to be naturally presented with HLA-A*0201. We succeeded to isolate autorestricted and allorestricted T lymphocytes with low, intermediate or high avidity TCRs against the NY-ESO-1 peptide. The avidity of the established CTL populations correlated with their capacity of lysing HLA-A2-positive, NY-ESO-1-expressing tumor cell lines derived from different origins, e.g. melanoma and myeloma. The allorestricted NY-ESO-1-specific T lymphocytes displayed TCRs with the highest avidity and best anti-tumor recognition activity. TCRs derived from allorestricted, NY-ESO-1-specific T cells may be useful reagents for redirecting primary T cells by TCR gene transfer and, therefore, may facilitate the development of adoptive transfer regimens based on TCR-transduced T cells for the treatment of NY-ESO-1-expressing hematological malignancies and solid tumors.

  12. Anti-tumor activity of patient-derived NK cells after cell-based immunotherapy – a case report

    PubMed Central

    Milani, Valeria; Stangl, Stefan; Issels, Rolf; Gehrmann, Mathias; Wagner, Beate; Hube, Kathrin; Mayr, Doris; Hiddemann, Wolfgang; Molls, Michael; Multhoff, Gabriele

    2009-01-01

    Background Membrane-bound heat shock protein 70 (Hsp70) serves as a tumor-specific recognition structure for Hsp70-peptide (TKD) plus IL-2 activated NK cells. A phase I clinical trial has shown that repeated re-infusions of ex vivo TKD/IL-2-activated, autologous leukapheresis product is safe. This study investigated the maintenance of the cytolytic activity of NK cells against K562 cells and autologous tumor after 6 plus 3 infusions of TKD/IL-2-activated effector cells. Methods A stable tumor cell line was generated from the resected anastomotic relapse of a patient with colon carcinoma (pT3, N2, M0, G2). Two months after surgery, the patient received the first monthly i.v. infusion of his ex vivo TKD/IL-2-activated peripheral blood mononuclear cells (PBMNC). After 6 infusions and a pause of 3 months, the patient received another 3 cell infusions. The phenotypic characteristics and activation status of tumor and effector cells were determined immediately before and at times after each infusion. Results The NK cell ligands Hsp70, MICA/B, and ULBP-1,2,3 were expressed on the patient's anastomotic relapse. An increased density of activatory NK cell receptors following ex vivo stimulation correlated with an enhanced anti-tumoricidal activity. After 4 re-infusion cycles, the intrinsic cytolytic activity of non-stimulated PBMNC was significantly elevated and this heightened responsiveness persisted for up to 3 months after the last infusion. Another 2 re-stimulations with TKD/IL-2 restored the cytolytic activity after the therapeutic pause. Conclusion In a patient with colon carcinoma, repeated infusions of ex vivo TKD/IL-2-activated PBMNC initiate an intrinsic NK cell-mediated cytolytic activity against autologous tumor cells. PMID:19549307

  13. Anti-tumor Activity of Ferulago angulata Boiss. Extract in Gastric Cancer Cell Line via Induction of Apoptosis

    PubMed Central

    Heidari, Shafagh; Akrami, Hassan; Gharaei, Roghaye; Jalili, Ali; Mahdiuni, Hamid; Golezar, Elham

    2014-01-01

    Ferulago angulata Boiss. known in Iran as Chavir, has some bioactive compounds having antioxidant activity. Because of its antioxidant activities, it sounded Chavir extract can be a good candidate for finding chemopreventive agents having inductive apoptosis properties on cancer cells. In this study, the cytotoxic effects and proapoptotic activities of Chavir’s leaf and flower extracts were investigated on human adenocarcinoma gastric cell line (AGS). The ferric reducing antioxidant power (FRAP) assay was used to determine antioxidant activity of the extract. Cytotoxic effects of the extract were performed by trypan blue and neutral red assays. For apoptosis detection, we used Annexin V staining, flow cytometry and DNA fragmentation assays. The FRAP assay results showed that antioxidant activity of leaf extract was higher than flower extract. Cytotoxicity and apoptosis–inducing activity of flower and leaf extracts changed coordinately, indicating the cytotoxicity of chavir extracts is due probably to induce apoptosis. Our results revealed that the cytotoxic effects of F. angulate Boiss. extracts on AGS cell line is close to some other plant extracts such as Rhus verniciflua Stokes (RVS) and Scutellaria litwinowii. This is the first study on cytotoxic and apoptosis–inducing effects of chavir leaf and flower extracts against AGS cell line. The Further investigation can be identification of the agent(s) by which these effects is observed. PMID:25587323

  14. Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: a short review.

    PubMed

    Surh, Young-Joon

    2002-08-01

    A wide variety of phenolic substances derived from spice possess potent antimutagenic and anticarcinogenic activities. Examples are curcumin, a yellow colouring agent, contained in turmeric (Curcuma longa L., Zingiberaceae), [6]-gingerol, a pungent ingredient present in ginger (Zingiber officinale Roscoe, Zingiberaceae) and capsaicin, a principal pungent principle of hot chili pepper (Capsicum annuum L, Solanaceae). The chemopreventive effects exerted by these phytochemicals are often associated with their antioxidative and anti-inflammatory activities. Cyclo-oxygenase-2 (COX-2) has been recognized as a molecular target of many chemopreventive as well as anti-inflammatory agents. Recent studies have shown that COX-2 is regulated by the eukaryotic transcription factor NF-kappaB. This short review summarizes the molecular mechanisms underlying chemopreventive effects of the aforementioned spice ingredients in terms of their effects on intracellular signaling cascades, particularly those involving NF-kappaB and mitogen-activated protein kinases. PMID:12067569

  15. Anti-Tumor Activity of Eurycoma longifolia Root Extracts against K-562 Cell Line: In Vitro and In Vivo Study

    PubMed Central

    Majid, Amin Malik Shah Abdul; Kit-Lam, Chan; Abdullah, Wan Zaidah; Zaki, Abdelhamid; Jamal Din, Shah Kamal Khan; Yusoff, Narazah Mohd

    2014-01-01

    Eurycoma longifolia Jack has been widely used in traditional medicine for its antimalarial, aphrodisiac, anti-diabetic, antimicrobial and anti-pyretic activities. Its anticancer activity has also been recently reported on different solid tumors, however no anti-leukemic activity of this plant has been reported. Thus the present study assesses the in vitro and in vivo anti-proliferative and apoptotic potentials of E. longifolia on K-562 leukemic cell line. The K-562 cells (purchased from ATCC) were isolated from patients with chronic myelocytic leukemia (CML) were treated with the various fractions (TAF273, F3 and F4) of E. longifolia root methanolic extract at various concentrations and time intervals and the anti-proliferative activity assessed by MTS assay. Flow cytometry was used to assess the apoptosis and cell cycle arrest. Nude mice injected subcutaneously with 107 K-562 cells were used to study the anti-leukemic activity of TAF273 in vivo. TAF273, F3 and F4 showed various degrees of growth inhibition with IC50 values of 19, 55 and 62 µg/ml, respectively. TAF273 induced apoptosis in a dose and time dependent manner. TAF273 arrested cell cycle at G1and S phases. Intraperitoneal administration of TAF273 (50 mg/kg) resulted in a significant growth inhibition of subcutaneous tumor in TAF273-treated mice compared with the control mice (P = 0.024). TAF273 shows potent anti-proliferative activity in vitro and in vivo models of CML and therefore, justifies further efforts to define more clearly the potential benefits of using TAF273 as a novel therapeutic strategy for CML management. PMID:24409284

  16. Anti-tumor activity of Eurycoma longifolia root extracts against K-562 cell line: in vitro and in vivo study.

    PubMed

    Al-Salahi, Omar Saeed Ali; Ji, Dan; Majid, Amin Malik Shah Abdul; Kit-Lam, Chan; Abdullah, Wan Zaidah; Zaki, Abdelhamid; Jamal Din, Shah Kamal Khan; Yusoff, Narazah Mohd; Majid, Aman Shah Abdul

    2014-01-01

    Eurycoma longifolia Jack has been widely used in traditional medicine for its antimalarial, aphrodisiac, anti-diabetic, antimicrobial and anti-pyretic activities. Its anticancer activity has also been recently reported on different solid tumors, however no anti-leukemic activity of this plant has been reported. Thus the present study assesses the in vitro and in vivo anti-proliferative and apoptotic potentials of E. longifolia on K-562 leukemic cell line. The K-562 cells (purchased from ATCC) were isolated from patients with chronic myelocytic leukemia (CML) were treated with the various fractions (TAF273, F3 and F4) of E. longifolia root methanolic extract at various concentrations and time intervals and the anti-proliferative activity assessed by MTS assay. Flow cytometry was used to assess the apoptosis and cell cycle arrest. Nude mice injected subcutaneously with 10(7) K-562 cells were used to study the anti-leukemic activity of TAF273 in vivo. TAF273, F3 and F4 showed various degrees of growth inhibition with IC50 values of 19, 55 and 62 µg/ml, respectively. TAF273 induced apoptosis in a dose and time dependent manner. TAF273 arrested cell cycle at G1 and S phases. Intraperitoneal administration of TAF273 (50 mg/kg) resulted in a significant growth inhibition of subcutaneous tumor in TAF273-treated mice compared with the control mice (P = 0.024). TAF273 shows potent anti-proliferative activity in vitro and in vivo models of CML and therefore, justifies further efforts to define more clearly the potential benefits of using TAF273 as a novel therapeutic strategy for CML management. PMID:24409284

  17. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.

    PubMed

    Kawano, Satoshi; Grassian, Alexandra R; Tsuda, Masumi; Knutson, Sarah K; Warholic, Natalie M; Kuznetsov, Galina; Xu, Shanqin; Xiao, Yonghong; Pollock, Roy M; Smith, Jesse S; Kuntz, Kevin K; Ribich, Scott; Minoshima, Yukinori; Matsui, Junji; Copeland, Robert A; Tanaka, Shinya; Keilhack, Heike

    2016-01-01

    The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers. PMID:27391784

  18. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma

    PubMed Central

    Tsuda, Masumi; Knutson, Sarah K.; Warholic, Natalie M.; Kuznetsov, Galina; Xu, Shanqin; Xiao, Yonghong; Pollock, Roy M.; Smith, Jesse S.; Kuntz, Kevin K.; Ribich, Scott; Minoshima, Yukinori; Matsui, Junji; Copeland, Robert A.; Tanaka, Shinya; Keilhack, Heike

    2016-01-01

    The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma—a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein—display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers. PMID:27391784

  19. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent anti-tumor activity

    PubMed Central

    Caruso, Hillary G.; Hurton, Lenka V.; Najjar, Amer; Rushworth, David; Ang, Sonny; Olivares, Simon; Mi, Tiejuan; Switzer, Kirsten; Singh, Harjeet; Huls, Helen; Lee, Dean A.; Heimberger, Amy B.; Champlin, Richard E.; Cooper, Laurence J. N.

    2015-01-01

    Many tumors over express tumor-associated antigens relative to normal tissue, such as epidermal growth factor receptor (EGFR). This limits targeting by human T cells modified to express chimeric antigen receptors (CARs) due to potential for deleterious recognition of normal cells. We sought to generate CAR+ T cells capable of distinguishing malignant from normal cells based on the disparate density of EGFR expression by generating two CARs from monoclonal antibodies which differ in affinity. T cells with low affinity Nimo-CAR selectively targeted cells over-expressing EGFR, but exhibited diminished effector function as the density of EGFR decreased. In contrast, the activation of T cells bearing high affinity Cetux-CAR was not impacted by the density of EGFR. In summary, we describe the generation of CARs able to tune T-cell activity to the level of EGFR expression in which a CAR with reduced affinity enabled T cells to distinguish malignant from non-malignant cells. PMID:26330164

  20. 2,9-Dimethyl-1,10-phenanthroline (neocuproine): a potent, copper-dependent cytotoxin with anti-tumor activity.

    PubMed

    Mohindru, A; Fisher, J M; Rabinovitz, M

    1983-12-01

    2,9-Dimethyl-1,10-phenanthroline (2,9-DMP), a copper-specific chelator, was a potent cytotoxin against L1210 cells in vitro; its activity was dependent upon available Cu2+ in the medium. Other divalent ions, Fe2+ and Zn2+, were ineffective as promoters of growth inhibition. As the copper chelate, a 4 microM solution produced a 4 log kill after a 1-hr incubation. This was in marked contrast to 1,10-phenanthroline, whose inhibition of cell growth was overcome by added Cu2+, Fe2+ and Zn2+. Cellular uptake of labeled 2,9-dimethyl-1,10-phenanthroline also required added Cu2+ in the medium. This transport was energy dependent, and the drug was concentrated over 200-fold by the cells. In preliminary evaluations, copper-2,9-DMP showed significant chemotherapeutic activity against the P388 murine lymphoma in vivo.

  1. BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2.

    PubMed

    Zhang, Zong Xin; Jin, Wen Jun; Yang, Sheng; Ji, Cun Li

    2016-01-01

    Most anti-angiogenic therapies currently being evaluated in clinical trials targetvascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified BRAF kinase inhibitor, vemurafenibas an agent with potential anti-angiogenic and anti-breast cancer activities. Vemurafenib demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor (bFGF). In ex vivo and in vivo angiogenesis assays, vemurafenib suppressed bFGF-induced microvessel sprouting of rat aortic rings and angiogenesis in vivo. To understand the underlying molecular basis, we examined the effects of vemurafenib on different molecular components in treated endothelial cell, and found that vemurafenib suppressed bFGF-triggered activation of FGFR2 and protein kinase B (AKT). Moreover, vemurafenib directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer cells MDA-MB-231, vemurafenib showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Taken together, our results indicate that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis.

  2. Allicin sensitizes hepatocellular cancer cells to anti-tumor activity of 5-fluorouracil through ROS-mediated mitochondrial pathway.

    PubMed

    Zou, Xuejing; Liang, Jiyun; Sun, Jingyuan; Hu, Xiaoyun; Lei, Ling; Wu, Dehua; Liu, Li

    2016-08-01

    Drug resistance and hepatic dysfunction are the two major factors that limit the application of chemotherapy for hepatocellular carcinoma (HCC). It has been reported that allicin has the hepatic protective effect and antitumor activity. Hence allicin may be an ideal enhancer to chemotherapy regimen of HCC. In the present study, we demonstrated that allicin enhanced 5-fluorouracil (5-FU) inducing cytotoxicity in HCC cells. In vivo experiment, combined treatment group with allicin (5 mg/kg/d; every two days for 3 weeks) and 5-FU (20 mg/kg/d; 5 consecutive days) showed a dramatic inhibitory effect on the growth of HCC xenograft tumors in nude mice. The co-treatment group showed highly apoptotic level compared with 5-FU treated alone. Cells combined treatment with allicin and 5-FU increased intracellular reactive oxygen species (ROS) level, reduced mitochondrial membrane potential (ΔΨm), activated caspase-3 and PARP, and down-regulated Bcl-2 compared with DMSO, allicin and 5-FU treated alone. Moreover, the increase of activated caspase-3 and PARP was blocked by the ROS inhibitor antioxidant N-acetyl cysteine (NAC). In conclusion, this is the first study to demonstrate that allicin sensitized HCC cells to 5-FU induced apoptosis through ROS-mediated mitochondrial pathway. These results provided evidences for the combination used of allicin and 5-FU as a novel chemotherapy regimen in HCC. PMID:27177453

  3. BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

    PubMed Central

    Zhang, Zong Xin; Jin, Wen Jun; Yang, Sheng; Ji, Cun Li

    2016-01-01

    Most anti-angiogenic therapies currently being evaluated in clinical trials targetvascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified BRAF kinase inhibitor, vemurafenibas an agent with potential anti-angiogenic and anti-breast cancer activities. Vemurafenib demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor (bFGF). In ex vivo and in vivo angiogenesis assays, vemurafenib suppressed bFGF-induced microvessel sprouting of rat aortic rings and angiogenesis in vivo. To understand the underlying molecular basis, we examined the effects of vemurafenib on different molecular components in treated endothelial cell, and found that vemurafenib suppressed bFGF-triggered activation of FGFR2 and protein kinase B (AKT). Moreover, vemurafenib directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer cells MDA-MB-231, vemurafenib showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Taken together, our results indicate that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. PMID:27293997

  4. In Vivo Anti-Tumor Activity and Toxicological Evaluations of Perillaldehyde 8,9-Epoxide, a Derivative of Perillyl Alcohol

    PubMed Central

    Andrade, Luciana Nalone; Amaral, Ricardo Guimarães; Dória, Grace Anne Azevedo; Fonseca, Cecília Santos; da Silva, Tayane Kayane Mariano; Albuquerque Júnior, Ricardo Luiz Cavalcante; Thomazzi, Sara Maria; do Nascimento, Lázaro Gomes; Carvalho, Adriana Andrade; de Sousa, Damião Pergentino

    2016-01-01

    Recent studies have revealed the high cytotoxicity of p-menthane derivatives against human tumor cells. In this study, the substance perillaldehyde 8,9-epoxide, a p-menthane class derivative obtained from (S)-(−)-perillyl alcohol, was selected in order to assess antitumor activity against experimental sarcoma 180 tumors. Toxicological effects related to the liver, spleen, kidneys and hematology were evaluated in mice submitted to treatment. The tumor growth inhibition rate was 38.4%, 58.7%, 35.3%, 45.4% and 68.1% at doses of 100 and 200 mg/kg/day for perillaldehyde 8,9-epoxide, perillyl alcohol and 25 mg/kg/day for 5-FU intraperitoneal treatments, respectively. No toxicologically significant effect was found in liver and kidney parameters analyzed in Sarcoma 180-inoculated mice treated with perillaldehyde 8,9-epoxide. Histopathological analyses of the liver, spleen, and kidneys were free from any morphological changes in the organs of the animals treated with perillaldehyde 8,9-epoxide. In conclusion, the data suggest that perillaldehyde 8,9-epoxide possesses significant antitumor activity without systemic toxicity for the tested parameters. By comparison, there was no statistical difference for the antitumor activity between perillaldehyde 8,9-epoxide and perillyl alcohol. PMID:26742032

  5. Structural modification of resveratrol leads to increased anti-tumor activity, but causes profound changes in the mode of action

    SciTech Connect

    Scherzberg, Maria-Christina; Kiehl, Andreas; Zivkovic, Aleksandra; Stark, Holger; Stein, Jürgen; Fürst, Robert; Steinhilber, Dieter; Ulrich-Rückert, Sandra

    2015-08-15

    (Z)-3,5,4′-Trimethoxystilbene (Z-TMS) is a resveratrol analog with increased antiproliferative activity towards a number of cancer cell lines compared to resveratrol, which has been shown to inhibit tubulin polymerization in vitro. The purpose of this study was to investigate if Z-TMS still shows potential for the prevention of metabolic diseases as known for resveratrol. Cell growth inhibition was determined with IC{sub 50} values for Z-TMS between 0.115 μM and 0.473 μM (resveratrol: 110.7 μM to 190.2 μM). Flow cytometric analysis revealed a G{sub 2}/M arrest after Z-TMS treatment, whereas resveratrol caused S phase arrest. Furthermore, Z-TMS was shown to impair microtubule polymerization. Beneficial effects on lipid accumulation were observed for resveratrol, but not for Z-TMS in an in vitro steatosis model. (E)-Resveratrol was confirmed to elevate cAMP levels, and knockdown of AMPK attenuated the antiproliferative activity, while Z-TMS did not show significant effects in these experiments. SIRT1 and AMPK activities were further measured indirectly via induction of the target gene small heterodimer partner (SHP). Thereby, (E)-resveratrol, but not Z-TMS, showed potent induction of SHP mRNA levels in an AMPK- and SIRT1-dependent manner, as confirmed by knockdown experiments. We provide evidence that Z-TMS does not show beneficial metabolic effects, probably due to loss of activity towards resveratrol target genes. Moreover, our data support previous findings that Z-TMS acts as an inhibitor of tubulin polymerization. These findings confirm that the methylation of resveratrol leads to profound changes in the mode of action, which should be taken into consideration when conducting lead structure optimization approaches. - Highlights: • Methylation of resveratrol leads to profound changes in biologic activity. • Z-TMS does not prevent hepatic steatosis, but inhibits tubulin polymerization. • Resveratrol analog Z-TMS does not influence known targets like

  6. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

    PubMed Central

    Roit, Fabio Da; Engelberts, Patrick J.; Taylor, Ronald P.; Breij, Esther C.W.; Gritti, Giuseppe; Rambaldi, Alessandro; Introna, Martino; Parren, Paul W.H.I.; Beurskens, Frank J.; Golay, Josée

    2015-01-01

    The novel Bruton tyrosine kinase inhibitor ibrutinib and phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib are promising drugs for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma, either alone or in combination with anti-CD20 antibodies. We investigated the possible positive or negative impact of these drugs on all known mechanisms of action of both type I and type II anti-CD20 antibodies. Pretreatment with ibrutinib for 1 hour did not increase direct cell death of cell lines or chronic lymphocytic leukemia samples mediated by anti-CD20 antibodies. Pre-treatment with ibrutinib did not inhibit complement activation or complement-mediated lysis. In contrast, ibrutinib strongly inhibited all cell-mediated mechanisms induced by anti-CD20 antibodies rituximab, ofatumumab or obinutuzumab, either in purified systems or whole blood assays. Activation of natural killer cells, and antibody-dependent cellular cytotoxicity by these cells, as well as phagocytosis by macrophages or neutrophils were inhibited by ibrutinib with a half maximal effective concentration of 0.3–3 μM. Analysis of anti-CD20 mediated activation of natural killer cells isolated from patients on continued oral ibrutinib treatment suggested that repeated drug dosing inhibits these cells in vivo. Finally we show that the phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib similarly inhibited the immune cell-mediated mechanisms induced by anti-CD20 antibodies, although the effects of this drug at 10 μM were weaker than those observed with ibrutinib at the same concentration. We conclude that the design of combined treatment schedules of anti-CD20 antibodies with these kinase inhibitors should consider the multiple negative interactions between these two classes of drugs. PMID:25344523

  7. Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity.

    PubMed

    Valicherla, Guru R; Dave, Kandarp M; Syed, Anees A; Riyazuddin, Mohammed; Gupta, Anand P; Singh, Akhilesh; Wahajuddin; Mitra, Kalyan; Datta, Dipak; Gayen, Jiaur R

    2016-05-31

    Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 ± 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 ± 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy.

  8. Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity.

    PubMed

    Valicherla, Guru R; Dave, Kandarp M; Syed, Anees A; Riyazuddin, Mohammed; Gupta, Anand P; Singh, Akhilesh; Wahajuddin; Mitra, Kalyan; Datta, Dipak; Gayen, Jiaur R

    2016-01-01

    Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 ± 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 ± 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy. PMID:27241877

  9. Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity

    PubMed Central

    Valicherla, Guru R.; Dave, Kandarp M.; Syed, Anees A.; Riyazuddin, Mohammed; Gupta, Anand P.; Singh, Akhilesh; Wahajuddin; Mitra, Kalyan; Datta, Dipak; Gayen, Jiaur R.

    2016-01-01

    Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 ± 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 ± 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy. PMID:27241877

  10. Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity

    PubMed Central

    Hargadon, Kristian M.

    2016-01-01

    TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1’s contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed. PMID:27589814

  11. Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity.

    PubMed

    Hargadon, Kristian M

    2016-01-01

    TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1's contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed. PMID:27589814

  12. Anti-tumor activity of Aloe vera against DMBA/croton oil-induced skin papillomagenesis in Swiss albino mice.

    PubMed

    Saini, M; Goyal, Pradeep Kumar; Chaudhary, Geeta

    2010-01-01

    Human populations are increasingly exposed to various carcinogens such as chemicals, radiation, and viruses in the environment. Chemopreventive drugs of plant origin are a promising strategy for cancer control because they are generally nontoxic or less toxic than synthetic che-mopreventive agents, and can be effective at different stages of carcinogenesis. The present investigation was undertaken to explore the antitumor activity of topical treatment with aloe vera (Aloe vera) gel, oral treatment with aloe vera extract, and topical and oral treatment with both gel and extract in stage-2 skin carcinogenesis in Swiss albino mice induced by 7,12-dim ethylbenz(a)anthracene (DMBA) and promoted croton (Croton tiglium) oil. The animals were randomly divided into 4 groups and treated as follows: Group I, DMBA + croton oil only (controls); Group II, DMBA + croton oil + topical aloe vera gel; Group III, DMBA + croton oil + oral aloe vera extract; Group I V, DMBA + croton oil + topical aloe vera gel + oral aloe vera extract. Results showed that body weight was significantly increased from 78.6% in the control group (Group I) to 92.5%, 87.5%, and 90.0% in Groups II, III, and I V, respectively. A 100% incidence of tumor development was noted in Group I, which was decreased to 50%, 60%, and 40% in Groups II, III, and I V, respectively. Also in Groups II, III, and IV, the cumulative number of papillomas was reduced significantly from 36 to 12, 15, and 11; tumor yield from 3.6 to 1.2, 1.5, and 1.1; and tumor burden from 3.6 to 2.4, 2.50, and 2.75, respectively, after treatment with aloe vera. Conversely, the average latent period increased significantly from 4.9 (Group I) to 5.23, 5.0, and 6.01 weeks in Groups II, III, and I V, respectively. We conclude that aloe vera protects mice against DMBA/croton oil-induced skin papillomagenesis, likely due to the chemopreventive activity of high concentrations of antioxidants such as vitamins A, C, and E; glutathione peroxidase; several

  13. Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity

    NASA Astrophysics Data System (ADS)

    Li, Huafei; Sun, Yun; Chen, Di; Zhao, He; Zhao, Mengxin; Zhu, Xiandi; Ke, Changhong; Zhang, Ge; Jiang, Cheng; Zhang, Li; Zhang, Fulei; Wei, Huafeng; Li, Wei

    2015-10-01

    Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.

  14. Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity

    PubMed Central

    Li, Huafei; Sun, Yun; Chen, Di; Zhao, He; Zhao, Mengxin; Zhu, Xiandi; Ke, Changhong; Zhang, Ge; Jiang, Cheng; Zhang, Li; Zhang, Fulei; Wei, Huafeng; Li, Wei

    2015-01-01

    Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency. PMID:26508306

  15. Combined inhibition of MEK and Plk1 has synergistic anti-tumor activity in NRAS mutant melanoma

    PubMed Central

    Vujic, I; Sanlorenzo, M; Ma, J; Kim, ST; Kleffel, S; Schatton, T; Rappersberger, K; Gutteridge, R; Ahmad, N; Ortiz/Urda, S

    2015-01-01

    About one third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS driven malignancies barely impact overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Plk1 expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of MEK and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo and first mechanistic data, that a MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS driven melanoma. Since mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins. PMID:26016894

  16. Synthesis, X-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives.

    PubMed

    An, Lin; Han, Li-Li; Zheng, You-Guang; Peng, Xian-Na; Xue, Yun-Sheng; Gu, Xiao-Ke; Sun, Jing; Yan, Chao-Guo

    2016-11-10

    Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined through X-ray diffraction. We assessed the ability of the prepared calix [n]arene polyhydroxyamine derivatives to induce cytotoxicity in six cancer cell lines by performing cancer cell growth inhibition assays. Results demonstrated that compounds 3a-3d achieved IC50 values ranging from 1.6 μM to 11.3 μM. Among the different compounds, 3a and 3b exerted the strongest cytotoxic effect in inhibiting the growth of SKOV3 cells. In relation to the underlying mechanisms of cytotoxic effects, cell cycle analysis revealed that the exposure of SKOV3 cells to 3a induced cell cycle arrest in the G0/G1 phase, suggesting a reduction in DNA synthesis. Immunofluorescent staining indicated that the protein expression levels of caspase-3 and p53 in cells significantly increased, whereas that of Bcl-2 was effectively suppressed. Meanwhile, no significant changes in Bax were observed in SKOV3 cells. These results highlight that calixarene 3a can be further studied as a potential anticancer agent.

  17. Roles of polysaccharide from Branchiostoma belcheri in anti-DNA oxidation and anti-tumor activity in S180 mice

    NASA Astrophysics Data System (ADS)

    Liang, Hui; Zhang, Shicui

    2009-11-01

    In this study, we isolated a polysaccharide from Branchiostoma belcheri (PBB) by enzymatic protein hydrolysis and alcohol precipitation. We investigated the effects of PBB supplementation on DNA oxidation and growth of the transplanted tumor cells Sarcoma (S180) in mice. Sixty healthy Kunming mice weighing between 18 and 25 g were randomly assigned to 6 groups, each consisting of 10 animals. All the mice, except for the blank control group, were inoculated with S180 sarcoma cells into the axilla of the left foreleg. PBB was given to mice by gavage at doses of 0 (model control), 25, 50, or 100 mg/kg b.w. in 0.2 ml saline for 30 days. The fifth group of S180-mice was given cytoxan (50 mg/kg) by peritoneal injection as a positive control group. The animals had free access to food and water. The mice were sacrificed after the final treatment and blood was quickly collected. Spontaneous and oxidized DNA damage of peripheral lymphocytes induced by H2O2 were analyzed by SCGE. O6-methyl-guanine (O6-MeG) was measured by high-performance capillary zone electrophoresis. The average tumor weights (0.856-1.118 g) of the three PBB groups were significantly lower than that of the model control group (1.836 g) ( p<0.05). The tumor inhibition ratios of the PBB groups were 39.1%-53.4% and similar to the cytoxan positive group (57.5%). There were no significant differences in spontaneous DNA damage in peripheral lymphocytes among the groups. The oxidative DNA damage induced by 10 µmol/L H2O2 in the 50 and 100 mg/kg b.w. groups were 246.1 AU and 221.7 AU, respectively, both of which were significantly lower than that in the model group (289.0 AU; p<0.05). The plasma concentrations of O6-MeG in the 25, 50, and 100 mg/kg supplemented groups were 2.09 µmol/L, 1.86 µmol/L, and 1.63 µmol/L, respectively, all of which were significantly lower than that of the model group (2.67 µmol/L; p<0.05). These results indicated that PBB may have antioxidative activity and thus reduce oxidation

  18. Development of natural anti-tumor drugs by microorganisms.

    PubMed

    Chang, Chia-Che; Chen, Wei-Chuan; Ho, Tsing-Fen; Wu, Ho-Shing; Wei, Yu-Hong

    2011-05-01

    Discoveries of tumor-resistant pharmacological drugs have mainly resulted from screening of natural products and their analogs. Some are also discovered incidentally when studying organisms. The great biodiversity of microorganisms raises the possibility of producing secondary metabolites (e.g., mevastatin, lovastatin, epothilone, salinosporamide A) to cope with adverse environments. Recently, natural plant pigments with anti-tumor activities such as β-carotene, lycopene, curcumin and anthocyanins have been proposed. However, many plants have a long life cycle. Therefore, pigments from microorganisms represent another option for the development of novel anti-tumor drugs. Prodigiosin (PG) is a natural red pigment produced by microorganisms, i.e., Serratia marcescens and other gram-negative bacteria. The anti-tumor potential of PG has been widely demonstrated. The families of PG (PGs), which share a common pyrrolylpyrromethene (PPM) skeleton, are produced by various bacteria. PGs are bioactive pigments and are known to exert immunosuppressive properties, in vitro apoptotic effects, and in vivo anti-tumor activities. Currently the most common strain used for producing PGs is S. marcescens. However, few reports have discussed PGs production. This review therefore describes the development of an anti-tumor drug, PG, that can be naturally produced by microorganisms, and evaluates the microbial production system, fermentation strategies, purification and identification processes. The application potential of PGs is also discussed. PMID:21277252

  19. Development of natural anti-tumor drugs by microorganisms.

    PubMed

    Chang, Chia-Che; Chen, Wei-Chuan; Ho, Tsing-Fen; Wu, Ho-Shing; Wei, Yu-Hong

    2011-05-01

    Discoveries of tumor-resistant pharmacological drugs have mainly resulted from screening of natural products and their analogs. Some are also discovered incidentally when studying organisms. The great biodiversity of microorganisms raises the possibility of producing secondary metabolites (e.g., mevastatin, lovastatin, epothilone, salinosporamide A) to cope with adverse environments. Recently, natural plant pigments with anti-tumor activities such as β-carotene, lycopene, curcumin and anthocyanins have been proposed. However, many plants have a long life cycle. Therefore, pigments from microorganisms represent another option for the development of novel anti-tumor drugs. Prodigiosin (PG) is a natural red pigment produced by microorganisms, i.e., Serratia marcescens and other gram-negative bacteria. The anti-tumor potential of PG has been widely demonstrated. The families of PG (PGs), which share a common pyrrolylpyrromethene (PPM) skeleton, are produced by various bacteria. PGs are bioactive pigments and are known to exert immunosuppressive properties, in vitro apoptotic effects, and in vivo anti-tumor activities. Currently the most common strain used for producing PGs is S. marcescens. However, few reports have discussed PGs production. This review therefore describes the development of an anti-tumor drug, PG, that can be naturally produced by microorganisms, and evaluates the microbial production system, fermentation strategies, purification and identification processes. The application potential of PGs is also discussed.

  20. Ex vivo evaluation of the effect of regulatory T cells on the anti-tumor activity of bortezomib in multiple myeloma.

    PubMed

    Ercetin, Ayse Pinar; Ozcan, Mehmet Ali; Aktas, Safiye; Yuksel, Faize; Solmaz, Serife Medeni; Sevindik, Gokmen Omur; Katgi, Abdullah; Piskin, Ozden; Undar, Bulent

    2016-04-01

    Multiple myeloma (MM) is a hematologic cancer characterized by malignant proliferation of plasma cells and their precursors. Immunosuppressive CD4+CD25+Foxp3+ regulatory T (Treg) cells are increased in the peripheral blood of patients with MM. On the basis of this finding, we sought to evaluate the ex vivo effect of CD4+CD25+Foxp3+ Treg cells on the anti-tumor effect of the proteosome inhibitor bortezomib on MM cells. We collected peripheral blood and bone marrow aspiration samples from 20 patients with newly diagnosed MM and isolated CD4+CD25+Foxp3+ Treg cells from peripheral blood mononuclear cells. The bone marrow mononuclear cells were cultivated in RPMI at 37°C and 5% CO2 for 72 hours. The LD50 doses of bortezomib, isolated Treg cells, and their combination were added. After 24 hours, the viability of CD138+ myeloma cells was evaluated by WST-1. We compared the anti-tumor effect of bortezomib alone and in combination with Treg expansion and statistically analyzed the measured differences with respect to the clinical parameters of the patients. Treg cells had varied effects on bortezomib, increasing, decreasing, or not changing its anti-tumor effect. The increased in vitro anti-tumor effect of bortezomib after Treg cell expansion was correlated in patients who did not develop bortezomib resistance in vivo (p = 0.022). These patients with in vivo non-bortezomib-resistant MM also responded to Treg expansion with decreased cell viability (p = 0.024). Our data indicate that the ex vivo expansion of Treg cells increased the cytotoxic effect of bortezomib in clinically sensitive cases.

  1. Interleukin-35 Limits Anti-Tumor Immunity.

    PubMed

    Turnis, Meghan E; Sawant, Deepali V; Szymczak-Workman, Andrea L; Andrews, Lawrence P; Delgoffe, Greg M; Yano, Hiroshi; Beres, Amy J; Vogel, Peter; Workman, Creg J; Vignali, Dario A A

    2016-02-16

    Regulatory T (Treg) cells pose a major barrier to effective anti-tumor immunity. Although Treg cell depletion enhances tumor rejection, the ensuing autoimmune sequelae limits its utility in the clinic and highlights the need for limiting Treg cell activity within the tumor microenvironment. Interleukin-35 (IL-35) is a Treg cell-secreted cytokine that inhibits T cell proliferation and function. Using an IL-35 reporter mouse, we observed substantial enrichment of IL-35(+) Treg cells in tumors. Neutralization with an IL-35-specific antibody or Treg cell-restricted deletion of IL-35 production limited tumor growth in multiple murine models of human cancer. Limiting intratumoral IL-35 enhanced T cell proliferation, effector function, antigen-specific responses, and long-term T cell memory. Treg cell-derived IL-35 promoted the expression of multiple inhibitory receptors (PD1, TIM3, LAG3), thereby facilitating intratumoral T cell exhaustion. These findings reveal previously unappreciated roles for IL-35 in limiting anti-tumor immunity and contributing to T cell dysfunction in the tumor microenvironment.

  2. Design and synthesis of the novel DNA topoisomerase II inhibitors: esterification and amination substituted 4'-demethylepipodophyllotoxin derivates exhibiting anti-tumor activity by activating ATM/ATR signaling pathways.

    PubMed

    Xiao, Li; Zhao, Wei; Li, Hong-Mei; Wan, Duan-Ji; Li, Dong-Sheng; Chen, Tao; Tang, Ya-Jie

    2014-06-10

    According to the structure-activity relationship, drug combination principle and bioisosterism, a series of the novel esterification and amination 4'-demethylepipodophyllotoxin derivates were rationally designed in order to discover the potential antitumor prodrug. And then these compounds were tested by the drug-topoisomerase II docking models for virtual screening. Thus, twelve target compounds were screened out and synthesized. Most of compounds exhibited promising in vitro anti-tumor activity, particularly 4-N-tris(hydroxymethyl)metylaminomethane-4-deoxy-4'-demethylepipodophyllotoxin (Compound 1). The anti-tumor activity of Compound 1 against the tumor cell lines BGC-823 (i.e., the IC50 value of 5.35 ± 0.77 μM), HeLa (i.e., the IC50 value of 160.48 ± 14.50 μM), and A549 (i.e., the IC50 value of 13.95 ± 5.41 μM) was significantly improved by 706%, 31% and 900% than that of etoposide (i.e., the IC50 values of 43.74 ± 5.13, 209.90 ± 13.42, and 139.54 ± 7.05 μM), respectively. Moreover, the IC50 value of Compound 1 against the normal human cell line HK-2 (i.e., 16.3 ± 3.77 μM) was 78% lower than that of etoposide (i.e., 9.17 ± 1.58 μM). Compound 1 could diminish the relaxation reaction topoisomerase II DNA decatenation at a concentration of 10 μM and induce BGC-823 apoptosis by breaking DNA double-strand and activating ATM/ATR signaling pathways.

  3. p53-independent anti-tumor effects of the nitrogen-containing bisphosphonate zoledronic acid.

    PubMed

    Kuroda, Junya; Kimura, Shinya; Segawa, Hidekazu; Sato, Kiyoshi; Matsumoto, Seiji; Nogawa, Masaki; Yuasa, Takeshi; Kobayashi, Yutaka; Yoshikawa, Toshikazu; Ottmann, Oliver G; Maekawa, Taira

    2004-02-01

    Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, exerts anti-tumor effects by inhibiting the prenylation of small GTPases. We have also reported that ZOL shows an anti-leukemic effect by inducing apoptosis throughout the S phase to the G(2) / M boundary. Here, we studied the effects of ZOL on various cell cycle regulators, including p53, cyclin-dependent kinases (CDKs), CDK inhibitors and cyclins, using BV173 leukemia and HCT116 colorectal carcinoma cell lines, harboring wild-type (wt-) p53. ZOL induced the accumulation of neither p53 nor p21(WAF1/CIP1) during the execution of apoptosis in BV173 cells. Therefore, we investigated the dependence of ZOL-induced apoptosis on intact p53 by using wt-p53 HCT116 and a p53-degraded HCT116 subline, and observed no significant difference. p57(KIP2) was upregulated by ZOL in BV173 cells, but not in HCT116 cells. Flow cytometric analyses showed that ZOL also impaired the cell cycle-dependent expression patterns of cyclins A, B and D3 in BV173. In conclusion, the p53-independent anti-tumor activities of ZOL suggest that it may be an attractive agent for treating cancers, including those with chemoresistance resulting from the loss of p53 function. ZOL also affected the coordinate expression patterns of several cell cycle regulators during the execution of anti-tumor activity.

  4. Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy

    PubMed Central

    Sckisel, Gail D.; Mirsoian, Annie; Bouchlaka, Myriam N.; Tietze, Julia K.; Chen, Mingyi; Blazar, Bruce R.

    2016-01-01

    We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8+ T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities. PMID:26423422

  5. 15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPAR{gamma} pathways

    SciTech Connect

    Yamamoto, Yasuhiro; Fujita, Megumi; Koma, Hiromi; Yamamori, Motohiro; Nakamura, Tsutomu; Okamura, Noboru; Yagami, Tatsurou

    2011-07-08

    Highlights: {yields} A topoisomerase-I inhibitor, camptothecin, exhibited synergistically toxicity with 15d-PGJ{sub 2}. {yields} The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. {yields} A PPAR{gamma} antagonist did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. {yields} The treatment of camptothecin combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. -- Abstract: Renal cell carcinoma (RCC) is chemoresistant cancer. Although several clinical trials were conducted to explore effective medications, the chemoresistance of RCC has not yet been conquered. An endogenous ligand for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), 15-deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{sub 2}), induces apoptosis in RCC. Here, we examined synergistic effects of several carcinostatics on the anti-tumor activity of 15d-PGJ{sub 2} in Caki-2 cell line by MTT assay. A topoisomerase-I inhibitor, camptothecin (CPT), exhibited synergistically toxicity with 15d-PGJ{sub 2}, but neither 5-fluorouracil nor cisplatin did. The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. The synergistic effect of topoisomerase-I and II inhibitors was not also detected. A PPAR{gamma} antagonist, GW9662, did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. The treatment of CPT combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. These results suggest that 15d-PGJ{sub 2} exhibited the anti-tumor activity synergistically with CPT independent of topoisomerase-II and PPAR{gamma}.

  6. An Investigation on a Novel Anti-tumor Fusion Peptide of FSH33-53-IIKK

    PubMed Central

    Yang, Runlin; Liu, Ping; Pan, Donghui; zhang, Pengjun; Bai, Zhicheng; Xu, Yuping; Wang, Lizhen; Yan, Junjie; Yan, Yongjun; Liu, Xingdang; Yang, Min

    2016-01-01

    A novel fusion peptide FSH33-53-IIKK was designed and expected to combine the follicle stimulating hormone receptor (FSHR) targeting and tumor toxicity. In vitro and in vivo study showed the anti-tumor activity of FSH33-53-IIKK was enhanced compared to that of IIKK only. FSH33-53-IIKK could inhibit the growth of tumor via apoptosis and autophagy pathways. In summary, combining the tumor marker-target peptide and anti-tumor peptide together may be an efficient way to search for better anti-tumor candidates. PMID:27313792

  7. An Investigation on a Novel Anti-tumor Fusion Peptide of FSH33-53-IIKK.

    PubMed

    Yang, Runlin; Liu, Ping; Pan, Donghui; Zhang, Pengjun; Bai, Zhicheng; Xu, Yuping; Wang, Lizhen; Yan, Junjie; Yan, Yongjun; Liu, Xingdang; Yang, Min

    2016-01-01

    A novel fusion peptide FSH33-53-IIKK was designed and expected to combine the follicle stimulating hormone receptor (FSHR) targeting and tumor toxicity. In vitro and in vivo study showed the anti-tumor activity of FSH33-53-IIKK was enhanced compared to that of IIKK only. FSH33-53-IIKK could inhibit the growth of tumor via apoptosis and autophagy pathways. In summary, combining the tumor marker-target peptide and anti-tumor peptide together may be an efficient way to search for better anti-tumor candidates. PMID:27313792

  8. The anti-tumor potential of zoledronic acid.

    PubMed

    Croucher, P; Jagdev, S; Coleman, R

    2003-08-01

    Bone is a favorable microenvironment for tumor cell colonization because of abundant growth factors released during active bone resorption. Bisphosphonates can dramatically affect the ability of tumor cells to grow in bone by inhibiting osteoclast-mediated bone resorption and by depriving tumors of growth-promoting signals. Moreover, bisphosphonates have direct anti-tumor effects in vitro via induction of apoptosis. Zoledronic acid is a nitrogen-containing bisphosphonate that has demonstrated potent anti-tumor activity in vitro and in vivo. In vitro studies have provided important clues as to the molecular mechanisms by which zoledronic acid induces apoptosis of human breast cancer cell lines. Studies in multiple myeloma and breast cancer models have shed further light on the possible mechanisms underlying the in vivo anti-tumor effects of zoledronic acid. These studies have led to the development of novel strategies to target specific molecular pathways involved in osteoclast maturation and activity, tumor cell metastasis, and tumor growth and survival. The clinical application of these strategies may ultimately prevent bone metastasis.

  9. Anti-tumor effects and cellular mechanisms of resveratrol.

    PubMed

    Han, Guohua; Xia, Jufeng; Gao, Jianjun; Inagaki, Yoshinori; Tang, Wei; Kokudo, Norihiro

    2015-02-01

    Resveratrol (3, 5, 4'-trihydroxystilbene) is a phytoalexin contained in a variety of plants, such as grapes, berries and especially in the dried roots of Polygonum cuspidatum Sieb. et Zucc. It has been shown to exhibit anti-oxidative and anti-inflammation activity, and to reverse the effects of aging. Its ability to suppress cell proliferation, induce apoptosis and suppress the metastasis and invasion in a number of cell lines has prompted a large interest from people for its use as an anti-tumor component. In this review, evidence of resveratrol's anti-tumor effects and molecular mechanisms are recapitulated. First, we present the anti-apoptosis, anti-invasion/metastasis and anti-inflammation effect of resveratrol; second, the main signaling pathways involved in these activities are described and summarized with the studies of different tumors involved. Resveratrol not only induces apoptosis of tumor cells through intrinsic/extrinsic pathways and cell cycle arrest, but also inhibits the invasion and metastasis abilities of tumors via modulating collagen degradation-related molecular targets. Altogether, the present findings suggest the anti-tumor potential of resveratrol against various types of cancers. PMID:25788047

  10. The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer

    PubMed Central

    2011-01-01

    Background HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity. Methods In this study we examined the effect of α-TEA plus HER2/neu-specific antibody treatment on HER2/neu-expressing breast cancer cells in vitro and in a HER2/neu positive human xenograft tumor model in vivo. Results We show in vitro that α-TEA plus anti-HER2/neu antibody has an increased cytotoxic effect against murine mammary tumor cells and human breast cancer cells and that the anti-tumor effect of α-TEA is independent of HER2/neu status. More importantly, in a human breast cancer xenograft model, the combination of α-TEA plus trastuzumab resulted in faster tumor regression and more tumor-free animals than trastuzumab alone. Conclusion Due to the cancer cell selectivity of α-TEA, and because α-TEA kills both HER2/neu positive and HER2/neu negative breast cancer cells, it has the potential to be effective and less toxic than existing

  11. Recombinant expression and purification of a MAP30-cell penetrating peptide fusion protein with higher anti-tumor bioactivity.

    PubMed

    Lv, Qiang; Yang, Xu-Zhong; Fu, Long-Yun; Lu, Yv-Ting; Lu, Yan-Hua; Zhao, Jian; Wang, Fu-Jun

    2015-07-01

    MAP30 (Momordica Antiviral Protein 30 Kd), a single-stranded type-I ribosome inactivating protein, possesses versatile biological activities including anti-tumor abilities. However, the low efficiency penetrating into tumor cells hampers the tumoricidal effect of MAP30. This paper describes MAP30 fused with a human-derived cell penetrating peptide HBD which overcome the low uptake efficiency by tumor cells and exhibits higher anti-tumor bioactivity. MAP30 gene was cloned from the genomic DNA of Momordica charantia and the recombinant plasmid pET28b-MAP30-HBD was established and transferred into Escherichia coli BL21 (DE3). The recombinant MAP30-HBD protein (rMAP30-HBD) was expressed in a soluble form after being induced by 0.5mM IPTG for 14h at 15°C. The recombinant protein was purified to greater than 95% purity with Ni-NTA affinity chromatography. The rMAP30-HBD protein not only has topological inactivation and protein translation inhibition activity but also showed significant improvements in cytotoxic activity compared to that of the rMAP30 protein without HBD in the tested tumor cell lines, and induced higher apoptosis rates in HeLa cells analyzed by Annexin V-FITC with FACS. This paper demonstrated a new method for improving MAP30 protein anti-tumor activity and might have potential applications in cancer therapy area.

  12. Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer

    PubMed Central

    Song, Xuejiao; Gao, Tiantao; Wang, Ningyu; Feng, Qiang; You, Xinyu; Ye, Tinghong; Lei, Qian; Zhu, Yongxia; Xiong, Menghua; Xia, Yong; Yang, Fangfang; Shi, Yaojie; Wei, Yuquan; Zhang, Lidan; Yu, Luoting

    2016-01-01

    Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overexpression including breast cancers. Here, we described ZLD1039 a potent, highly selective, and orally bioavailable small molecule inhibitor of EZH2, which inhibited breast tumor growth and metastasis. ZLD1039 considerably inhibited EZH2 methyltransferase activity with nanomolar potency, decreased global histone-3 lysine-27 (H3K27) methylation, and reactivated silenced tumor suppressors connected to increased survival of patients with breast cancer. Comparable to conditional silencing of EZH2, its inhibition by ZLD1039 decreased cell proliferation, cell cycle arrest, and induced apoptosis. Comparably, treatment of xenograft-bearing mice with ZLD1039 led to tumor growth regression and metastasis inhibition. These data confirmed the dependency of breast cancer progression on EZH2 activity and the usefulness of ZLD1039 as a promising treatment for breast cancer. PMID:26868841

  13. Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo.

    PubMed

    Roghanian, Ali; Teige, Ingrid; Mårtensson, Linda; Cox, Kerry L; Kovacek, Mathilda; Ljungars, Anne; Mattson, Jenny; Sundberg, Annika; Vaughan, Andrew T; Shah, Vallari; Smyth, Neil R; Sheth, Bhavwanti; Chan, H T Claude; Li, Zhan-Chun; Williams, Emily L; Manfredi, Giusi; Oldham, Robert J; Mockridge, C Ian; James, Sonya A; Dahal, Lekh N; Hussain, Khiyam; Nilsson, Björn; Verbeek, J Sjef; Juliusson, Gunnar; Hansson, Markus; Jerkeman, Mats; Johnson, Peter W M; Davies, Andrew; Beers, Stephen A; Glennie, Martin J; Frendéus, Björn; Cragg, Mark S

    2015-04-13

    Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment. PMID:25873171

  14. Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo.

    PubMed

    Roghanian, Ali; Teige, Ingrid; Mårtensson, Linda; Cox, Kerry L; Kovacek, Mathilda; Ljungars, Anne; Mattson, Jenny; Sundberg, Annika; Vaughan, Andrew T; Shah, Vallari; Smyth, Neil R; Sheth, Bhavwanti; Chan, H T Claude; Li, Zhan-Chun; Williams, Emily L; Manfredi, Giusi; Oldham, Robert J; Mockridge, C Ian; James, Sonya A; Dahal, Lekh N; Hussain, Khiyam; Nilsson, Björn; Verbeek, J Sjef; Juliusson, Gunnar; Hansson, Markus; Jerkeman, Mats; Johnson, Peter W M; Davies, Andrew; Beers, Stephen A; Glennie, Martin J; Frendéus, Björn; Cragg, Mark S

    2015-04-13

    Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment.

  15. High dose CD11c-driven IL15 is sufficient to drive NK cell maturation and anti-tumor activity in a trans-presentation independent manner

    PubMed Central

    Polansky, Julia K.; Bahri, Rajia; Divivier, Mylene; Duitman, Erwin H.; Vock, Christina; Goyeneche-Patino, Diego A.; Orinska, Zane; Bulfone-Paus, Silvia

    2016-01-01

    The common gamma (γc)-chain cytokine interleukin 15 (IL15) is a multifunctional immune-modulator which impacts the generation, maturation and activity of many cell types of the innate, as well as the adaptive immune system, including natural killer (NK) and CD8+ T cells. Using a new series of transgenic mice, we analyzed the in vivo potential of IL15 as an immune-regulator when available at different concentrations or delivery modes, i.e. soluble monomer or complexed to its specific receptor α (Rα)-chain. We have identified distinct effects on selected IL15-responsive populations. While CD8+ T cells required complexed forms of IL15/IL15Rα for full functionality, mature NK populations were rescued in an IL15/IL15Rα-deficient environment by high levels of CD11c-restricted IL15. These IL15-conditions were sufficient to limit tumor formation in a lung metastasis model indicating that the NK cell populations were fully functional. These data underline the potential of “free” IL15 in the absence of Rα-complex as a powerful and specific immuno-modulator, which may be beneficial where selective immune-activation is desired. PMID:26822794

  16. Gypenosides Synergistically Enhances the Anti-Tumor Effect of 5-Fluorouracil on Colorectal Cancer In Vitro and In Vivo: A Role for Oxidative Stress-Mediated DNA Damage and p53 Activation

    PubMed Central

    Kong, Lulu; Wang, Xiaobing; Zhang, Kun; Yuan, Wenjuan; Yang, Qiwen; Fan, Jianping; Wang, Pan; Liu, Quanhong

    2015-01-01

    Objective 5-Fluorouracil (5-Fu) has been widely used as a first-line drug for colorectal cancer (CRC) treatment but limited by drug resistance and severe toxicity. The chemo-sensitizers that augment its efficiency and overcome its limitation are urgently needed. Gypenosides (Gyp), the main components from Gynostemma pentaphyllum (Thunb.) Makino, has shown potential anti-tumor property with little side-effect. Here, we carefully explored the chemo-sensitization of Gyp to potentiate the anti-tumor effect of 5-Fu in vitro and in vivo. Methodology / Principal Findings 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltertrazolium bromide tetrazolium assay and colony formation test reveal that Gyp could significantly enhance the 5-Fu-caused SW-480,SW-620 and Caco2 cells viability loss. Calcusyn analysis shows that Gyp acts synergistically with 5-Fu. Annexin V-PE/7-AAD staining indicates 5-Fu + Gyp could induce SW-480 cell apoptosis. The activations of caspase 3, caspase 9 and poly (ADP-ribose) polymerase (PARP) were involved in the process. Gyp was also found to up-regulate 5-Fu-caused phospho-p53 expression and thus augment 5-Fu-induced G0/G1 phase arrest. Gyp elevated intracellular ROS level, significantly enhanced 5-Fu-triggered DNA damage response as evidenced by flow cytometry, comet assay and the expression of Ser139-Histone H2A.X. Inhibition of ROS and p53 respectively reversed the cell death induced by 5-Fu + Gyp, suggesting the key roles of ROS and p53 in the process. Moreover, 5-Fu and Gyp in combination exhibits much superior tumor volume and weight inhibition on CT-26 xenograft mouse model in comparison to 5-Fu or Gyp alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation. Preliminary toxicological results show that 5-Fu + Gyp treatment is relatively safe. Conclusions As a potential chemo-sensitizer, Gyp displays a splendid synergistic effect with 5-Fu to inhibit cancer cell proliferation and tumor growth. By using 5

  17. Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer

    PubMed Central

    Howe, Grant A.; Xiao, Bin; Zhao, Huijun; Al-Zahrani, Khalid N.; Hasim, Mohamed S.; Villeneuve, James; Sekhon, Harmanjatinder S.; Goss, Glenwood D.; Sabourin, Luc A.; Dimitroulakos, Jim; Addison, Christina L.

    2016-01-01

    Blockade of epidermal growth factor receptor (EGFR) activity has been a primary therapeutic target for non-small cell lung cancers (NSCLC). As patients with wild-type EGFR have demonstrated only modest benefit from EGFR tyrosine kinase inhibitors (TKIs), there is a need for additional therapeutic approaches in patients with wild-type EGFR. As a key component of downstream integrin signalling and known receptor cross-talk with EGFR, we hypothesized that targeting focal adhesion kinase (FAK) activity, which has also been shown to correlate with aggressive stage in NSCLC, would lead to enhanced activity of EGFR TKIs. As such, EGFR TKI-resistant NSCLC cells (A549, H1299, H1975) were treated with the EGFR TKI erlotinib and FAK inhibitors (PF-573,228 or PF-562,271) both as single agents and in combination. We determined cell viability, apoptosis and 3-dimensional growth in vitro and assessed tumor growth in vivo. Treatment of EGFR TKI-resistant NSCLC cells with FAK inhibitor alone effectively inhibited cell viability in all cell lines tested; however, its use in combination with the EGFR TKI erlotinib was more effective at reducing cell viability than either treatment alone when tested in both 2- and 3-dimensional assays in vitro, with enhanced benefit seen in A549 cells. This increased efficacy may be due in part to the observed inhibition of Akt phosphorylation when the drugs were used in combination, where again A549 cells demonstrated the most inhibition following treatment with the drug combination. Combining erlotinib with FAK inhibitor was also potent in vivo as evidenced by reduced tumor growth in the A549 mouse xenograft model. We further ascertained that the enhanced sensitivity was irrespective of the LKB1 mutational status. In summary, we demonstrate the effectiveness of combining erlotinib and FAK inhibitors for use in known EGFR wild-type, EGFR TKI resistant cells, with the potential that a subset of cell types, which includes A549, could be particularly

  18. Isolation and Characterization of Neutrophils with Anti-Tumor Properties.

    PubMed

    Sionov, Ronit Vogt; Assi, Simaan; Gershkovitz, Maya; Sagiv, Jitka Y; Polyansky, Lola; Mishalian, Inbal; Fridlender, Zvi G; Granot, Zvi

    2015-01-01

    Neutrophils, the most abundant of all white blood cells in the human circulation, play an important role in the host defense against invading microorganisms. In addition, neutrophils play a central role in the immune surveillance of tumor cells. They have the ability to recognize tumor cells and induce tumor cell death either through a cell contact-dependent mechanism involving hydrogen peroxide or through antibody-dependent cell-mediated cytotoxicity (ADCC). Neutrophils with anti-tumor activity can be isolated from peripheral blood of cancer patients and of tumor-bearing mice. These neutrophils are termed tumor-entrained neutrophils (TEN) to distinguish them from neutrophils of healthy subjects or naïve mice that show no significant tumor cytotoxic activity. Compared with other white blood cells, neutrophils show different buoyancy making it feasible to obtain a > 98% pure neutrophil population when subjected to a density gradient. However, in addition to the normal high-density neutrophil population (HDN), in cancer patients, in tumor-bearing mice, as well as under chronic inflammatory conditions, distinct low-density neutrophil populations (LDN) appear in the circulation. LDN co-purify with the mononuclear fraction and can be separated from mononuclear cells using either positive or negative selection strategies. Once the purity of the isolated neutrophils is determined by flow cytometry, they can be used for in vitro and in vivo functional assays. We describe techniques for monitoring the anti-tumor activity of neutrophils, their ability to migrate and to produce reactive oxygen species, as well as monitoring their phagocytic capacity ex vivo. We further describe techniques to label the neutrophils for in vivo tracking, and to determine their anti-metastatic capacity in vivo. All these techniques are essential for understanding how to obtain and characterize neutrophils with anti-tumor function. PMID:26132785

  19. Human Monoclonal Antibodies to Sialyl-Lewis a (CA19.9) with Potent CDC, ADCC and Anti-Tumor Activity

    PubMed Central

    Sawada, Ritsuko; Sun, Shu-Man; Wu, Xiaohong; Hong, Feng; Ragupathi, Govind; Livingston, Philip O.; Scholz, Wolfgang W.

    2011-01-01

    Purpose The carbohydrate antigen sialyl-Lewis A (sLea), also known as CA19.9, is widely expressed on epithelial tumors of the gastrointestinal tract and breast, and on small cell lung cancers. Since over-expression of sLea appears to be a key event in invasion and metastasis of many tumors and results in susceptibility to antibody mediated lysis, sLea is an attractive molecular target for tumor therapy. Experimental Design We generated and characterized fully human monoclonal antibodies (mAbs) from blood lymphocytes from individuals immunized with a sLea –KLH vaccine. Results Several mAbs were selected based on ELISA and FACS including two mAbs with high affinity for sLea (5B1 and 7E3, binding affinities 0.14 nM and 0.04 nM, respectively) and further characterized. Both antibodies were specific for Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ as determined by glycan array analysis. Complement dependent cytotoxicity against DMS-79 cells was higher for r7E3 (IgM) compared to r5B1 (IgG1), (EC50 0.1 μg/ml vs 1.7 μg/ml). In addition, r5B1 antibodies showed high level ADCC activity on DMS-79 cells with human NK cells or peripheral blood mononuclear cells. To evaluate in vivo efficacy, the antibodies were tested in a xenograft model with Colo205 tumor cells engrafted into SCID mice. Treatment during the first 21 days with 4 doses r5B1 (100 μg/dose) doubled the median survival time to 207 days, and 3/5 animals survived with 6 doses. Conclusion Based on the potential of sLea as a target for immune attack and their affinity, specificity and effector functions, 5B1and 7E3 may have clinical utility. PMID:21343375

  20. Anti-tumor effects of an engineered 'killer' transfer RNA

    SciTech Connect

    Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey; Geslain, Renaud; Rosner, Marsha; Pan, Tao

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer tRNA with anti-cancer effects. Black-Right-Pointing-Pointer tRNA induced protein misfolding. Black-Right-Pointing-Pointer tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA{sup Ser}(AAU) is an engineered human tRNA{sup Ser} with an anticodon coding for isoleucine. Here we test the possibility that tRNA{sup Ser}(AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA{sup Ser}(AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA{sup Ser}(AAU) in both tumorigenic and non-tumorigenic cells. tRNA{sup Ser}(AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA{sup Ser}(AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA{sup Ser}(AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA{sup Ser}(AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.

  1. Anti-tumor effects of Rubratoxin B on cell toxicity, inhibition of cell proliferation, cytotoxic activity and matrix metalloproteinase-2,9.

    PubMed

    Wang, Tao; Zhang, Yi; Wang, Yi; Pei, Yue-hu

    2007-06-01

    Terrestrial fungi are a prolific source of metabolites with significant biological activities. Many important anticancer, antifungal and antibacterial chemotherapeutics are either microbial metabolites or semisynthetic derivatives. Investigating the metabolites of fungi may increase the chance of finding novel compounds. A bioassay-guided fractionation of soil fungus Penicillium purpurogenum fermentation, yielded the metabolite Rubratoxin B using morphological deformation of Pyricularia oryzae mycelia. Analysis by flow cytometry showed that Rubratoxin B inhibited the cell cycle progression of tsFT210 cells in the G2/M phase at the concentration of 24 microM. Cytotoxic activity analysis showed that Rubratoxin B has a cytotoxic activity and IC50 was 67.3 +/- 1.4 microM on human fibrosarcoma cell (HT1080), and Rubratoxin B exhibited inhibitory activities against matrix metalloproteinase (MMP)-2 and 9 on HT 1080 cells with an inhibitory rate of 61.5% and 74.7% at 30 microM, respectively. PMID:17306501

  2. Anti-Tumor Activity of Yuanhuacine by Regulating AMPK/mTOR Signaling Pathway and Actin Cytoskeleton Organization in Non-Small Cell Lung Cancer Cells.

    PubMed

    Kang, Ji In; Hong, Ji-Young; Lee, Hye-Jung; Bae, Song Yi; Jung, Cholomi; Park, Hyen Joo; Lee, Sang Kook

    2015-01-01

    Yuanhuacine (YC), a daphnane diterpenoid from the flowers of Daphne genkwa, exhibited a potential growth inhibitory activity against human non-small cell lung cancer (NSCLC) cells. YC also suppressed the invasion and migration of lung cancer cells. However, the precise molecular mechanisms remain to be elucidated. In the present study, we report that YC significantly activated AMP-activated protein kinase (AMPK) signaling pathway and suppressed mTORC2-mediated downstream signaling pathway in H1993 human NSCLC cells. AMPK plays an important role in energy metabolism and cancer biology. Therefore, activators of AMPK signaling pathways can be applicable to the treatment of cancer. YC enhanced the expression of p-AMPKα. The co-treatment of YC and compound C (an AMPK inhibitor) or metformin (an AMPK activator) also confirmed that YC increases p-AMPKα. YC also suppressed the activation of the mammalian target of rapamycin (mTOR) expression, a downstream target of AMPK. Further study revealed that YC modulates mTORC2-associated downstream signaling pathways with a decreased expressions of p-Akt, p-protein kinase C alpha (PKCα), p-ras-related C3 botulinum toxin substrate 1 (Rac1) and filamentous actin (F-actin) that are known to activate cell growth and organize actin cytoskeleton. In addition, YC inhibited the tumor growth in H1993 cell-implanted xenograft nude mouse model. These data suggest the YC could be a potential candidate for cancer chemotherapeutic agents derived from natural products by regulating AMPK/mTORC2 signaling pathway and actin cytoskeleton organization. PMID:26656173

  3. Structure-Activity Relationship and in Vivo Anti-Tumor Evaluations of Dictyoceratin-A and -C, Hypoxia-Selective Growth Inhibitors from Marine Sponge.

    PubMed

    Sumii, Yuji; Kotoku, Naoyuki; Fukuda, Akinori; Kawachi, Takashi; Arai, Masayoshi; Kobayashi, Motomasa

    2015-12-01

    Oral dictyoceratin-C (1) and A (2), hypoxia-selective growth inhibitors, showed potent in vivo antitumor effects in mice subcutaneously inoculated with sarcoma S180 cells. Structurally modified analogs were synthesized to assess the structure-activity relationship of the natural compounds 1 and 2 isolated from a marine sponge. Biological evaluation of these analogs showed that the exo-olefin and hydroxyl and methyl ester moieties were important for the hypoxia-selective growth inhibitory activities of 1 and 2. Thus far, only substitution of the methyl ester with propargyl amide in 1 was found to be effective for the synthesis of probe molecules for target identification.

  4. Structure-Activity Relationship and in Vivo Anti-Tumor Evaluations of Dictyoceratin-A and -C, Hypoxia-Selective Growth Inhibitors from Marine Sponge.

    PubMed

    Sumii, Yuji; Kotoku, Naoyuki; Fukuda, Akinori; Kawachi, Takashi; Arai, Masayoshi; Kobayashi, Motomasa

    2015-12-01

    Oral dictyoceratin-C (1) and A (2), hypoxia-selective growth inhibitors, showed potent in vivo antitumor effects in mice subcutaneously inoculated with sarcoma S180 cells. Structurally modified analogs were synthesized to assess the structure-activity relationship of the natural compounds 1 and 2 isolated from a marine sponge. Biological evaluation of these analogs showed that the exo-olefin and hydroxyl and methyl ester moieties were important for the hypoxia-selective growth inhibitory activities of 1 and 2. Thus far, only substitution of the methyl ester with propargyl amide in 1 was found to be effective for the synthesis of probe molecules for target identification. PMID:26694423

  5. Enhanced anti-tumor activity induced by adoptive T cell transfer and the adjunctive use of the HDAC Inhibitor LAQ824

    PubMed Central

    Vo, Dan D.; Prins, Robert M.; Begley, Jonathan L.; Donahue, Timothy R.; Morris, Lilah F.; Bruhn, Kevin W.; de la Rocha, Pilar; Yang, Meng-Yin; Mok, Stephen; Garban, Hermes J.; Craft, Noah; Economou, James S.; Marincola, Francesco M.; Wang, Ena; Ribas, Antoni

    2009-01-01

    Tumors grow in the presence of antigen-specific T cells, suggesting the existence of intrinsic cancer cell escape mechanisms. We hypothesized that a histone deacetylase (HDAC) inhibitor could sensitize tumor cells to immunotherapy because this class of agents has been reported to increase tumor antigen expression and shift gene expression to a pro-apoptotic milieu in cancer cells. To test this question, we treated B16 murine melanoma with the combination of the HDAC inhibitor LAQ824 together with the adoptive transfer (AT) of gp100 melanoma antigen-specific pmel-1 T cells. The combined therapy significantly improved antitumor activity through several mechanisms: 1) increase in MHC and tumor-associated antigen (TAA) expression by tumor cells; 2) decrease in competing endogenous lymphocytes in recipient mice, resulting in a proliferative advantage for the adoptively transferred cells; and 3) improvement in the functional activity of the adoptively transferred lymphocytes. We confirmed the beneficial effects of this HDAC inhibitor as sensitizer to immunotherapy in a different model of prophylactic prime-boost vaccination with the melanoma antigen tyrosinase-related protein-2 (TRP2), which also demonstrated a significant improvement in antitumor activity against B16 melanoma. In conclusion, the HDAC inhibitor LAQ824 significantly enhances tumor immunotherapy through effects on target tumor cells as well as improving the antitumor activity of tumor antigen-specific lymphocytes. PMID:19861533

  6. Utility of Clostridium difficile toxin B for inducing anti-tumor immunity.

    PubMed

    Huang, Tuxiong; Li, Shan; Li, Guangchao; Tian, Yuan; Wang, Haiying; Shi, Lianfa; Perez-Cordon, Gregorio; Mao, Li; Wang, Xiaoning; Wang, Jufang; Feng, Hanping

    2014-01-01

    Clostridium difficile toxin B (TcdB) is a key virulence factor of bacterium and induces intestinal inflammatory disease. Because of its potent cytotoxic and proinflammatory activities, we investigated the utility of TcdB in developing anti-tumor immunity. TcdB induced cell death in mouse colorectal cancer CT26 cells, and the intoxicated cells stimulated the activation of mouse bone marrow-derived dendritic cells and subsequent T cell activation in vitro. Immunization of BALB/c mice with toxin-treated CT26 cells elicited potent anti-tumor immunity that protected mice from a lethal challenge of the same tumor cells and rejected pre-injected tumors. The anti-tumor immunity generated was cell-mediated, long-term, and tumor-specific. Further experiments demonstrated that the intact cell bodies were important for the immunogenicity since lysing the toxin-treated tumor cells reduced their ability to induce antitumor immunity. Finally, we showed that TcdB is able to induce potent anti-tumor immunity in B16-F10 melanoma model. Taken together, these data demonstrate the utility of C. difficile toxin B for developing anti-tumor immunity.

  7. Zephycandidine A, the First Naturally Occurring Imidazo[1,2-f]phenanthridine Alkaloid from Zephyranthes candida, Exhibits Significant Anti-tumor and Anti-acetylcholinesterase Activities

    PubMed Central

    Zhan, Guanqun; Qu, Xiaolan; Liu, Junjun; Tong, Qingyi; Zhou, Junfei; Sun, Bin; Yao, Guangmin

    2016-01-01

    Zephycandidine A (1), the first naturally occurring imidazo[1,2-f]phenanthridine alkaloid, was isolated from Zephyranthes candida (Amaryllidaceae). The structure of 1 was elucidated by spectroscopic analyses and NMR calculation, and a plausible biogenetic pathway for zephycandidine A (1) was proposed. Zephycandidine A (1) exhibited significant cytotoxicity against five cancer cell lines with IC50 values ranging from 1.98 to 7.03 μM with selectivity indices as high as 10 when compared to the normal Beas-2B cell. Further studies suggested that zephycandidine A (1) induces apoptosis in leukemia cells by the activation of caspase-3, upregulation of Bax, downregulation of Bcl-2, and degradation of PARP expression. In addition, zephycandidine A (1) showed acetylcholinesterase (AChE) inhibitory activity, and the docking studies of zephycandidine A (1) and galanthamine (2) with AChE revealed that interactions with W286 and Y337 are necessary. PMID:27658482

  8. Zephycandidine A, the First Naturally Occurring Imidazo[1,2-f]phenanthridine Alkaloid from Zephyranthes candida, Exhibits Significant Anti-tumor and Anti-acetylcholinesterase Activities

    NASA Astrophysics Data System (ADS)

    Zhan, Guanqun; Qu, Xiaolan; Liu, Junjun; Tong, Qingyi; Zhou, Junfei; Sun, Bin; Yao, Guangmin

    2016-09-01

    Zephycandidine A (1), the first naturally occurring imidazo[1,2-f]phenanthridine alkaloid, was isolated from Zephyranthes candida (Amaryllidaceae). The structure of 1 was elucidated by spectroscopic analyses and NMR calculation, and a plausible biogenetic pathway for zephycandidine A (1) was proposed. Zephycandidine A (1) exhibited significant cytotoxicity against five cancer cell lines with IC50 values ranging from 1.98 to 7.03 μM with selectivity indices as high as 10 when compared to the normal Beas-2B cell. Further studies suggested that zephycandidine A (1) induces apoptosis in leukemia cells by the activation of caspase-3, upregulation of Bax, downregulation of Bcl-2, and degradation of PARP expression. In addition, zephycandidine A (1) showed acetylcholinesterase (AChE) inhibitory activity, and the docking studies of zephycandidine A (1) and galanthamine (2) with AChE revealed that interactions with W286 and Y337 are necessary.

  9. Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats.

    PubMed

    Mundhe, Nitin Arunrao; Kumar, Parveen; Ahmed, Sahabuddin; Jamdade, Vinayak; Mundhe, Sanjay; Lahkar, Mangala

    2015-09-01

    Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti-inflammatory and anticancer activity. The present study was undertaken to evaluate the possible beneficial effects of NDGA on cisplatin induced nephrotoxicity as well as its anticancer activity in rats bearing DMBA induced mammary tumors. The effect of NDGA on cisplatin induced nephrotoxicity was evaluated by checking serum nephrotoxicity markers, antioxidant enzymes and inflammatory markers level and kidney histopathology. NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (-10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-α (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. The current study demonstrated that NDGA may modify the therapeutic effect of cisplatin in DMBA induced breast cancer in female Sprague-Dawley rats. PMID:26247680

  10. Activation of antigen-exposed iMC-DCs at the "right place" and "right time" promotes potent anti-tumor immunity.

    PubMed

    Spencer, David M

    2012-05-01

    To better control the "licensing" of pro-Th1 dendritic cells (DCs), Spencer and colleagues have developed a synthetic ligand-inducible chimeric receptor, iMyD88/CD40 (iMC), incorporating synergistic Toll-like receptor (TLR) and costimulatory signaling elements, permitting DC regulation in vivo within the context of an immunological synapse. This novel technology results in potent anti-cancer activity.

  11. Design, synthesis, anti-tumor activity, and molecular modeling of quinazoline and pyrido[2,3-d]pyrimidine derivatives targeting epidermal growth factor receptor.

    PubMed

    Hou, Ju; Wan, Shanhe; Wang, Guangfa; Zhang, Tingting; Li, Zhonghuang; Tian, Yuanxin; Yu, Yonghuan; Wu, Xiaoyun; Zhang, Jiajie

    2016-08-01

    Three series of novel quinazoline and pyrido[2,3-d]pyrimidine derivatives were designed, synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase and a panel of five human cancer cell lines (MCF-7, A549, BT-474, SK-BR-3, and MDA-MB-231). Bioassay results indicated that five of these prepared compounds (12c-12e and 13c-13d) exhibited remarkably higher inhibitory activities against EGFR and SK-BR-3 cell line. Compounds 12c and 12e displayed the most potent EGFR inhibitory activity (IC50 = 2.97 nM and 3.58 nM, respectively) and good anti-proliferative effect against SK-BR-3 cell with the IC50 values of 3.10 μM and 5.87 μM, respectively. Furthermore, molecular docking and molecular dynamics simulation studies verified that compound 12c and 12e shared similar binding pattern with gefitinib in the binding pocket of EGFR. MM-GBSA binding free energy revealed that the compound 12c and 12e have almost the same inhibitory activity against EGFR as gefitinib, and that the dominating effect of van der Waals interactions drives the binding process. PMID:27132165

  12. Design, synthesis, anti-tumor activity, and molecular modeling of quinazoline and pyrido[2,3-d]pyrimidine derivatives targeting epidermal growth factor receptor.

    PubMed

    Hou, Ju; Wan, Shanhe; Wang, Guangfa; Zhang, Tingting; Li, Zhonghuang; Tian, Yuanxin; Yu, Yonghuan; Wu, Xiaoyun; Zhang, Jiajie

    2016-08-01

    Three series of novel quinazoline and pyrido[2,3-d]pyrimidine derivatives were designed, synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase and a panel of five human cancer cell lines (MCF-7, A549, BT-474, SK-BR-3, and MDA-MB-231). Bioassay results indicated that five of these prepared compounds (12c-12e and 13c-13d) exhibited remarkably higher inhibitory activities against EGFR and SK-BR-3 cell line. Compounds 12c and 12e displayed the most potent EGFR inhibitory activity (IC50 = 2.97 nM and 3.58 nM, respectively) and good anti-proliferative effect against SK-BR-3 cell with the IC50 values of 3.10 μM and 5.87 μM, respectively. Furthermore, molecular docking and molecular dynamics simulation studies verified that compound 12c and 12e shared similar binding pattern with gefitinib in the binding pocket of EGFR. MM-GBSA binding free energy revealed that the compound 12c and 12e have almost the same inhibitory activity against EGFR as gefitinib, and that the dominating effect of van der Waals interactions drives the binding process.

  13. Chimeric antigen receptor T cells with dissociated signaling domains exhibit focused anti-tumor activity with reduced potential for toxicity in vivo

    PubMed Central

    Lanitis, Evripidis; Poussin, Mathilde; Klattenhoff, Alex W.; Song, Degang; Sandaltzopoulos, Raphael; June, Carl H.; Powell, Daniel J.

    2013-01-01

    Adoptive immunotherapy using lymphocytes genetically-modified to express a chimeric antigen receptor (CART) holds considerable promise for the treatment of cancer. However, CAR-based therapies may involve on-target toxicity against normal tissues expressing low amounts of the targeted tumor-associated antigen (TAA). To specify T cells for robust effector function that is selective for tumor but not normal tissue, we developed a trans-signaling CAR strategy whereby T cell activation signal 1 (CD3ζ) is physically dissociated from costimulatory signal 2 (CD28) in two CARs of differing antigen specificity; mesothelin and a-folate receptor (FRa). Human T cells were genetically modified to co-express signal 1 (Anti-Meso scFv-CD3ζ) and signal 2 (Anti-FRa scFv-CD28) CARs in trans. Trans-signaling CART cells showed weak cytokine secretion against target cells expressing only one TAA in vitro, similar to first generation CART cells bearing CD3ζ only, but demonstrated enhanced cytokine secretion upon encountering natural or engineered tumor cells co-expressing both antigens, equivalent to that of second generation CART cells with dual signaling in cis. CART cells with dual specificity also showed potent anti-cancer activity and persistence in vivo which was superior to first generation CART cells and equivalent to second generation CARs. Importantly, second generation CART cells exhibited potent activity against cells expressing mesothelin alone, recapitulating normal tissue, whereas trans-signaling CART cells did not. Thus, a dual specificity, trans-signaling CAR approach can potentiate the therapeutic efficacy of CART cells against cancer while minimizing parallel reactivity against normal tissues bearing single antigen. PMID:24409448

  14. Plasma membrane targeting by short chain sphingolipids inserted in liposomes improves anti-tumor activity of mitoxantrone in an orthotopic breast carcinoma xenograft model.

    PubMed

    Cordeiro Pedrosa, Lília R; van Tellingen, Olaf; Soullié, Thomas; Seynhaeve, Ann L; Eggermont, Alexander M M; Ten Hagen, Timo L M; Verheij, Marcel; Koning, Gerben A

    2015-08-01

    Mitoxantrone (MTO) is clinically used for treatment of various types of cancers providing an alternative for similarly active, but more toxic chemotherapeutic drugs such as anthracyclines. To further decrease its toxicity MTO was encapsulated into liposomes. Although liposomal drugs can accumulate in target tumor tissue, they still face the plasma membrane barrier for effective intracellular delivery. Aiming to improve MTO tumor cell availability, we used short chain lipids to target and modulate the tumor cell membrane, promoting MTO plasma membrane traversal. MTO was encapsulated in liposomes containing the short chain sphingolipid (SCS), C8-Glucosylceramide (C8-GluCer) or C8-Galactosylceramide (C8-GalCer) in their bilayer. These new SCS-liposomes containing MTO (SCS-MTOL) were tested in vivo for tolerability, pharmacokinetics, biodistribution, tumor drug delivery by intravital microscopy and efficacy, and compared to standard MTO liposomes (MTOL) and free MTO. Liposomal encapsulation decreased MTO toxicity and allowed administration of higher drug doses. SCS-MTOL displayed increased clearance and lower skin accumulation compared to standard MTOL. Intratumoral liposomal drug delivery was heterogeneous and rather limited in hypoxic tumor areas, yet SCS-MTOL improved intracellular drug uptake in comparison with MTOL. The increased MTO availability correlated well with the improved antitumor activity of SCS-MTOL in a MDAMB-231 breast carcinoma model. Multiple dosing of liposomal MTO strongly delayed tumor growth compared to free MTO and prolonged mouse survival, whereas among the liposomal MTO treatments, C8-GluCer-MTOL was most effective. Targeting plasma membranes with SCS improved MTO tumor availability and thereby therapeutic activity and represents a promising approach to improve MTO-based chemotherapy.

  15. Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone

    PubMed Central

    Cheng, Wing Yin; Huynh, HoangDinh; Chen, Peiwen; Peña-Llopis, Samuel; Wan, Yihong

    2016-01-01

    Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPARγ loss-of-function mutations, but inhibited by PPARγ agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARγ tumor-suppressive functions. Here we report that macrophage PPARγ deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARγ target in macrophage whose expression is enhanced by PPARγ loss but repressed by PPARγ activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARγ and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPARγ and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects. DOI: http://dx.doi.org/10.7554/eLife.18501.001 PMID:27692066

  16. Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity

    PubMed Central

    Zhang, Wen; Chen, Min; Ling Wu, Yan; Tanaka, Yoshimasa; Juan Ji, Yan; Lin Zhang, Su; He Wei, Chuan; Xu, Yan

    2015-01-01

    G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1–S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1–S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics. PMID:26329134

  17. pH-responsive drug delivery of chitosan nanoparticles as Tamoxifen carriers for effective anti-tumor activity in breast cancer cells.

    PubMed

    Vivek, R; Nipun Babu, V; Thangam, R; Subramanian, K S; Kannan, S

    2013-11-01

    Tamoxifen (Tam) has a broad spectrum of anticancer activity, but is limited in clinical application. The aim of this study was to explore the smart pH-responsive drug delivery system (DDS) based on chitosan (CH) nanoparticles (NPs) for its potential in enabling more intelligent controlled release and enhancing chemotherapeutic efficiency of Tamoxifen. Tamoxifen was loaded onto CH-nanoparticles by forming complexes and Tamoxifen was released from the DDS much more rapidly at pH 4.0 and 6.0 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. Tamoxifen-loaded CH nanoparticles induced remarkable improvement in anticancer activity, as demonstrated by MTT-assay, AO/EtBr and Hoechst nuclear staining. Furthermore, the possible signaling pathway was explored by RT-PCR. For instance, in human breast cancer MCF-7 cells, it was demonstrated that Tamoxifen-loaded CH nanoparticles increase intracellular concentration of Tamoxifen and enhance its anticancer efficiency by inducing apoptosis in a caspase-dependent manner, indicating that drug loaded nanoparticles could act as an efficient DDS importing Tamoxifen into target cancer cells. PMID:23787278

  18. Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity.

    PubMed

    Zhang, Wen; Chen, Min; Ling Wu, Yan; Tanaka, Yoshimasa; Juan Ji, Yan; Lin Zhang, Su; He Wei, Chuan; Xu, Yan

    2015-09-02

    G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1-S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1-S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

  19. Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Zhang, Wen; Chen, Min; Ling Wu, Yan; Tanaka, Yoshimasa; Juan Ji, Yan; Lin Zhang, Su; He Wei, Chuan; Xu, Yan

    2015-09-01

    G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1-S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1-S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

  20. Anti-tumor activity of arjunolic acid against Ehrlich Ascites Carcinoma cells in vivo and in vitro through blocking TGF-β type 1 receptor.

    PubMed

    Elsherbiny, Nehal M; Al-Gayyar, Mohammed M H

    2016-08-01

    We aimed to evaluate therapeutic potential of arjunolic acid (AA), in Terminalia Arjuna bark, on Ehrlich Ascites carcinoma (EAC) in-vivo and in-vitro. EAC was induced in fifty female Swiss albino mice. Two doses of AA was used 100 and 250mg/kg. Arjunulic acid reduced tumor volume and cells count. AA decreased EAC cells viability and increased cell toxicity. Moreover, AA reduced TNF-α, IL-1β, TGF-β, TGF-β type I receptor and latency-associated peptide levels associated with elevated IL-10 in-vivo and in-vitro. In conclusion, AA produced antitumor activity against EAC by increasing cytotoxicity and apoptosis and partially blocking the TGF-βR1 and affecting inflammatory cytokine levels. PMID:27470335

  1. Cellular and Molecular Mechanisms Underlie the Anti-Tumor Activities Exerted by Walterinnesia aegyptia Venom Combined with Silica Nanoparticles against Multiple Myeloma Cancer Cell Types

    PubMed Central

    Badr, Gamal; Al-Sadoon, Mohamed K.; Abdel-Maksoud, Mostafa A.; Rabah, Danny M.; El-Toni, Ahmed M.

    2012-01-01

    Multiple myeloma (MM) is a clonal disease of plasma cells that remains incurable despite the advent of several novel therapeutics. In this study, we aimed to delineate the impact of snake venom extracted from Walterinnesia aegyptia (WEV) alone or in combination with silica nanoparticles (WEV+NP) on primary MM cells isolated from patients diagnosed with MM as well as on two MM cell lines, U266 and RPMI 8226. The IC50 values of WEV and WEV+NP that significantly decreased MM cell viability without affecting the viability of normal peripheral mononuclear cells (PBMCs) were determined to be 25 ng/ml and 10 ng/ml, respectively. Although both WEV (25 ng/ml) and WEV+NP (10 ng/ml) decreased the CD54 surface expression without affecting the expression of CXCR4 (CXCL12 receptor) on MM cells, they significantly reduced the ability of CXC chemokine ligand 12 (CXCL12) to induce actin cytoskeleton rearrangement and the subsequent reduction in chemotaxis. It has been established that the binding of CXCL12 to its receptor CXCR4 activates multiple intracellular signal transduction pathways that regulate MM cell chemotaxis, adhesion, and proliferation. We found that WEV and WEV+NP clearly decreased the CXCL12/CXCR4-mediated activation of AKT, ERK, NFκB and Rho-A using western blot analysis; abrogated the CXCL12-mediated proliferation of MM cells using the CFSE assay; and induced apoptosis in MM cell as determined by PI/annexin V double staining followed by flow cytometry analysis. Monitoring the expression of B-cell CCL/Lymphoma 2 (Bcl-2) family members and their role in apoptosis induction after treatment with WEV or WEV+NP revealed that the combination of WEV with NP robustly decreased the expression of the anti-apoptotic effectors Bcl-2, BclXL and Mcl-1; conversely increased the expression of the pro-apoptotic effectors Bak, Bax and Bim; and altered the mitochondrial membrane potential in MM cells. Taken together, our data reveal the biological effects of WEV and WEV+NP and the

  2. Cellular and molecular mechanisms underlie the anti-tumor activities exerted by Walterinnesia aegyptia venom combined with silica nanoparticles against multiple myeloma cancer cell types.

    PubMed

    Badr, Gamal; Al-Sadoon, Mohamed K; Abdel-Maksoud, Mostafa A; Rabah, Danny M; El-Toni, Ahmed M

    2012-01-01

    Multiple myeloma (MM) is a clonal disease of plasma cells that remains incurable despite the advent of several novel therapeutics. In this study, we aimed to delineate the impact of snake venom extracted from Walterinnesia aegyptia (WEV) alone or in combination with silica nanoparticles (WEV+NP) on primary MM cells isolated from patients diagnosed with MM as well as on two MM cell lines, U266 and RPMI 8226. The IC(50) values of WEV and WEV+NP that significantly decreased MM cell viability without affecting the viability of normal peripheral mononuclear cells (PBMCs) were determined to be 25 ng/ml and 10 ng/ml, respectively. Although both WEV (25 ng/ml) and WEV+NP (10 ng/ml) decreased the CD54 surface expression without affecting the expression of CXCR4 (CXCL12 receptor) on MM cells, they significantly reduced the ability of CXC chemokine ligand 12 (CXCL12) to induce actin cytoskeleton rearrangement and the subsequent reduction in chemotaxis. It has been established that the binding of CXCL12 to its receptor CXCR4 activates multiple intracellular signal transduction pathways that regulate MM cell chemotaxis, adhesion, and proliferation. We found that WEV and WEV+NP clearly decreased the CXCL12/CXCR4-mediated activation of AKT, ERK, NFκB and Rho-A using western blot analysis; abrogated the CXCL12-mediated proliferation of MM cells using the CFSE assay; and induced apoptosis in MM cell as determined by PI/annexin V double staining followed by flow cytometry analysis. Monitoring the expression of B-cell CCL/Lymphoma 2 (Bcl-2) family members and their role in apoptosis induction after treatment with WEV or WEV+NP revealed that the combination of WEV with NP robustly decreased the expression of the anti-apoptotic effectors Bcl-2, Bcl(XL) and Mcl-1; conversely increased the expression of the pro-apoptotic effectors Bak, Bax and Bim; and altered the mitochondrial membrane potential in MM cells. Taken together, our data reveal the biological effects of WEV and WEV+NP and

  3. Lack of anti-tumor activity with the β-catenin expression inhibitor EZN-3892 in the C57BL/6J Min/+ model of intestinal carcinogenesis

    SciTech Connect

    Hasson, Rian M.; Briggs, Alexandra; Rizvi, Hira; Carothers, Adelaide M.; Davids, Jennifer S.; Bertagnolli, Monica M.; Cho, Nancy L.

    2014-02-14

    Highlights: • Wnt/β-catenin signaling is aberrantly activated in most colorectal cancers. • Locked nucleic acid (LNA)-based antisense is a novel tool for cancer therapy. • β-Catenin inhibition was observed in mature intestinal tissue of LNA-treated mice. • Further investigation of Wnt/β-catenin targeted therapies is warranted. - Abstract: Background: Previously, we showed that short-term inhibition of β-catenin expression and reversal of aberrant β-catenin subcellular localization by the selective COX-2 inhibitor celecoxib is associated with adenoma regression in the C57BL/6J Min/+ mouse. Conversly, long-term administration resulted in tumor resistance, leading us to investigate alternative methods for selective β-catenin chemoprevention. In this study, we hypothesized that disruption of β-catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based β-catenin inhibitor, would counteract the tumorigenic effect of Apc loss in Min/+ adenomas while preserving normal intestinal function. Materials and methods: C57BL/6J Apc{sup +/+} wild-type (WT) and Min/+ mice were treated with the maximum tolerated dose (MTD) of EZN-3892 (30 mg/kg). Drug effect on tumor numbers, β-catenin protein expression, and nuclear β-catenin localization were determined. Results: Although the tumor phenotype and β-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in β-catenin expression levels in the mature intestinal tissue of treated Min/+ and WT mice, providing proof of principle regarding successful delivery of the LNA-based antisense vehicle. Higher doses of EZN-3892 resulted in fatal outcomes in Min/+ mice, likely due to β-catenin ablation in the intestinal tissue and loss of function. Conclusions: Our data support the critical role of Wnt/β-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent

  4. Combining Anti-ERBB3 Antibodies Specific for Domain I and Domain III Enhances the Anti-Tumor Activity over the Individual Monoclonal Antibodies

    PubMed Central

    D’Souza, Jimson W.; Shchaveleva, Irina; Marks, James D.; Litwin, Samuel; Robinson, Matthew K.

    2014-01-01

    Background Inappropriate signaling through the epidermal growth factor receptor family (EGFR1/ERBB1, ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4) of receptor tyrosine kinases leads to unregulated activation of multiple downstream signaling pathways that are linked to cancer formation and progression. In particular, ERBB3 plays a critical role in linking ERBB signaling to the phosphoinositide 3-kinase and Akt signaling pathway and increased levels of ERBB3-dependent signaling is also increasingly recognized as a mechanism for acquired resistance to ERBB-targeted therapies. Methods We had previously reported the isolation of a panel of anti-ERBB3 single-chain Fv antibodies through use of phage-display technology. In the current study scFv specific for domain I (F4) and domain III (A5) were converted into human IgG1 formats and analyzed for efficacy. Results Treatment of cells with an oligoclonal mixture of the A5/F4 IgGs appeared more effective at blocking both ligand-induced and ligand-independent signaling through ERBB3 than either single IgG alone. This correlated with improved ability to inhibit the cell growth both as a single agent and in combination with other ERBB-targeted therapies. Treatment of NCI-N87 tumor xenografts with the A5/F4 oligoclonal led to a statistically significant decrease in tumor growth rate that was further enhanced in combination with trastuzumab. Conclusion These results suggest that an oligoclonal antibody mixture may be a more effective approach to downregulate ERBB3-dependent signaling. PMID:25386657

  5. Preparation of intravenous injection nanoformulation of VESylated gemcitabine by co-assembly with TPGS and its anti-tumor activity in pancreatic tumor-bearing mice.

    PubMed

    Xu, Yanyun; Meng, Haijing; Du, Fang; Lu, Wei; Liu, Shiyuan; Huang, Jin; Yu, Jiahui

    2015-11-30

    Our recent publication showed that VES-dFdC nanocapsules in pure water could be obtained via the self-assembling of VES-dFdC prodrug synthesized by coupling gemcitabine (dFdC) with vitamin E succinate (VES). To prepare the intravenous injection nanoformulation, we present here a novel strategy to improve the stability and drug concentration of VES-dFdC nanoformulation in PBS or isotonic solution. Particularly, D-α-tocopheryl polyethylene glycol succinate (TPGS), usually used as drug solubilizer and coincidentally contains the same VES moiety as VES-dFdC prodrug and PEG chain, is selected to co-assemble with VES-dFdC prodrug. The zeta potentials of all the TPGS/VES-dFdC co-assemblies were close to 0 mV, and their particle size measured by dynamic light scattering (DLS) decreased from 113 to 36 nm with increasing TPGS/VES-dFdC molar ratios from 0.15 to 1.5. Stable colloidal suspensions were obtained without aggregates in PBS at 4 °C in one month or isotonic solution at 37 °C in one week, and the weight concentration of VES-dFdC prodrug increased from 7 to 17 mg/mL when the molar ratios of TPGS/VES-dFdC ranged from 0.5/1 to 1.5/1. The concentration of VES-dFdC prodrug was high enough to be used as intravenous injection nanoformulation in nude mice. Interestingly, along with the increase of TPGS/VES-dFdC molar ratios from 0.3/1 to 1.5/1, the morphology of TPGS/VES-dFdC co-assemblies changed from loose nanocapsule to compact micelle revealed by transmission electron microscope (TEM). Finally, the co-assembly of TPGS/VES-dFdC (TPGS/VES-dFdC: 1/1) was selected as intravenous injection nanoformulation to evaluate the antitumor activity. Compared with native dFdC, TPGS/VES-dFdC nanoformulation with 0.2mmol/kg of dosage showed similar low toxicity in vivo, but 4.7 times high of tumor inhibition rate in nude mice with pre-established BxPC-3 tumors.

  6. Preparation of intravenous injection nanoformulation of VESylated gemcitabine by co-assembly with TPGS and its anti-tumor activity in pancreatic tumor-bearing mice.

    PubMed

    Xu, Yanyun; Meng, Haijing; Du, Fang; Lu, Wei; Liu, Shiyuan; Huang, Jin; Yu, Jiahui

    2015-11-30

    Our recent publication showed that VES-dFdC nanocapsules in pure water could be obtained via the self-assembling of VES-dFdC prodrug synthesized by coupling gemcitabine (dFdC) with vitamin E succinate (VES). To prepare the intravenous injection nanoformulation, we present here a novel strategy to improve the stability and drug concentration of VES-dFdC nanoformulation in PBS or isotonic solution. Particularly, D-α-tocopheryl polyethylene glycol succinate (TPGS), usually used as drug solubilizer and coincidentally contains the same VES moiety as VES-dFdC prodrug and PEG chain, is selected to co-assemble with VES-dFdC prodrug. The zeta potentials of all the TPGS/VES-dFdC co-assemblies were close to 0 mV, and their particle size measured by dynamic light scattering (DLS) decreased from 113 to 36 nm with increasing TPGS/VES-dFdC molar ratios from 0.15 to 1.5. Stable colloidal suspensions were obtained without aggregates in PBS at 4 °C in one month or isotonic solution at 37 °C in one week, and the weight concentration of VES-dFdC prodrug increased from 7 to 17 mg/mL when the molar ratios of TPGS/VES-dFdC ranged from 0.5/1 to 1.5/1. The concentration of VES-dFdC prodrug was high enough to be used as intravenous injection nanoformulation in nude mice. Interestingly, along with the increase of TPGS/VES-dFdC molar ratios from 0.3/1 to 1.5/1, the morphology of TPGS/VES-dFdC co-assemblies changed from loose nanocapsule to compact micelle revealed by transmission electron microscope (TEM). Finally, the co-assembly of TPGS/VES-dFdC (TPGS/VES-dFdC: 1/1) was selected as intravenous injection nanoformulation to evaluate the antitumor activity. Compared with native dFdC, TPGS/VES-dFdC nanoformulation with 0.2mmol/kg of dosage showed similar low toxicity in vivo, but 4.7 times high of tumor inhibition rate in nude mice with pre-established BxPC-3 tumors. PMID:26410754

  7. Stimulation of anti-tumor immunity by photodynamic therapy

    PubMed Central

    Mroz, Pawel; Hashmi, Javad T; Huang, Ying-Ying; Lange, Norbert; Hamblin, Michael R

    2011-01-01

    Photodynamic therapy (PDT) is a rapidly developing cancer treatment that utilizes the combination of nontoxic dyes and harmless visible light to destroy tumors by generating reactive oxygen species. PDT produces tumor-cell destruction in the context of acute inflammation that acts as a ‘danger signal’ to the innate immune system. Activation of the innate immune system increases the priming of tumor-specific T lymphocytes that have the ability to recognize and destroy distant tumor cells and, in addition, lead to the development of an immune memory that can combat recurrence of the cancer at a later point in time. PDT may be also successfully combined with immunomodulating strategies that are capable of overcoming or bypassing the escape mechanisms employed by the progressing tumor to evade immune attack. This article will cover the role of the immune response in PDT anti-tumor effectiveness. It will highlight the milestones in the development of PDT-mediated anti-tumor immunity and emphasize the combination strategies that may improve this therapy. PMID:21162652

  8. Selection of a suitable disc bioassay for the screening of anti-tumor molecules.

    PubMed

    Trigui, Fatma; Pigeon, Pascal; Jalleli, Karim; Top, Siden; Aifa, Sami; El Arbi, Mehdi

    2013-12-01

    The crown gall induced in potato discs by Agrobacterium tumefaciens is becoming largely utilised in screening anti-tumor agents. The present work is showing that beet discs are more adequate for the anti-tumor screening test. In fact, maximal tumor induction was observed on beet discs (87.5%), followed by carrot discs (75%) and potato discs (68.5%). Beet discs present the most sensibility to crown gall disease with a fast expression of symptoms and more visible galls without any staining need. The beet discs bioassay was carried out by using some synthesized organometallics known for their antitumor activity in mammalian cells. We found significant crown gall inhibition (20.7% to 40.55%) of the tested compounds. Overall results supported that beet bioassay might be a potential prescreen system of anti-tumor molecules in mammalian cells. PMID:24711759

  9. Selection of a Suitable Disc Bioassay for the Screening of Anti-Tumor Molecules

    PubMed Central

    Trigui, Fatma; Pigeon, Pascal; Jalleli, Karim; Top, Siden; Aifa, Sami; El Arbi, Mehdi

    2013-01-01

    The crown gall induced in potato discs by Agrobacterium tumefaciens is becoming largely utilised in screening anti-tumor agents. The present work is showing that beet discs are more adequate for the anti-tumor screening test. In fact, maximal tumor induction was observed on beet discs (87.5%), followed by carrot discs (75%) and potato discs (68.5%). Beet discs present the most sensibility to crown gall disease with a fast expression of symptoms and more visible galls without any staining need. The beet discs bioassay was carried out by using some synthesized organometallics known for their antitumor activity in mammalian cells. We found significant crown gall inhibition (20.7% to 40.55%) of the tested compounds. Overall results supported that beet bioassay might be a potential prescreen system of anti-tumor molecules in mammalian cells. PMID:24711759

  10. The Anti-Tumor Activity of Succinyl Macrolactin A Is Mediated through the β-Catenin Destruction Complex via the Suppression of Tankyrase and PI3K/Akt

    PubMed Central

    Kim, Seung Joo; Banskota, Suhrid; Shah, Sajita; Kim, Jung-Ae

    2015-01-01

    Accumulated gene mutations in cancer suggest that multi-targeted suppression of affected signaling networks is a promising strategy for cancer treatment. In the present study, we report that 7-O-succinyl macrolactin A (SMA) suppresses tumor growth by stabilizing the β-catenin destruction complex, which was achieved through inhibition of regulatory components associated with the complex. SMA significantly reduced the activities of PI3K/Akt, which corresponded with a decrease in GSK3β phosphorylation, an increase in β-catenin phosphorylation, and a reduction in nuclear β-catenin content in HT29 human colon cancer cells. At the same time, the activity of tankyrase, which inhibits the β-catenin destruction complex by destabilizing the axin level, was suppressed by SMA. Despite the low potency of SMA against tankyrase activity (IC50 of 50.1 μM and 15.5 μM for tankyrase 1 and 2, respectively) compared to XAV939 (IC50 of 11 nM for tankyrase 1), a selective and potent tankyrase inhibitor, SMA had strong inhibitory effects on β-catenin-dependent TCF/LEF1 transcriptional activity (IC50 of 39.8 nM), which were similar to that of XAV939 (IC50 of 28.1 nM). In addition to suppressing the colony forming ability of colon cancer cells in vitro, SMA significantly inhibited tumor growth in CT26 syngenic and HT29 xenograft mouse tumor models. Furthermore, treating mice with SMA in combination with 5-FU in a colon cancer xenograft model or with cisplatin in an A549 lung cancer xenograft model resulted in greater anti-tumor activity than did treatment with the drugs alone. In the xenograft tumor tissues, SMA dose-dependently inhibited nuclear β-catenin along with reductions in GSK3β phosphorylation and increases in axin levels. These results suggest that SMA is a possible candidate as an effective anti-cancer agent alone or in combination with cytotoxic chemotherapeutic drugs, such as 5-FU and cisplatin, and that the mode of action for SMA involves stabilization of the

  11. Redesigning nature's poisons to create anti-tumor reagents.

    PubMed

    Vitetta, E S; Fulton, R J; May, R D; Till, M; Uhr, J W

    1987-11-20

    Immunotoxins are conjugates of cell-reactive antibodies and toxins or their subunits. In this report, the chemistry, biology, pharmacokinetics, and anti-tumor effects of first generation immunotoxins; the preparation of improved second generation immunotoxins that display greater anti-tumor efficacy; and the role of genetic engineering in creating third-generation immunotoxins are discussed.

  12. Redesigning Nature's Poisons to Create Anti-Tumor Reagents

    NASA Astrophysics Data System (ADS)

    Vitetta, Ellen S.; Jerrold Fulton, R.; May, Richard D.; Till, Mark; Uhr, Jonathan W.

    1987-11-01

    Immunotoxins are conjugates of cell-reactive antibodies and toxins or their subunits. In this report, the chemistry, biology, pharmacokinetics, and anti-tumor effects of first generation immunotoxins; the preparation of improved second generation immunotoxins that display greater anti-tumor efficacy; and the role of genetic engineering in creating third-generation immunotoxins are discussed.

  13. Enhancement of in vitro and in vivo anti-tumor activity of anti-GD2 monoclonal antibody 220-51 against human neuroblastoma by granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor.

    PubMed

    Fukuda, M; Horibe, K; Furukawa, K

    1998-10-01

    We have evaluated the anti-tumor effect of anti-GD2 mouse monoclonal antibody (mAb) 220-51 against human neuroblastoma cell line TGW in vitro and in vivo. The mAb 220-51 was able to mediate complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) using human effector cells. In the presence of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte ADCC was significantly augmented in vitro. When mAb 220-51 was administered to tumor-bearing nude mice, tumor growth was significantly inhibited as compared with untreated controls. Administration of recombinant murine GM-CSF in combination with mAb 220-51 significantly enhanced the anti-tumor effect of mAb in vivo. Recombinant human granulocyte colony-stimulating factor (G-CSF) combined with mAb 220-51 was also able to enhance it, although granulocyte ADCC was not affected by the presence of recombinant human G-CSF in vitro. Moreover, GM-CSF and G-CSF work additively to enhance the anti-tumor effect of mAb 220-51 in vivo. The GM-CSF and G-CSF may have a clinical potency in immunotherapy with anti-GD2 mAb for the treatment of neuroblastoma.

  14. In vitro and in vivo anti-tumor activity of CoQ0 against melanoma cells: inhibition of metastasis and induction of cell-cycle arrest and apoptosis through modulation of Wnt/β-catenin signaling pathways

    PubMed Central

    Hseu, You-Cheng; Thiyagarajan, Varadharajan; Tsou, Hsiao-Tung; Lin, Kai-Yuan; Chen, Hui-Jye; Lin, Chung-Ming; Liao, Jiuun-Wang; Yang, Hsin-Ling

    2016-01-01

    Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has been shown to modulate cellular redox balance. However, effect of this compound on melanoma remains unclear. This study examined the in vitro or in vivo anti-tumor, apoptosis, and anti-metastasis activities of CoQ0 (0-20 μM) through inhibition of Wnt/β-catenin signaling pathway. CoQ0 exhibits a significant cytotoxic effect on melanoma cell lines (B16F10, B16F1, and A2058), while causing little toxicity toward normal (HaCaT) cells. The suppression of β-catenin was seen with CoQ0 administration accompanied by a decrease in the expression of Wnt/β-catenin transcriptional target c-myc, cyclin D1, and survivin through GSK3β-independent pathway. We found that CoQ0 treatment caused G1 cell-cycle arrest by reducing the levels of cyclin E and CDK4. Furthermore, CoQ0 treatment induced apoptosis through caspase-9/-3 activation, PARP degradation, Bcl-2/Bax dysregulation, and p53 expression. Notably, non- or sub-cytotoxic concentrations of CoQ0 markedly inhibited migration and invasion, accompanied by the down-regulation of MMP-2 and -9, and up-regulation of TIMP-1 and -2 expressions in highly metastatic B16F10 cells. Furthermore, the in vivo study results revealed that CoQ0 treatment inhibited the tumor growth in B16F10 xenografted nude mice. Histological analysis and western blotting confirmed that CoQ0 significantly decreased the xenografted tumor progression as demonstrated by induction of apoptosis, suppression of β-catenin, and inhibition of cell cycle-, apoptotic-, and metastatic-regulatory proteins. The data suggest that CoQ0 unveils a novel mechanism by down-regulating Wnt/β-catenin pathways and could be used as a potential lead compound for melanoma chemotherapy. PMID:26968952

  15. ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.

    PubMed

    Cubillos-Ruiz, Juan R; Silberman, Pedro C; Rutkowski, Melanie R; Chopra, Sahil; Perales-Puchalt, Alfredo; Song, Minkyung; Zhang, Sheng; Bettigole, Sarah E; Gupta, Divya; Holcomb, Kevin; Ellenson, Lora H; Caputo, Thomas; Lee, Ann-Hwee; Conejo-Garcia, Jose R; Glimcher, Laurie H

    2015-06-18

    Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum (ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy.

  16. ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis

    PubMed Central

    Cubillos-Ruiz, Juan R.; Silberman, Pedro C.; Rutkowski, Melanie R.; Chopra, Sahil; Perales-Puchalt, Alfredo; Song, Minkyung; Zhang, Sheng; Bettigole, Sarah E.; Gupta, Divya; Holcomb, Kevin; Ellenson, Lora H.; Caputo, Thomas; Lee, Ann-Hwee; Conejo-Garcia, Jose R.; Glimcher, Laurie H.

    2015-01-01

    SUMMARY Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum (ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy. PMID:26073941

  17. Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX.

    PubMed

    Oudart, Jean-Baptiste; Brassart-Pasco, Sylvie; Vautrin, Alexia; Sellier, Christèle; Machado, Carine; Dupont-Deshorgue, Aurelie; Brassart, Bertrand; Baud, S; Dauchez, Manuel; Monboisse, Jean-Claude; Harakat, Dominique; Maquart, François-Xavier; Ramont, Laurent

    2015-02-28

    During tumor invasion, tumor cells degrade the extracellular matrix. Basement membrane degradation is responsible for the production of peptides with anti-tumor properties. Type XIX collagen is associated with basement membranes in vascular, neuronal, mesenchymal and epithelial tissues. Previously, we demonstrated that the non-collagenous NC1, C-terminal, domain of collagen XIX [NC1(XIX)] inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Here, we demonstrate that plasmin, one of the most important enzyme involved in tumor invasion, was able to release a fragment of NC1(XIX), which retained the anti-tumor activity. Molecular modeling studies showed that NC1(XIX) and the anti-tumor fragment released by plasmin (F4) adopted locally the same type I β-turn conformation. This suggests that the anti-tumor effect is conformation-dependent. This study demonstrates that collagen XIX is a novel proteolytic substrate for plasmin. Such release may constitute a defense of the organism against tumor invasion. PMID:25668817

  18. Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX

    PubMed Central

    Oudart, Jean-Baptiste; Brassart-Pasco, Sylvie; Vautrin, Alexia; Sellier, Christèle; Machado, Carine; Dupont-Deshorgue, Aurelie; Brassart, Bertrand; Baud, S.; Dauchez, Manuel; Monboisse, Jean-Claude; Harakat, Dominique; Maquart, François-Xavier; Ramont, Laurent

    2015-01-01

    During tumor invasion, tumor cells degrade the extracellular matrix. Basement membrane degradation is responsible for the production of peptides with anti-tumor properties. Type XIX collagen is associated with basement membranes in vascular, neuronal, mesenchymal and epithelial tissues. Previously, we demonstrated that the non-collagenous NC1, C-terminal, domain of collagen XIX [NC1(XIX)] inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Here, we demonstrate that plasmin, one of the most important enzyme involved in tumor invasion, was able to release a fragment of NC1(XIX), which retained the anti-tumor activity. Molecular modeling studies showed that NC1(XIX) and the anti-tumor fragment released by plasmin (F4) adopted locally the same type I β-turn conformation. This suggests that the anti-tumor effect is conformation-dependent. This study demonstrates that collagen XIX is a novel proteolytic substrate for plasmin. Such release may constitute a defense of the organism against tumor invasion. PMID:25668817

  19. Interleukin-6 Induced "Acute" Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics.

    PubMed

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L; Yan, Wei; Xu, Lisa X

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an "acute" phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated "acute" phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86(+)MHCII(+) dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such "acute" environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest "acute" response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated "acute" microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of "acute" and "danger" signals play a key

  20. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas

    PubMed Central

    Kim, Peter S.; Kwilas, Anna R.; Xu, Wenxin; Alter, Sarah; Jeng, Emily K.; Wong, Hing C.

    2016-01-01

    Interleukin (IL)-15-N72D superagonist-complexed with IL-15RαSushi-Fc fusion protein (IL-15SA/IL-15RαSu-Fc; ALT-803) has been reported to exhibit significant anti-tumor activity in murine myeloma, rat bladder cancer, and murine glioblastoma models. In this study, we examined the immunomodulatory and anti-tumor effects of IL-15SA/IL-15RαSu-Fc in tumor-free and highly metastatic tumor-bearing mice. Here, IL-15SA/IL-15RαSu-Fc significantly expanded natural killer (NK) and CD8+ T cells. In examining NK cell subsets, the greatest significant increase was in highly cytotoxic and migrating (CD11b+, CD27hi; high effector) NK cells, leading to enhanced function on a per-cell basis. CD8+ T cell subset analysis determined that IL-15SA/IL-15RαSu-Fc significantly increased IL-15 responding memory (CD122+, CD44+) CD8+ T cells, in particular those having the innate (NKG2D+, PD1−) phenotype. In 4T1 breast tumor–bearing mice, IL-15SA/IL-15RαSu-Fc induced significant anti-tumor activity against spontaneous pulmonary metastases, depending on CD8+ T and NK cells, and resulting in prolonged survival. Similar anti-tumor activity was seen in the experimental pulmonary metastasis model of CT26 colon carcinoma cells, particularly when IL-15SA/IL-15RαSu-Fc was combined with a cocktail of checkpoint inhibitors, anti-CTLA-4 and anti-PD-L1. Altogether, these studies showed for the first time that IL-15SA/IL-15RαSu-Fc (1) promoted the development of high effector NK cells and CD8+ T cell responders of the innate phenotype, (2) enhanced function of NK cells, and (3) played a vital role in reducing tumor metastasis and ultimately survival, especially in combination with checkpoint inhibitors. PMID:26910920

  1. Antagonists of IAP proteins: novel anti-tumor agents.

    PubMed

    Wan, Yichao; Liu, Tingting; Hou, Xuben; Dun, Yanyan; Guan, Peng; Fang, Hao

    2014-01-01

    Evasion of apoptosis is an important reason for tumor cells to resist the anticancer drugs in cancer therapy. As a critical regulator, the inhibitor of apoptosis proteins (IAPs) can block the apoptosis by inhibiting the activities of caspases. Scientists find that IAPs are over-expressed in many cancer cells, such as leukemia and B-cell lymphoma, which elucidate that high levels of IAPs are closely related to tumorigenesis and cancer development. Thus, targeting IAPs may be an attractive strategy for anti-tumor treatment. As an endogenous antagonist of IAPs, second mitochondria-derived activator of caspases (Smac) can suppress their activities through directly binding to IAPs. Based on structural biology study, Smac interacts with IAPs through the Ala-Val-Pro-Ile (AVPI) tetra-peptide of Smac. Therefore, many agents have been studied to suppress the IAPs which result in the activation of caspases and subsequently induce the apoptosis of tumor cells based on mimicking AVPI peptide strategy. In this review, the functions of IAPs in apoptosis and the recent advance of IAPs antagonists will be discussed.

  2. A Combretastatin-Mediated Decrease in Neutrophil Concentration in Peripheral Blood and the Impact on the Anti-Tumor Activity of This Drug in Two Different Murine Tumor Models

    PubMed Central

    Bohn, Anja Bille; Wittenborn, Thomas; Brems-Eskildsen, Anne Sofie; Laurberg, Tinne; Bertelsen, Lotte Bonde; Nielsen, Thomas; Stødkilde-Jørgensen, Hans; Møller, Bjarne Kuno; Horsman, Michael R.

    2014-01-01

    The vascular disrupting agent combretastatin A-4 disodium phosphate (CA4P) induces fluctuations in peripheral blood neutrophil concentration. Because neutrophils have the potential to induce both vascular damage and angiogenesis we analyzed neutrophil involvement in the anti-tumoral effects of CA4P in C3H mammary carcinomas in CDF1 mice and in SCCVII squamous cell carcinomas in C3H/HeN mice. Flow cytometry analyses of peripheral blood before and up to 144 h after CA4P administration (25 and 250 mg/kg) revealed a decrease 1 h after treatment, followed by an early (3–6 h) and a late (>72 h) increase in the granulocyte concentration. We suggest that the early increase (3–6 h) in granulocyte concentration was caused by the initial decrease at 1 h and found that the late increase was associated with tumor size, and hence independent of CA4P. No alterations in neutrophil infiltration into the C3H tumor after CA4P treatment (25 and 250 mg/kg) were found. Correspondingly, neutrophil depletion in vivo, using an anti-neutrophil antibody, followed by CA4P treatment (25 mg/kg) did not increase the necrotic fraction in C3H tumors significantly. However, by increasing the CA4P dose to 250 mg/kg we found a significant increase of 359% in necrotic fraction when compared to neutrophil-depleted mice; in mice with no neutrophil depletion CA4P induced an 89% change indicating that the presence of neutrophils reduced the effect of CA4P. In contrast, neither CA4P nor 1A8 affected the necrotic fraction in the SCCVII tumors significantly. Hence, we suggest that the initial decrease in granulocyte concentration was caused by non-tumor-specific recruitment of neutrophils and that neutrophils may attenuate CA4P-mediated anti-tumor effect in some tumor models. PMID:25299269

  3. Design, synthesis, and evaluation of novel galloyl pyrrolidine derivatives as potential anti-tumor agents.

    PubMed

    Li, Xun; Li, Yalin; Xu, Wenfang

    2006-03-01

    A series of novel galloyl pyrrolidine derivatives were synthesized as potential anti-tumor agents. Their inhibiting activities on gelatinase (MMP-2 and -9) were tested with succinylated gelatin as the substrate. Structure-activity analyses demonstrate that introduction of longer and more flexible side chains at the C(4) position of the pyrrolidine ring brings higher activity against gelatinase. Free phenol hydroxyl group is more favorable than the methylated one, which confirms the important role of the phenol hydroxyl group when inhibitors interact with gelatinase. In particular, (2S,4S)-4-(3-(3,4-dimethoxyphenyl)acrylamido)-N-hydroxy-1-(3,4,5- trimethoxybenzoyl)pyrrolidine-2-carboxamide (18) stood out as the most attractive compound (IC(50) = 0.9 nM). The anti-metastasis model of mice bearing H(22) tumor cells was used to evaluate their anti-tumor activities in vivo. The assay in vivo revealed that most of these inhibitors displayed favorable inhibitory activities (inhibitory rate >35%) and no significant toxic effects were observed. The inhibition for 62.37% of 19 indicates the strategy used to design MMP inhibitors (MMPIs) of galloyl pyrrolidine derivatives as potential anti-tumor agents is promising.

  4. [Progress of anti-tumor study based on BRAF].

    PubMed

    Yan, Gui-Rui; Xu, Zhi-Jian; Wang, He-Yao; Zhu, Wei-Liang

    2012-12-01

    BRAF is one of the most important pro-oncogenes, which is mutated in approximately 8% of human tumors. The most common BRAF mutation is a valine-to-glutamate transition (V600E) that is expressed primarily in melanoma, colorectal cancer and thyroid carcinoma. MEK/ERK is constitutively activated in the cells expressing BRAFV600E, leading to tumor development, invasion, and metastasis. Therefore, BRAFV600E is a therapeutic target for melanoma and some other BRAFV600E tumors. Vemurafenib, a BRAFV600E inhibitor, which was approved by FDA for the treatment of late-stage melanoma in 2011, produces improved rates of overall and progression-free survival in patients with the BRAFV600E mutation, making a dramatic breakthrough in melanoma treatment. Vemurafenib is also an individual target drug based on genetic diagnosis. However, its therapeutic success is limited by the emergence of drug resistance. Therefore, it is important to explore the mechanisms underlying the resistance for developing new inhibitor drugs and for preventing or delaying the resistance evolution to BRAF inhibitor drugs. In this review, we described the role of BRAFV600E as an anti-tumor drug target and the development of BRAF inhibitors. We also discussed the mechanisms leading to resistance of BRAFV600E inhibitors. Furthermore, therapeutic strategies that might be employed to overcome acquired resistance were proposed.

  5. Anti-Tumor Effects of Second Generation β-Hydroxylase Inhibitors on Cholangiocarcinoma Development and Progression

    PubMed Central

    Chung, Waihong; de la Monte, Suzanne; Thomas, John-Michael; Olsen, Mark; Carlson, Rolf; Yu, Tunan; Dong, Xiaoqun; Wands, Jack

    2016-01-01

    Cholangiocarcinoma (CCA) has a poor prognosis due to widespread intrahepatic spread. Aspartate β-hydroxylase (ASPH) is a transmembrane protein and catalyzes the hydroxylation of aspartyl and asparaginyl residues in calcium binding epidermal growth factor (cbEGF)-like domains of various proteins, including Notch receptors and ligands. ASPH is highly overexpressed (>95%) in human CCA tumors. We explored the molecular mechanisms by which ASPH mediated the CCA malignant phenotype and evaluated the potential of ASPH as a therapeutic target for CCA. The importance of expression and enzymatic activity of ASPH for CCA growth and progression was examined using shRNA “knockdown” and a mutant construct that reduced its catalytic activity. Second generation small molecule inhibitors (SMIs) of β-hydroxylase activity were developed and used to target ASPH in vitro and in vivo. Subcutaneous and intrahepatic xenograft rodent models were employed to determine anti-tumor effects on CCA growth and development. It was found that the enzymatic activity of ASPH was critical for mediating CCA progression, as well as inhibiting apoptosis. Mechanistically, ASPH overexpression promoted Notch activation and modulated CCA progression through a Notch1-dependent cyclin D1 pathway. Targeting ASPH with shRNAs or a SMI significantly suppressed CCA growth in vivo. PMID:26954680

  6. Phenotypically distinct helper NK cells are required for gp96-mediated anti-tumor immunity

    PubMed Central

    Sedlacek, Abigail L.; Kinner-Bibeau, Lauren B.; Binder, Robert J.

    2016-01-01

    A number of Heat Shock Proteins (HSPs), in the extracellular environment, are immunogenic. Following cross-presentation of HSP-chaperoned peptides by CD91+ antigen presenting cells (APCs), T cells are primed with specificity for the derivative antigen-bearing cell. Accordingly, tumor-derived HSPs are in clinical trials for cancer immunotherapy. We investigate the role of NK cells in gp96-mediated anti-tumor immune responses given their propensity to lyse tumor cells. We show that gp96-mediated rejection of tumors requires a unique and necessary helper role in NK cells. This helper role occurs during the effector phase of the anti-tumor immune response and is required for T cell and APC function. Gp96 activates NK cells indirectly via APCs to a phenotype distinct from NK cells activated by other mechanisms such as IL-2. While NK cells have both lytic and cytokine producing properties, we show that gp96 selectively activates cytokine production in NK cells, which is important in the HSP anti-tumor immune response, and leaves their cytotoxic capacity unchanged. PMID:27431727

  7. Synergistic anti-tumor effects of zoledronic acid and radiotherapy against metastatic hepatocellular carcinoma.

    PubMed

    Morii, Kazuhiko; Aoyama, Yuhki; Nakamura, Shinichiro; Okushin, Hiroaki

    2015-01-01

    A 72-year-old man with advanced hepatocellular carcinoma and decompensated hepatitis C virus-related cirrhosis suffered from a metastatic femoral fracture. After undergoing radiotherapy, he was only treated with supportive care, except for the administration of zoledronic acid (ZA). Thereafter, the initially elevated serum α-fetoprotein and des-gamma carboxyprothrombin levels declined to within the normal ranges. Hepatic and metastatic adrenal tumors, distant from the radiation field, exhibited a surprising regression. ZA is known to inhibit the activity of osteoclasts, bone-residential macrophages, and has been reported to have a direct anti-tumor effect. ZA may adjust the immunological milieu in tumor microenvironments by inhibiting the tumor-associated macrophages. Because radiotherapy can enhance the presentation of tumor-associated antigens, ZA and radiotherapy may exert synergistic anti-tumor effects. PMID:26466697

  8. Perspectives on Reprograming Cancer-Associated Dendritic Cells for Anti-Tumor Therapies

    PubMed Central

    Benencia, Fabian; Muccioli, Maria; Alnaeeli, Mawadda

    2014-01-01

    In recent years, the relevance of the tumor microenvironment (TME) in the progression of cancer has gained considerable attention. It has been shown that the TME is capable of inactivating various components of the immune system responsible for tumor clearance, thus favoring cancer cell growth and tumor metastasis. In particular, effects of the TME on antigen-presenting cells, such as dendritic cells (DCs) include rendering these cells unable to promote specific immune responses or transform them into suppressive cells capable of inducing regulatory T cells. In addition, under the influence of the TME, DCs can produce growth factors that induce neovascularization, therefore further contributing to tumor development. Interestingly, cancer-associated DCs harbor tumor antigens and thus have the potential to become anti-tumor vaccines in situ if properly reactivated. This perspective article provides an overview of the scientific background and experimental basis for reprograming cancer-associated DCs in situ to generate anti-tumor immune responses. PMID:24778991

  9. Anti-tumor properties of orally administered glucosamine and N-acetyl-D-glucosamine oligomers in a mouse model.

    PubMed

    Masuda, Sachie; Azuma, Kazuo; Kurozumi, Seiji; Kiyose, Masatoshi; Osaki, Tomohiro; Tsuka, Takeshi; Itoh, Norihiko; Imagawa, Tomohiro; Minami, Saburo; Sato, Kimihiko; Okamoto, Yoshiharu

    2014-10-13

    The current study evaluated the anti-tumor activities of N-acetyl-d-glucosamine oligomer (NACOS) and glucosamine oligomer (COS) after their oral administration in a tumor (colon 26)-bearing mouse model. Compared to the control group, NACOS and COS groups showed significantly suppressed tumor growth, and apparent, marked apoptosis in tumor tissues. Furthermore, serum interleukin-12p70 and interferon-γ levels significantly increased in the NACOS and COS groups compared to the corresponding levels in the control group. Collectively, the results indicate the oral administration of NACOS and COS could enhance innate immunity. Results of experiments in Myd-88 knockout mice revealed that the apparent effects were related to both Myd-88-dependent and Myd-88-independent pathways. The data indicated that oral administration of NACOS and COS produced anti-tumor effects through the induction of apoptosis and stimulation of the immune system, which suggests that NACOS and COS are candidate anti-tumor functional foods.

  10. Combined Yeast-derived β-Glucan with Anti-tumor Monoclonal Antibody for Cancer Immunotherapy

    PubMed Central

    Liu, Jingjing; Gunn, Lacey; Hansen, Richard; Yan, Jun

    2009-01-01

    β-Glucan is an immuno-stimulating agent that has been used to treat cancer and infectious disease for many years with varying and unpredictable efficacy. Recent studies have unraveled the action mode of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies (mAbs) in cancer therapy. It has demonstrated that particulate or large molecular weight soluble β-glucans are ingested and processed by macrophages. These macrophages secrete the active moiety that primes neutrophil complement receptor 3 (CR3) to kill iC3b-opsonized tumor cells. In vitro and in vivo data demonstrate that successful combination therapy requires complement activation and deposition on tumors and CR3 expression on granulocytes. Pre-clinical animal studies have demonstrated the efficacy of combined β-glucan with anti-tumor mAbs therapy in terms of tumor regression and long-term survival. Clinical trials are underway using anti-epidermal growth factor receptor mAb (Erbitux) in combination with β-glucan for metastatic colorectal cancer. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and structure, mechanism of action, and preclinical studies in human carcinoma xenograft models. It is proposed that the addition of β-glucan will further improve the therapeutic efficacy of anti-tumor mAbs in cancer patients. PMID:19454271

  11. Nanovectorized radiotherapy: a new strategy to induce anti-tumor immunity

    PubMed Central

    Vanpouille-Box, Claire; Hindré, François

    2012-01-01

    Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radiotherapy. However, clinically apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nanodevices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immunostimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome. PMID:23087900

  12. Antioxidants Impair Anti-Tumoral Effects of Vorinostat, but Not Anti-Neoplastic Effects of Vorinostat and Caspase-8 Downregulation

    PubMed Central

    Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel

    2014-01-01

    We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat induces formation of reactive oxygen species and DNA damage. To investigate the role of oxidative stress as anti-neoplastic mechanism, we have evaluated the effects of different antioxidants (Bha, Nac and Tiron) on endometrial carcinoma cell line Ishikawa treated with Vorinostat. We show that Bha, Nac and Tiron markedly inhibited the cytotoxic effects of Vorinostat, increasing cell viability in vitro. We found that all three antioxidants did not inhibited accumulation of acetyl Histone H4, so that antioxidants did not inhibit Vorinostat activity. Finally, we have evaluated the effects of antioxidants on anti-tumoral activity of Vorinostat as monotherapy or in combination with caspase-8 downregulation in vivo. Interestingly, antioxidants blocked the reduction of tumour growth caused by Vorinostat, but they were unable to inhibit anti-tumoral activity of Vorinostat plus caspase-8 inhibition. PMID:24651472

  13. Anti-Tumor Effect of Pinus massoniana Bark Proanthocyanidins on Ovarian Cancer through Induction of Cell Apoptosis and Inhibition of Cell Migration

    PubMed Central

    Liu, Jia; Bai, Jing; Jiang, Guoqiang; Li, Xinli; Wang, Jing; Wu, Dachang; Owusu, Lawrence; Zhang, Ershao; Li, Weiling

    2015-01-01

    Pinus massoniana bark proanthocyanidins (PMBPs), an active component isolated from Pinus massoniana bark, has been reported to possess a wide range of biochemical properties. Here, we investigated the anti-tumor effect of PMBPs on ovarian cancer. The results indicated that PMBPs significantly reduced the growth of ovarian cancer cells and induced dose-dependent apoptosis. The underlying mechanisms involved were elucidated to include the loss of mitochondrial membrane potential, down-regulation of the anti-apoptotic protein Bcl-2 and the activation of Caspase 3/9, suggesting that PMBPs triggered apoptosis through activation of mitochondria-associated apoptotic pathway. In addition, wound healing and transwell chamber assays revealed that PMBPs could suppress migration and invasion of ovarian cancer cells. PMBPs dramatically inhibited MMP-9 activity and expression, blocked the activity of NFκB and the activation of ERK1/2 and p38 MAPK. Our findings suggest that PMBPs has the potential to be developed as an anti-tumor drug for ovarian cancer treatment and/ or disease management. PMID:26539720

  14. T Cell Metabolic Fitness in Anti-Tumor Immunity

    PubMed Central

    Siska, Peter J.; Rathmell, Jeffrey C.

    2015-01-01

    SUMMARY T cell metabolism plays a central role to support and shape immune responses and may play a key role in anti-tumor immunity. T cell metabolism is normally held under tight regulation in an immune response of glycolysis to promote effector T cell expansion and function. However, tumors may deplete nutrients, generate toxic products, or stimulate conserved negative feedback mechanisms, such as through PD-1, to impair effector T cell nutrient uptake and metabolic fitness. In addition, regulatory T cells are favored in low glucose conditions and may inhibit anti-tumor immune responses. Here we review how the tumor microenvironment modifies metabolic and functional pathways in T cells and how these changes may uncover new targets and challenges for cancer immunotherapy and treatment. PMID:25773310

  15. Tumor-Derived Inducible Heat Shock Protein 70 (HSP70) is an Essential Component of Anti-Tumor Immunity

    PubMed Central

    Dodd, Keela; Nance, Stephanie; Quezada, Melanie; Janke, Laura; Morrison, Jeffrey B; Williams, Richard T; Beere, Helen M

    2014-01-01

    The anti-apoptotic function and tumor-associated expression of HSP70 is consistent with HSP70 functioning as a survival factor to promote tumorigenesis. However, its immunomodulatory activities to induce anti tumor immunity predict the suppression of tumor growth. Using the Hsp70.1/3−/− (Hsp70−/−) mouse model, we observed that tumor-derived HSP70 was neither required for cellular transformation nor for in vivo tumor growth. Hsp70−/− murine embryonic fibroblasts (MEFs) were transformed by E1A/Ras and generated tumors in immune deficient hosts as efficiently as WT transformants. Comparison of Bcr-Abl-mediated transformation of WT and Hsp70−/− bone marrow and progression of B cell leukemogenesis in vivo revealed no differences in disease onset or survival rates and Eμ-Myc driven lymphoma in Hsp70−/− mice was phenotypically indistinguishable from WT Eμ-Myc mice. However, Hsp70−/− E1A/Ras MEFs generated significantly larger tumors than their WT counterparts in C57BL/6J immune competent hosts. Concurrent with this was a reduction in intra-tumoral infiltration of innate and adaptive immune cells, including macrophages and CD8+ T cells. Evaluation of several potential mechanisms revealed an HSP70-chemokine-like activity to promote cellular migration. These observations support a role for tumor-derived HSP70 in facilitating anti-tumor immunity to limit tumor growth and highlight the potential consequences of anti-HSP70 therapy as an efficacious anti-cancer strategy. PMID:24662819

  16. Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine.

    PubMed

    Hu, Boqi; Wang, Juan; Guo, Yingying; Chen, Tanxiu; Ni, Weihua; Yuan, Hongyan; Zhang, Nannan; Xie, Fei; Tai, Guixiang

    2016-04-01

    Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-γ in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial.

  17. Treatment with targeted Vesicular Stomatitis Virus generates therapeutic multifunctional anti-tumor memory CD4 T-cells

    PubMed Central

    Gao, Yanhua; Whitaker-Dowling, Patricia; Griffin, Judith A.; Bergman, Ira

    2011-01-01

    A generally applicable, easy-to-use method of focusing a patient's immune system to eradicate or prevent cancer has been elusive. We are attempting to develop a targeted virus to accomplish these aims. We previously created a recombinant replicating Vesicular Stomatitis Virus that preferentially infected Her2/neu expressing breast cancer cells and showed therapeutic efficacy in an implanted Balb/c mouse tumor model. The current work shows that this therapy generated therapeutic anti-tumor CD4 T-cells against multiple tumor antigens. CD4 T-cells transferred directly from cured donor mice could eradicate established tumors in host mice. T-cells were transferred directly from donor mice and were not stimulated ex vivo. Both tumors that expressed Her2/neu and those that did not were cured by transferred T-cells. Analysis of cytokines secreted by anti-tumor memory CD4 T-cells displayed a multifunctional pattern with high levels of IFNγ, IL-4 and IL-17. Anti-tumor memory CD4 T-cells traveled to the mesenteric lymph nodes and were activated there. Treatment with targeted rrVSV is a potent immune adjuvant that generates therapeutic, multifunctional anti-tumor memory CD4 T-cells that recognize multiple tumor antigens. Immunity elicited by viral therapy is independent of host major histocompatibility complex (MHC) or knowledge of tumor antigens. Virus-induced tumor immunity could have great benefit in the prevention and treatment of tumor metastases. PMID:22240921

  18. Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET.

    PubMed

    Fang, Bing; Zhang, Ming; Tian, Mai; Jiang, Lu; Guo, Hui Yuan; Ren, Fa Zheng

    2014-04-01

    α-Lactalbumin (α-LA) can bind oleic acid (OA) to form HAMLET-like complexes, which exhibited highly selective anti-tumor activity in vitro and in vivo. Considering the structural similarity to α-LA, we conjectured that lactoferrin (LF) could also bind OA to obtain a complex with anti-tumor activity. In this study, LF-OA was prepared and its activity and structural changes were compared with α-LA-OA. The anti-tumor activity was evaluated by methylene blue assay, while the apoptosis mechanism was analyzed using flow cytometry and Western blot. Structural changes of LF-OA were measured by fluorescence spectroscopy and circular dichroism. The interactions of OA with LF and α-LA were evaluated by isothermal titration calorimetry (ITC). LF-OA was obtained by heat-treatment at pH8.0 with LD50 of 4.88, 4.95 and 4.62μM for HepG2, HT29, and MCF-7 cells, respectively, all of which were 10 times higher than those of α-LA-OA. Similar to HAMLET, LF-OA induced apoptosis in tumor cells through both death receptor- and mitochondrial-mediated pathways. Exposure of tryptophan residues and the hydrophobic regions as well as the loss of tertiary structure were observed in LF-OA. Besides these similarities, LF showed different secondary structure changes when compared with α-LA, with a decrease of α-helix and β-turn and an increase of β-sheet and random coil. ITC results showed that there was a higher binding number of OA to LF than to α-LA, while both of the proteins interacted with OA through van der Waals forces and hydrogen bonds. This study provides a theoretical basis for further exploration of protein-OA complexes.

  19. Involvement of nitric oxide in anti-tumor effects of OK-432, a streptococcal anti-tumor immunotherapeutic agent.

    PubMed

    Oshikawa, Tetsuya; Okamoto, Masato; Tano, Tomoyuki; Uddin Ahmed, Sharif; Sasai, Akiko; Kan, Shin; Moriya, Yoichiro; Ryoma, Yoshiki; Saito, Motoo; Sato, Mitsunobu

    2006-05-01

    We examined the role of nitric oxide (NO) induced by OK-432, a streptococcal immunotherapeutic agent, in anti-tumor effects of the OK-432 by in vitro and in vivo experiments using an NO synthase inhibitor, N-monomethyl-l-arginine acetate (NMA). The in vitro treatment of mouse splenocytes with OK-432 increased the expression of inducible NO synthase (iNOS) gene and NO production in a dose-dependent manner. Although it is well known that OK-432 induces cytokines such as interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, both of which are known to be potent NO inducers, we observed only a partial reduction of OK-432-induced NO production with the addition of anti-IFN-gamma and/or anti-TNF-alpha neutralizing antibodies. The cytotoxicity of the splenocytes increased by in vitro OK-432 stimulation was almost completely inhibited by the treatment with NMA. OK-432 administration resulted in a marked prolongation of survival and a significant inhibition of tumor growth in syngeneic tumor-bearing mice, whereas NMA significantly inhibited the anti-tumor effects of OK-432. Although the increased cytotoxicity of adherent splenocytes derived from OK-432-treated tumor-bearing mice was almost completely inhibited by NMA, only partial inhibition by NMA was observed in the cytotoxicity of the nonadherent splenocytes. These findings strongly suggest that the iNOS/NO induced by OK-432 is intimately involved in the anti-tumor effects of OK-432.

  20. Interleukin-6 Induced “Acute” Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics

    PubMed Central

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L.; Yan, Wei; Xu, Lisa X.

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an “acute” phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated “acute” phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86+MHCII+ dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such “acute” environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest “acute” response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated “acute” microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of “acute” and

  1. Anti-tumor immune response after photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Castano, Ana P.; Wu, Mei X.; Kung, Andrew L.; Hamblin, Michael R.

    2009-06-01

    Anti-tumor immunity is stimulated after PDT due a number of factors including: the acute inflammatory response caused by PDT, release of antigens from PDT-damaged tumor cells, priming of the adaptive immune system to recognize tumor-associated antigens (TAA), and induction of heat-shock proteins. The induction of specific CD8+ T-lymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy as it would allow the treatment of tumors that may have already metastasized. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. We have carried out in vivo PDT with a BPD-mediated vascular regimen using a pair of BALB/c mouse colon carcinomas: CT26 wild type expressing the naturally occurring retroviral antigen gp70 and CT26.CL25 additionally expressing beta-galactosidase (b-gal) as a model tumor rejection antigen. PDT of CT26.CL25 cured 100% of tumors but none of the CT26WT tumors (all recurred). Cured CT26.CL25 mice were resistant to rechallenge. Moreover mice with two bilateral CT26.CL25 tumors that had only one treated with PDT demonstrated spontaneous regression of 70% of untreated contralateral tumors. T-lymphocytes were isolated from lymph nodes of PDT cured mice that recognized a particular peptide specific to b-gal antigen. T-lymphocytes from LN were able to kill CT26.CL25 target cells in vitro but not CT26WT cells as shown by a chromium release assay. CT26.CL25 tumors treated with PDT and removed five days later had higher levels of Th1 cytokines than CT26 WT tumors showing a higher level of immune response. When mice bearing CT26WT tumors were treated with a regimen of low dose cyclophosphamide (CY) 2 days before, PDT led to 100% of cures (versus 0% without CY) and resistance to rechallenge. Low dose CY is thought to deplete regulatory T-cells (Treg, CD4+CD25+foxp

  2. Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells.

    PubMed

    Han, Xiaoyun; Sheng, Xiugui; Jones, Hannah M; Jackson, Amanda L; Kilgore, Joshua; Stine, Jessica E; Schointuch, Monica N; Zhou, Chunxiao; Bae-Jump, Victoria L

    2015-01-29

    High rates of aerobic glycolysis represent a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. The present study was aimed at evaluating the potential of a novel lactate dehydrogenase (LDH) inhibitor, Galloflavin, as a therapeutic agent for endometrial cancer. Our results revealed that Galloflavin effectively inhibited cell growth in endometrial cancer cell lines and primary cultures of human endometrial cancer through its involvement in multiple signaling pathways that regulate metabolism, cell cycle, apoptosis, cell stress and metastasis.

  3. Computational and anti-tumor studies of 7a-Aza-B-homostigmast-5-eno [7a, 7-d] tetrazole-3β-yl chloride

    NASA Astrophysics Data System (ADS)

    Alam, Mahboob; Alam, Mohammad Jane; Nami, Shahab A. A.; Lee, Dong-Ung; Azam, Mohammad; Ahmad, Shabbir

    2016-03-01

    The present paper reports the detailed computational study including molecular docking of a biologically active steroidal tetrazole, 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole-3β-yl chloride. The molecular structure, IR and NMR (13C and 1H) spectra of the tetrazole were interpreted by comparing the experimental results with the theoretical, B3LYP/6-311G(d,p) calculations. The vibrational bands appearing in the FTIR are assigned with great accuracy using animated modes. Molecular properties like HOMO-LUMO analysis, chemical reactivity descriptors, MEP mapping, dipole moment and natural atomic charges have been presented at the same level of theory. The theoretical results are found in good correlation with the experimental data. Moreover, the Hirshfeld analysis was carried out to ascertain the secondary interactions and associated 2D fingerprint plots. The in vitro anti-tumor activity of 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole-3β-yl chloride has also been carried out against five human tumor cell lines. Doxorubicin is used as a standard drug for the in vitro anti-tumor screening.

  4. In vivo pharmacokinetics, biodistribution and the anti-tumor effect of cyclic RGD-modified doxorubicin-loaded polymers in tumor-bearing mice.

    PubMed

    Wang, Chen; Li, Yuan; Chen, Binbin; Zou, Meijuan

    2016-10-01

    In our previous study, we successfully produced and characterized a multifunctional drug delivery system with doxorubicin (RC/GO/DOX), which was based on graphene oxide (GO) and cyclic RGD-modified chitosan (RC). Its characteristics include: pH-responsiveness, active targeting of hepatocarcinoma cells, and efficient loading with controlled drug release. Here, we report the pharmacokinetics, biodistribution, and anti-tumor efficacy of RC/GO/DOX polymers in tumor-bearing nude mice. The objective of this study is to assess its targeting potential for tumors. Pharmacokinetic and biodistribution profiles demonstrated that tumor accumulation of RC/GO/DOX polymers was almost three times higher than the others, highlighting the efficacy of the active targeting strategy. Furthermore, the tumor inhibition rate of RC/GO/DOX polymers was 56.64%, 2.09 and 2.93 times higher than that of CS/GO/DOX polymers (without modification) and the DOX solution, respectively. Anti-tumor efficacy results indicated that the tumor growth was better controlled by RC/GO/DOX polymers than the others. Hematoxylin and eosin (H&E) staining showed remarkable changes in tumor histology. Compared with the saline group, the tumor section from the RC/GO/DOX group revealed a marked increase in the quantity of apoptotic and necrotic cells, and a reduction in the quantity of the blood vessels. Together, these studies show that this new system could be regarded as a suitable form of DOX-based treatment of the hepatocellular carcinoma.

  5. Computational and anti-tumor studies of 7a-Aza-B-homostigmast-5-eno [7a, 7-d] tetrazole-3β-yl chloride

    NASA Astrophysics Data System (ADS)

    Alam, Mahboob; Alam, Mohammad Jane; Nami, Shahab A. A.; Lee, Dong-Ung; Azam, Mohammad; Ahmad, Shabbir

    2016-03-01

    The present paper reports the detailed computational study including molecular docking of a biologically active steroidal tetrazole, 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole-3β-yl chloride. The molecular structure, IR and NMR (13C and 1H) spectra of the tetrazole were interpreted by comparing the experimental results with the theoretical, B3LYP/6-311G(d,p) calculations. The vibrational bands appearing in the FTIR are assigned with great accuracy using animated modes. Molecular properties like HOMO-LUMO analysis, chemical reactivity descriptors, MEP mapping, dipole moment and natural atomic charges have been presented at the same level of theory. The theoretical results are found in good correlation with the experimental data. Moreover, the Hirshfeld analysis was carried out to ascertain the secondary interactions and associated 2D fingerprint plots. The in vitro anti-tumor activity of 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole-3β-yl chloride has also been carried out against five human tumor cell lines. Doxorubicin is used as a standard drug for the in vitro anti-tumor screening.

  6. Selected anti-tumor vaccines merit a place in multimodal tumor therapies

    PubMed Central

    Weiss, Eva-Maria; Wunderlich, Roland; Ebel, Nina; Rubner, Yvonne; Schlücker, Eberhard; Meyer-Pittroff, Roland; Ott, Oliver J.; Fietkau, Rainer; Gaipl, Udo S.; Frey, Benjamin

    2012-01-01

    Multimodal approaches are nowadays successfully applied in cancer therapy. Primary locally acting therapies such as radiotherapy (RT) and surgery are combined with systemic administration of chemotherapeutics. Nevertheless, the therapy of cancer is still a big challenge in medicine. The treatments often fail to induce long-lasting anti-tumor responses. Tumor recurrences and metastases result. Immunotherapies are therefore ideal adjuncts to standard tumor therapies since they aim to activate the patient's immune system against malignant cells even outside the primary treatment areas (abscopal effects). Especially cancer vaccines may have the potential both to train the immune system against cancer cells and to generate an immunological memory, resulting in long-lasting anti-tumor effects. However, despite promising results in phase I and II studies, most of the concepts finally failed. There are some critical aspects in development and application of cancer vaccines that may decide on their efficiency. The time point and frequency of medication, usage of an adequate immune adjuvant, the vaccine's immunogenic potential, and the tumor burden of the patient are crucial. Whole tumor cell vaccines have advantages compared to peptide-based ones since a variety of tumor antigens (TAs) are present. The master requirements of cell-based, therapeutic tumor vaccines are the complete inactivation of the tumor cells and the increase of their immunogenicity. Since the latter is highly connected with the cell death modality, the inactivation procedure of the tumor cell material may significantly influence the vaccine's efficiency. We therefore also introduce high hydrostatic pressure (HHP) as an innovative inactivation technology for tumor cell-based vaccines and outline that HHP efficiently inactivates tumor cells by enhancing their immunogenicity. Finally studies are presented proving that anti-tumor immune responses can be triggered by combining RT with selected immune

  7. Augmented anti-tumor effect of dendritic cells genetically engineered by interleukin-12 plasmid DNA.

    PubMed

    Yoshida, Masataka; Jo, Jun-Ichiro; Tabata, Yasuhiko

    2010-01-01

    The objective of this study was to genetically engineer dendritic cells (DC) for biological activation and evaluate their anti-tumor activity in a tumor-bearing mouse model. Mouse DC were incubated on the surface of culture dishes which had been coated with the complexes of a cationized dextran and luciferase plasmid DNA complexes plus a cell adhesion protein, Pronectin, for gene transfection (reverse transfection). When compared with the conventional transfection where DC were transfected in the medium containing the complexes, the level of gene expression by the reverse method was significantly higher and the time period of gene expression was prolonged. Following the reverse transfection of DC by a plasmid DNA of mouse interleukin-12 (mIL-12) complexed with the cationized dextran, the mIL-12 protein was secreted at higher amounts for a longer time period. When injected intratumorally into mice carrying a mass of B16 tumor cells, the DC genetically activated showed significant anti-tumor activity. PMID:20338099

  8. Zinc as an anti-tumor agent in prostate cancer and in other cancers.

    PubMed

    Franklin, Renty B; Costello, Leslie C

    2007-07-15

    Human prostate glandular epithelial cells have the unique capability of accumulating high levels of zinc. This is essential to inhibit m-aconitase activity so that citrate can accumulate for secretion into prostatic fluid, which is a major function of the prostate gland. As a result, the Krebs cycle is truncated with the consequence of the lost ATP production that would result from citrate oxidation. The cellular accumulation of zinc also inhibits mitochondrial terminal oxidation and respiration. In addition to these metabolic effects, zinc accumulation exhibits anti-proliferative effects via its induction of mitochondrial apoptogenesis. Zinc accumulation also inhibits the invasive/migration activities in malignant prostate cells. The anti-proliferative effects and the effects on invasion and migration occur through zinc activation of specific intracellular signaling pathways. Consequently, these effects impose anti-tumor actions by zinc. The ability of prostate cells to accumulate zinc is due to the expression and activity of the zinc uptake transporter, ZIP1. To avoid the anti-tumor effects of zinc, in prostate cancer the malignant prostate cells exhibit a silencing of ZIP1 gene expression accompanied by a depletion of cellular zinc. Therefore we regard ZIP1 as a tumor suppressor gene in prostate cancer. In addition to prostate cells, similar tumor suppressor effects of zinc have been identified in several other types of tumors. PMID:17400177

  9. High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin

    PubMed Central

    Bortolotti, Massimo; Bolognesi, Andrea; Battelli, Maria Giulia; Polito, Letizia

    2016-01-01

    The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20+ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric) and LMW-IT (monomeric) maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates. PMID:27338475

  10. High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin.

    PubMed

    Bortolotti, Massimo; Bolognesi, Andrea; Battelli, Maria Giulia; Polito, Letizia

    2016-01-01

    The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20⁺ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric) and LMW-IT (monomeric) maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates. PMID:27338475

  11. Enhanced Anti-tumor Reactivity of Cytotoxic T Lymphocytes Expressing PD-1 Decoy.

    PubMed

    Shin, Jae Hun; Park, Hyung Bae; Choi, Kyungho

    2016-04-01

    Programmed death-1 (PD-1) is a strong negative regulator of T lymphocytes in tumor-microenvironment. By engaging PD-1 ligand (PD-L1) on tumor cells, PD-1 on T cell surface inhibits anti-tumor reactivity of tumor-infiltrating T cells. Systemic blockade of PD-1 function using blocking antibodies has shown significant therapeutic efficacy in clinical trials. However, approximately 10 to 15% of treated patients exhibited serious autoimmune responses due to the activation of self-reactive lymphocytes. To achieve selective activation of tumor-specific T cells, we generated T cells expressing a dominant-negative deletion mutant of PD-1 (PD-1 decoy) via retroviral transduction. PD-1 decoy increased IFN-γ secretion of antigen-specific T cells in response to tumor cells expressing the cognate antigen. Adoptive transfer of PD-1 decoy-expressing T cells into tumor-bearing mice potentiated T cell-mediated tumor regression. Thus, T cell-specific blockade of PD-1 could be a useful strategy for enhancing both efficacy and safety of anti-tumor T cell therapy. PMID:27162530

  12. The novel CA IX inhibition antibody chKM4927 shows anti-tumor efficacy in vivo.

    PubMed

    Yamaguchi, Ayami; Usami, Katsuaki; Shimabe, Munetake; Hasegawa, Kazumasa; Asada, Masao; Motoki, Kazuhiro; Tahara, Tomoyuki; Masuda, Kazuhiro

    2015-04-01

    Carbonic anhydrase IX (CA IX) is an attractive target for cancer therapy. Many anti-CA IX antibodies have been reported but few have been shown to possess inhibition activity. Furthermore, effective use of CA IX-inhibition antibodies for cancer immunotherapy has not been well-validated since data are mainly limited to in vitro assays. In this study, we established that chKM4927, an anti-CA IX chimeric antibody, recognizes CA IX and has CA IX-specific inhibition activity. ChKM4927 also retains antibody-dependent cellular cytotoxicity (ADCC) activity against CA IX-expressing cancer cells. Compared to controls, chKM4927 treatment (10 mg/kg) showed anti-tumor activity in the VMRC-RCW xenograft model in vivo. ChKM4927-attenuated ADCC activity showed equally effective anti-tumor activity. These results suggest that the CA IX-inhibition antibody chKM4927 has an anti-tumor effect in the VMRC-RCW xenograft model via an ADCC-independent mechanism. PMID:25862852

  13. Increased anti-tumor effects using IL2 with anti-TGFβ reveals competition between mouse NK and CD8 T cells

    PubMed Central

    Alvarez, Maite; Bouchlaka, Myriam N.; Sckisel, Gail D.; Sungur, Can M.; Chen, Mingyi; Murphy, William J.

    2014-01-01

    Due to increasing interest in the removal of immunosuppressive pathways in cancer, the combination of IL2 with antibodies to neutralize TGFβ, a potent immunosuppressive cytokine, was assessed. Combination immunotherapy resulted in significantly greater anti-tumor effects. These were correlated with significant increases in the numbers and functionality of NK cells, NK progenitors and activated CD8 T cells resulting in the observed anti-tumor effects. Combination immunotherapy was also accompanied with lesser toxicities than IL2 therapy alone. Additionally, we observed a dual competition between NK and activated CD8 T cells such that after immunotherapy, the depletion of either effector population resulted in the increased total expansion of the other population and compensatory anti-tumor effects. This study demonstrates the efficacy of this combination immunotherapeutic regimen as a promising cancer therapy and illustrates the existence of potent competitive regulatory pathways between NK and CD8 T cells in response to systemic activation. PMID:25000978

  14. Anti-tumor effect of β-glucan from Lentinus edodes and the underlying mechanism

    PubMed Central

    Xu, Hui; Zou, Siwei; Xu, Xiaojuan; Zhang, Lina

    2016-01-01

    β-Glucans are well known for its various bioactivities, but the underlying mechanism has not been fully understood. This study focuses on the anti-tumor effect and the potential mechanism of a branched β-(1, 3)-glucan (LNT) extracted from Lentinus edodes. The in vivo data indicated that LNT showed a profound inhibition ratio of ~75% against S-180 tumor growth, even significantly higher than the positive control of Cytoxan (~54%). Interestingly, LNT sharply promoted immune cells accumulation into tumors accompanied by cell apoptosis and inhibition of cell proliferation during tumor development. Furthermore, LNT not only up-regulated expressions of the tumor suppressor p53, cell cycle arrestin p21 and pro-apoptotic proteins of Bax and caspase 3/9, but also down-regulated PARP1 and anti-apoptotic protein Bcl-2 expressions in tumor tissues. It was first found that LNT initiated p53-dependent signaling pathway to suppress cell proliferation in vitro, and the caspase-dependent pathway to induce cell apoptosis in vivo. The underlying anti-tumor mechanism was proposed that LNT activated immune responses to induce cell apoptosis through caspase 3-dependent signaling pathway and to inhibit cell proliferation possibly via p53-dependent signaling pathway in vivo. Besides, LNT inhibited angiogenesis by suppressing VEGF expression, leading to slow progression of tumors. PMID:27353254

  15. BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.

    PubMed

    Zhu, Hengrui; Bengsch, Fee; Svoronos, Nikolaos; Rutkowski, Melanie R; Bitler, Benjamin G; Allegrezza, Michael J; Yokoyama, Yuhki; Kossenkov, Andrew V; Bradner, James E; Conejo-Garcia, Jose R; Zhang, Rugang

    2016-09-13

    Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression. PMID:27626654

  16. Synthesis of some novel D-glucuronic acid acetylated derivatives as potential anti-tumor agents.

    PubMed

    El-Nezhawy, Ahmed O H; Adly, Frady G; Eweas, Ahmed F; Hanna, Atef G; El-Kholy, Yehya M; El-Sayed, Shahenaz H; El-Naggar, Tarek B A

    2011-10-01

    A structurally diverse series of Δ(4,5) -uronamide derivatives have been chemically synthesized starting from D-glucuronic acid itself by means of acetylation, activation, amide bond formation and base-catalyzed elimination protocols. Structure elucidation for all products along with optimization of the synthetic steps is described. The synthesized compounds were evaluated for their in-vitro anti-tumor activity against MCF-7, TK-10 and UACC-62 cell lines. The compounds 5, 11, 13, 15 and 16 were the most active against TK-10 cell line. On the other hand, the most active compounds against the MCF-7 cell line were 11 and 15. However, compounds 5, 7, 11, 13, 15 and 16 were the most active against the UACC-62 cell line.

  17. 1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, anti-tumor and anti-oxidant activities.

    PubMed

    Shaikh, Qurat-Ul-Ain; Yang, Meiting; Memon, Khadim Hussain; Lateef, Mehreen; Na, Du; Wan, Shengbiao; Eric, Deslandes; Zhang, Lijuan; Jiang, Tao

    2016-07-22

    1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) 12 has been reported for its antioxidant activities, where the free OH groups in PGG seem to be critical for activities. To explore PGG-based compounds as chemotherapeutic agents and to analyze the contribution of specific OH groups in PGG for anti-cancer activities, we designed and synthesized a series of 27 benzoic and cinnamic acid analogs of PGG. These analogs were tested for cytotoxicities against two human lung (A549 and H1299) and two human colon (HCT116 and HT29) cancer cell lines. Compound 12 (PGG) had highest cytotoxicities against HCT116 and A549 cells with IC50 of 1.61 µM and 3.02 µM, respectively. In contrast, the compound 16 (1,2,3,4,6-pentakis[-O-(4-hydroxy-3-methoxybenzoyl)]-α,β-D-glucopyranose, PVG) was most effective at killing HT29 and H1299 cells with IC50 of 1.76 µM and 3.65 µM, respectively, indicating the mutual contribution of m-methoxy and p-hydroxy groups to the observed cytotoxicities. Moreover, cinnamic acid analogs were less active than the benzoic acid analogs evidenced by higher IC50 values. Furthermore, in cinnamic acid analogs the hydrogenation of double bond to saturated 2-C side chain enhance the cytotoxicities in all four cell lines. Compounds also possess good anti-oxidant and reducing activities. Compound 12 and 26 show the highest antioxidant and reducing activities. PMID:27196315

  18. Imatinib potentiates anti-tumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido

    PubMed Central

    Balachandran, Vinod P.; Cavnar, Michael J.; Zeng, Shan; Bamboat, Zubin M.; Ocuin, Lee M.; Obaid, Hebroon; Sorenson, Eric C.; Popow, Rachel; Ariyan, Charlotte; Rossi, Ferdinand; Besmer, Peter; Guo, Tianhua; Antonescu, Cristina R.; Taguchi, Takahiro; Yuan, Jianda; Wolchok, Jedd D.; Allison, James P.; DeMatteo, Ronald P.

    2012-01-01

    Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and achieves a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the anti-tumor effects of imatinib. Imatinib therapy activated CD8+ T cells and induced regulatory T cell (T reg) apoptosis within the tumor by reducing tumor cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are critical to the anti-tumor effects of imatinib in GIST and concomitant immunotherapy may further improve outcome in human cancers treated with targeted agents. PMID:21873989

  19. Immunomodulatory and anti-tumor effects of Nigella glandulifera freyn and sint seeds on ehrlich ascites carcinoma in mouse model

    PubMed Central

    Aikemu, Ainiwaer; Xiaerfuding, Xiadiya; Shiwenhui, Chengyufeng; Abudureyimu, Meiliwan; Maimaitiyiming, Dilinuer

    2013-01-01

    Aim: This study investigated the immunomodulatory and anti-tumor effects of Nigella glandulifera Freyn and Sint seeds (NGS) on Ehrlich ascites carcinoma in a mouse model. Materials and Methods: Kunming mice with transplanted Ehrlich ascites tumor cells (EAC) were treated with NGS by oral administration. On the 11th day after the EAC implant, mouse thymus, liver, spleen and kidney tumors were removed for histopathological analysis. Blood samples were taken for hematological and biochemical analyses. Results: The results indicate that NGS treatment leads to an increase in TNF-α, IL-1β, and IL-2 blood serum levels. Absence of viable EAC and presence of necrotic cells were observed in the tumor tissue of the NGS-treated animals. Conclusions: The study results indicated that a water extract of NGS had the highest anti-tumor effect. Moreover, NGS treatment also showed an increase in the immune system activity. PMID:23929999

  20. Cancer vaccines: harnessing the potential of anti-tumor immunity.

    PubMed

    Suckow, Mark A

    2013-10-01

    Although the presence of cancer suggests failure of the immune system to protect against development of tumors, the possibility that immunity can be redirected and focused to generate an anti-tumor response offers great translational possibility. The key to this is identifying antigens likely to be present in any given tumor and functionally critical to tumor survival and growth. Such tumor-associated antigens (TAAs) are varied and optimally should be absent from normal tissue. Of particular interest are TAAs associated with the tumor stroma, as immunity directed against the stroma may restrict the ability of the tumor to grow and metastasize. Important to directing the immune system toward an effect anti-tumor response is the understanding of how TAAs are processed and how the tumor is able to evade immune elimination. The process of immunoediting happens in response to the selective pressure that the immune system places upon tumor cell populations and allows for emergence of tumor cells capable of escaping immune destruction. Efforts to harness the immune system for clinical application has been aided by vaccines based on purified recombinant protein or nucleic acid TAAs. For example, a vaccine for canine melanoma has been developed and approved based on immunization with DNA components of tyrosinase, a glycoprotein essential to melanin synthesis. The performance of cancer vaccines has been aided in some cases when supplemented with immunostimulatory molecules such as interleukin 2 or a novel extracellular matrix vaccine adjuvant. Vaccines with the broadest menu of antigenic targets may be those most likely to succeed against cancer. For this reason, tissue vaccines produced from harvested tumor material may offer significant benefit. With several cancer vaccines on the veterinary and human markets, efforts to understand basic tumor immunology are soon to yield great dividends. PMID:23850019

  1. Transient Low Doses of DNA Demethylating Agents Exert Durable Anti-tumor Effects on Hematological and Epithelial Tumor Cells

    PubMed Central

    Tsai, Hsing-Chen; Li, Huili; Van Neste, Leander; Cai, Yi; Robert, Carine; Rassool, Feyruz V.; Shin, James J.; Harbom, Kirsten M.; Beaty, Robert; Pappou, Emmanouil; Harris, James; Yen, Ray-Whay Chiu; Ahuja, Nita; Brock, Malcolm V.; Stearns, Vered; Feller-Kopman, David; Yarmus, Lonny B.; Lin, Yi-Chun; Welm, Alana L.; Issa, Jean-Pierre; Minn, Il; Matsui, William; Jang, Yoon-Young; Sharkis, Saul J.; Baylin, Stephen B.; Zahnow, Cynthia A.

    2012-01-01

    SUMMARY Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity, produce an anti-tumor “memory” response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genome-wide promoter DNA methylation, gene re-expression, and anti-tumor changes in key cellular regulatory pathways. Low dose decitabine and azacitidine may have broad applicability for cancer management. PMID:22439938

  2. A threshold hazard model for estimating serious infection risk following anti-tumor necrosis factor therapy in rheumatoid arthritis patients.

    PubMed

    Fu, Bo; Lunt, Mark; Galloway, James; Dixon, Will; Hyrich, Kimme; Symmons, Deborah

    2013-03-11

    Over recent years novel biologic agents have been developed for the treatment of rheumatoid arthritis. The most common type of biologic agent in use in the United Kingdom is the anti-tumor necrosis factor inhibitor class. To fully appreciate the potential risks of anti-tumor necrosis factor therapy in patients, knowledge about the baseline hazard (risk pattern) and the characteristics of patients associated with serious infection is important. We propose a nonproportional hazard model for estimating the infection risk, by including the drug exposure history information into the baseline hazard. We found that the infection risk reaches a peak within 1 month after drug exposure starts and then declines steadily for nearly 2 years before stabilizing out.

  3. Isolation and Assessment of the in Vitro Anti-Tumor Activity of Smenothiazole A and B, Chlorinated Thiazole-Containing Peptide/Polyketides from the Caribbean Sponge, Smenospongia aurea

    PubMed Central

    Esposito, Germana; Teta, Roberta; Miceli, Roberta; Ceccarelli, Luca S.; Della Sala, Gerardo; Camerlingo, Rosa; Irollo, Elena; Mangoni, Alfonso; Pirozzi, Giuseppe; Costantino, Valeria

    2015-01-01

    The study of the secondary metabolites contained in the organic extract of Caribbean sponge Smenospongia aurea led to the isolation of smenothiazole A (3) and B (4), hybrid peptide/polyketide compounds. Assays performed using four solid tumor cell lines showed that smenothiazoles exert a potent cytotoxic activity at nanomolar levels, with selectivity over ovarian cancer cells and a pro-apoptotic mechanism. PMID:25603342

  4. Optimizing the extraction of anti-tumor polysaccharides from the fruit of Capparis spionosa L. by response surface methodology.

    PubMed

    Ji, Yu-Bin; Dong, Fang; Ma, Dong-Bin; Miao, Jing; Jin, Li-Na; Liu, Zhen-Feng; Zhang, Ling-Wen

    2012-01-01

    Capparis spionosa L. is a traditional medicinal plant in China and central Asia. In this study, an experiment was designed to investigate the optimization of the extraction of anti-tumor polysaccharides from the fruit of Capparis spionosa L. (CSPS) by response surface methodology (RSM). Four independent variables (extraction temperature, extraction time, ratio of water to sample and extraction cycles) were explored. Meanwhile, the in vivo anti-tumor activity of CSPS was investigated. The results showed that the experimental data could be fitted to a second-order polynomial equation using multiple regression analysis. The optimum extraction conditions were as follows: extraction temperature 92 °C, extraction time 140 min, ratio of water to sample 26 mL/g, and three extraction cycle. Under these conditions, the yield of polysaccharides reached 13.01%, which was comparable to the predicted yield (12.94%, p > 0.05). This indicated that the model was adequate for the extraction process. Additionally, CSPS could prolong the survival time of H22 bearing mice in vivo. The anti-tumor activities of CSPS were dose-dependent.

  5. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma

    PubMed Central

    Montraveta, Arnau; Xargay-Torrent, Sílvia; López-Guerra, Mónica; Rosich, Laia; Pérez-Galán, Patricia; Salaverria, Itziar; Beà, Silvia; Kalko, Susana G.; de Frias, Mercè; Campàs, Clara; Roué, Gaël; Colomer, Dolors

    2014-01-01

    Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses. The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients. PMID:24519895

  6. Enhanced dendritic cell maturation by TNF-alpha or cytidine-phosphate-guanosine DNA drives T cell activation in vitro and therapeutic anti-tumor immune responses in vivo.

    PubMed

    Brunner, C; Seiderer, J; Schlamp, A; Bidlingmaier, M; Eigler, A; Haimerl, W; Lehr, H A; Krieg, A M; Hartmann, G; Endres, S

    2000-12-01

    Dendritic cells (DC) manipulated ex vivo can induce tumor immunity in experimental murine tumor models. To improve DC-based tumor vaccination, we studied whether DC maturation affects the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4 alone or by further addition of TNF-alpha or a cytidine-phosphate-guanosine (CpG)-containing oligonucleotide (ODN-1826), which mimics the immunostimulatory effect of bacterial DNA. Flow cytometric analysis of costimulatory molecules and MHC class II showed that DC maturation was stimulated most by ODN-1826, whereas TNF-alpha had an intermediate effect. The extent of maturation correlated with the secretion of IL-12 and the induction of alloreactive T cell proliferation. In BALB/c mice, s.c. injection of colon carcinoma cells resulted in rapidly growing tumors. In this model, CpG-ODN-stimulated DC cocultured with irradiated tumor cells also induced prophylactic protection most effectively and were therapeutically effective when administered 3 days after tumor challenge. Thus, CpG-ODN-enhanced DC maturation may represent an efficient means to improve clinical tumor vaccination.

  7. Potentiating the cellular targeting and anti-tumor activity of Dp44mT via binding to human serum albumin: two saturable mechanisms of Dp44mT uptake by cells

    PubMed Central

    Merlot, Angelica M.; Sahni, Sumit; Lane, Darius J.R.; Fordham, Ashleigh M.; Pantarat, Namfon; Hibbs, David E.; Richardson, Vera; Doddareddy, Munikumar R.; Ong, Jennifer A.; Huang, Michael L.H.

    2015-01-01

    Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) demonstrates potent anti-cancer activity. We previously demonstrated that 14C-Dp44mT enters and targets cells through a carrier/receptor-mediated uptake process. Despite structural similarity, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT) and pyridoxal isonicotinoyl hydrazone (PIH) enter cells via passive diffusion. Considering albumin alters the uptake of many drugs, we examined the effect of human serum albumin (HSA) on the cellular uptake of Dp44mT, Bp4eT and PIH. Chelator-HSA binding studies demonstrated the following order of relative affinity: Bp4eT≈PIH>Dp44mT. Interestingly, HSA decreased Bp4eT and PIH uptake, potentially due to its high affinity for the ligands. In contrast, HSA markedly stimulated Dp44mT uptake by cells, with two saturable uptake mechanisms identified. The first mechanism saturated at 5-10 μM (Bmax:1.20±0.04 × 107 molecules/cell; Kd:33±3 μM) and was consistent with a previously identified Dp44mT receptor/carrier. The second mechanism was of lower affinity, but higher capacity (Bmax:2.90±0.12 × 107 molecules/cell; Kd:65±6 μM), becoming saturated at 100 μM and was only evident in the presence of HSA. This second saturable Dp44mT uptake process was inhibited by excess HSA and had characteristics suggesting it was mediated by a specific binding site. Significantly, the HSA-mediated increase in the targeting of Dp44mT to cancer cells potentiated apoptosis and could be important for enhancing efficacy. PMID:25848850

  8. Experimental and theoretical advances in functional understanding of flavonoids as anti-tumor agents.

    PubMed

    Babu, Bandarugattu V; Konduru, Naveen K; Nakanishi, Waro; Hayashi, Satoko; Ahmed, Naseem; Mitrasinovic, Petar M

    2013-02-01

    The potential of flavonoids to act as anti-tumor agents has been recognized but not fully understood because flavonoids are acting at several stages in cancer progression with distinct structure-function relationships. A whole family of structurally different flavonoids is herein described by reviewing some critical aspects of their pro-oxidant behavior in vitro/vivo and in cell systems by which they may work as antioxidants. Different classes of flavonoids (chalcones, flavones, isoflavones, flavanols, flavanones and anthocyanins) are synthetically mimicked using natural product structure-antioxidant activity relationships that are relevant for their enhanced function against cancer as well as severe inflammation conditions under which an increased oxidative stress is often implicated. In the context of the common mechanisms of flavonoid action, clinical data on benefits of flavonoids in fighting against cancer are discussed. A structural basis needed to improve antioxidant activity of these agents is elaborated in more detail.

  9. Reduction of Splenic Immunosuppressive Cells and Enhancement of Anti-Tumor Immunity by Synergy of Fish Oil and Selenium Yeast

    PubMed Central

    Li, Tsung-Lin; Bauer, Brent A.; Hsia, Simon; Wang, Cheng-Hsu; Huang, Jen-Seng; Wang, Hung-Ming; Yeh, Kun-Yun; Huang, Tse-Hung; Wu, Gwo-Jang; Wu, Chang-Jer

    2013-01-01

    Growing evidence has shown that regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) abnormally increase in cancer cachectic patients. Suppressions of Tregs and MDSCs may enhance anti-tumor immunity for cancer patients. Fish oil and selenium have been known to have many biological activities such as anti-inflammation and anti-oxidation. Whether fish oil and/or selenium have an additional effect on population of immunosuppressive cells in tumor-bearing hosts remained elusive and controversial. To gain insights into their roles on anti-tumor immunity, we studied the fish oil- and/or selenium-mediated tumor suppression and immunity on lung carcinoma, whereof cachexia develops. Advancement of cachexia in a murine lung cancer model manifested with such indicative symptoms as weight loss, chronic inflammation and disturbed immune functionality. The elevation of Tregs and MDSCs in spleens of tumor-bearing mice was positively correlated with tumor burdens. Consumption of either fish oil or selenium had little or no effect on the levels of Tregs and MDSCs. However, consumption of both fish oil and selenium together presented a synergistic effect-The population of Tregs and MDSCs decreased as opposed to increase of anti-tumor immunity when both fish oil and selenium were supplemented simultaneously, whereby losses of body weight and muscle/fat mass were alleviated significantly. PMID:23349693

  10. Anti-tumoral activity of human salivary peptides.

    PubMed

    da Costa, João Pinto; Carvalhais, Virginia; Amado, Francisco; Silva, Artur; Nogueira-Ferreira, Rita; Ferreira, Rita; Helguero, Luísa; Vitorino, Rui

    2015-09-01

    Chemotherapy continues to be the standard treatment for advanced or metastasized cancer. However, commonly used chemotherapeutic agents may induce damage in healthy cells and tissues. Thus, in recent years, there has been an increased focus on the development of new, efficient anticancer drugs exhibiting low toxicity and that are not affected by mechanisms of chemoresistance. In the present work, we tested synthetic and naturally obtained human salivary peptides against breast, prostate, colon, osteosarcoma and bladder cancer cell lines (T47-D, PC-3, HT-29, MG63, T-24, respectively). Results have showed that there is a reduced cell population increase that is peptide-, cell- and possibly pathway-specific, with the most potent effect observed in observed in T-47D breast cancer cells. Protein expression and microscopy results further indicate that, in this cell line, the peptide with the sequence GPPPQGGRPQG (GG peptide) interferes with the ability of cell adhesion proteins to stabilize adherens junctions, such as E-cadherin, leading to apoptosis. These promising results encourage future works aimed at disclosing the vast potential of salivary peptides as new therapeutic agents.

  11. Fasting protects against the side effects of irinotecan but preserves its anti-tumor effect in Apc15lox mutant mice

    PubMed Central

    Huisman, Sander A; Bijman-Lagcher, Wendy; IJzermans, Jan NM; Smits, Ron; de Bruin, Ron WF

    2015-01-01

    Irinotecan is a widely used topoisomerase-I-inhibitor with a very narrow therapeutic window because of its severe toxicity. In the current study we have examined the effects of fasting prior to irinotecan treatment on toxicity and anti-tumor activity. FabplCre;Apc15lox/+ mice, which spontaneously develop intestinal tumors, of 27 weeks of age were randomized into 3-day fasted and ad libitum fed groups, followed by treatment with a flat-fixed high dose of irinotecan or vehicle. Side-effects were recorded until 11 days after the start of the experiment. Tumor size, and markers for cell-cycle activity, proliferation, angiogenesis, and senescence were measured. Fasted mice were protected against the side-effects of irinotecan treatment. Ad libitum fed mice developed visible signs of discomfort including weight loss, lower activity, ruffled coat, hunched-back posture, diarrhea, and leukopenia. Irinotecan reduced tumor size in fasted and ad libitum fed groups similarly compared to untreated controls (2.4 ± 0.67 mm and 2.4 ± 0.82 mm versus 3.0 ± 1.05 mm and 2.8 ± 1.08 mm respectively, P < 0.001). Immunohistochemical analysis showed reduced proliferation, a reduced number of vascular endothelial cells, and increased levels of senescence in tumors of both irinotecan treated groups. In conclusion, 3 days of fasting protects against the toxic side-effects of irinotecan in a clinically relevant mouse model of spontaneously developing colorectal cancer without affecting its anti-tumor activity. These results support fasting as a powerful way to improve treatment of colorectal carcinoma patients. PMID:25955194

  12. Anti-tumor potential of ethanol extract of Curcuma phaeocaulis Valeton against breast cancer cells.

    PubMed

    Chen, Xiuping; Pei, Lixia; Zhong, Zhangfeng; Guo, Jiajie; Zhang, Qingwen; Wang, Yitao

    2011-11-15

    Curcuma phaeocaulis Valeton is a commonly prescribed Chinese medical herb for tumor therapy. In this study, an extract of Curcuma phaeocaulis Valeton referred as Cpv was prepared and its anti-tumor effect was evaluated with MCF-7 and MDA-MB-231 cells. Curcuma phaeocaulis Valeton power was extracted with ethanol and the main components of the extract (Cpv) were analyzed with HPLC. The effect of Cpv on MCF-7 cells proliferation, intracellular reactive oxygen species (ROS) formation, mitochondrial membrane potential (ΔΨm), apoptosis, apoptotic related proteins, MDA-MB-231 cell migration, and integrins expression were determined. Furthermore, the effect of Cpv on some key signal transduction molecules was also investigated. Furanodienone, germacrone and furanodiene were identified as the main components of Cpv. Cpv treatment significantly inhibited cell proliferation, increased LDH release, induced intracellular ROS formation, and decreased ΔΨm in a dose-dependent manner in MCF-7 cells. Cpv induced apoptosis without affecting cell migration. Cpv increased protein expression of Bax, PARP, cleaved PARP, caspase-3, 7, JNK1, p-p42/44MAPK, NF-κB, IKKα, IKKβ, decreased protein expression of Bcl-2, Bcl-xL, Bim, Bik, Bad, integrin β5, p42/44MAPK without affecting integrin α5, β1, and p38MAPK protein expression. We concluded that Cpv inhibited MCF-7 cells proliferation by inducing apoptosis mediated by increasing ROS formation, decreasing ΔΨm, regulating Bcl-2 family proteins expression, and activating caspases. Cpv treatment also modulated several signaling transduction pathways. These results might provide some molecular basis for the anti-tumor activity of Curcuma phaeocaulis Valeton.

  13. Orally Administered Particular β-Glucan Modulates Tumor-capturing Dendritic Cells and Improves Anti-tumor T Cell Responses in Cancer

    PubMed Central

    Li, Bing; Cai, Yihua; Qi, Chunjian; Hansen, Richard; Ding, Chuanlin; Mitchell, Thomas C.; Yan, Jun

    2010-01-01

    Purpose The beneficial properties of β-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 (CR3) for eliciting CR3-dependent cellular cytotoxicity of iC3b-opsonized tumor cells. The current study is to investigate whether β-glucan therapy has any impact on anti-tumor adaptive T cell responses. Experimental Design We first examined the trafficking of orally administered particulate yeast-derived β-glucan and its interaction with dendritic cells (DCs) that captured tumor materials. Antigen-specific T cells were adoptively transferred into recipient mice to determine whether oral β-glucan therapy induces augmented T cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral β-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined. Results Orally administered particulate β-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-γ production of tumor-infiltrating T cells and CTL responses were significantly enhanced upon β-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, β-glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment. Conclusions These data highlight the ability of yeast-derived β-glucan to bridge innate and adaptive anti-tumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy. PMID:20855461

  14. Allogeneic IgG combined with dendritic cell stimuli induces anti-tumor T cell immunity

    PubMed Central

    Carmi, Yaron; Spitzer, Matthew H.; Linde, Ian L.; Burt, Bryan M; Prestwood, Tyler R.; Perlman, Nikola; Davidson, Matthew G.; Kenkel, Justin A.; Segal, Ehud; Pusapati, Ganesh V.; Bhattacharya, Nupur; Engleman, Edgar G.

    2015-01-01

    While cancers grow in their hosts and evade host immunity through immunoediting and immunosuppression1–5, tumors are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumors are reliably rejected by host T cells, even when the tumor and host share the same major histocompatibility complex (MHC) alleles, the most potent determinants of transplant rejection6–10. How such tumor-eradicating immunity is initiated remains unknown, though elucidating this process could provide a roadmap for inducing similar responses against naturally arising tumors. We found that allogeneic tumor rejection is initiated by naturally occurring tumor-binding IgG antibodies, which enable dendritic cells (DC) to internalize tumor antigens and subsequently activate tumor-reactive T cells. We exploited this mechanism to successfully treat autologous and autochthonous tumors. Either systemic administration of DC loaded with allogeneic IgG (alloIgG)-coated tumor cells or intratumoral injection of alloIgG in combination with DC stimuli induced potent T cell mediated anti-tumor immune responses, resulting in tumor eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumors and metastases, as well as the injected primary tumors. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumor antigens after culture with alloIgG-loaded DC, recapitulating our findings in mice. These results reveal that tumor-binding alloIgG can induce powerful anti-tumor immunity that can be exploited for cancer immunotherapy. PMID:25924063

  15. Comparison of the Anti-tumor Effects of Selective Serotonin Reuptake Inhibitors as Well as Serotonin and Norepinephrine Reuptake Inhibitors in Human Hepatocellular Carcinoma Cells.

    PubMed

    Kuwahara, Jun; Yamada, Takaaki; Egashira, Nobuaki; Ueda, Mitsuyo; Zukeyama, Nina; Ushio, Soichiro; Masuda, Satohiro

    2015-01-01

    The anti-tumor effects of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) on several types of cancer cells have been reported. However, comparison of the anti-tumor effects of these drugs on human hepatocellular carcinoma (HepG2) cells has not been studied. We compared the anti-tumor effects of four SSRIs and two SNRIs on HepG2 cells. SSRIs and duloxetine dose-dependently decreased cell viability. Milnacipran had no effect on cell viability. The half-maximal inhibitory concentration was lower in the order of: sertraline, paroxetine, duloxetine, fluvoxamine, escitalopram, and milnacipran. Exposure to sertraline (2 µM) significantly increased caspase-3/7 activity. These results suggest that, of the agents tested here, sertraline had the highest sensitivity to HepG2 cells, and activation of the caspase pathway is involved in the anti-tumor effects of sertraline in HepG2 cells. PMID:26328498

  16. Xanthatin anti-tumor cytotoxicity is mediated via glycogen synthase kinase-3β and β-catenin.

    PubMed

    Tao, Li; Sheng, Xiaobo; Zhang, Lei; Li, Weidong; Wei, Zhonghong; Zhu, Pinting; Zhang, Feng; Wang, Aiyun; Woodgett, James R; Lu, Yin

    2016-09-01

    Xanthatin, a xanthanolide sesquiterpene lactone isolated from Xanthium strumarium L. (Asteraceae), has prominent anti-tumor activity. Initial mechanism of action studies suggested xanthatin triggered activation of Wnt/β-catenin. We examined the effects of xanthatin on signaling pathways in A459 lung cancer cells and mouse embryonic fibroblasts to ascertain requirements for xanthatin-induced cell death and tumor growth in xenografts. Genetic inactivation of GSK-3β, but not the related isoform GSK-3α, compromised xanthatin cytotoxicity while inactivation of β-catenin enhanced xanthatin-mediated cell death. These data provide insight into how xanthatin and related molecules could be effectively targeted toward certain tumors. PMID:27321043

  17. Fine-tuning anti-tumor immunotherapies via stochastic simulations

    PubMed Central

    2012-01-01

    Background Anti-tumor therapies aim at reducing to zero the number of tumor cells in a host within their end or, at least, aim at leaving the patient with a sufficiently small number of tumor cells so that the residual tumor can be eradicated by the immune system. Besides severe side-effects, a key problem of such therapies is finding a suitable scheduling of their administration to the patients. In this paper we study the effect of varying therapy-related parameters on the final outcome of the interplay between a tumor and the immune system. Results This work generalizes our previous study on hybrid models of such an interplay where interleukins are modeled as a continuous variable, and the tumor and the immune system as a discrete-state continuous-time stochastic process. The hybrid model we use is obtained by modifying the corresponding deterministic model, originally proposed by Kirschner and Panetta. We consider Adoptive Cellular Immunotherapies and Interleukin-based therapies, as well as their combination. By asymptotic and transitory analyses of the corresponding deterministic model we find conditions guaranteeing tumor eradication, and we tune the parameters of the hybrid model accordingly. We then perform stochastic simulations of the hybrid model under various therapeutic settings: constant, piece-wise constant or impulsive infusion and daily or weekly delivery schedules. Conclusions Results suggest that, in some cases, the delivery schedule may deeply impact on the therapy-induced tumor eradication time. Indeed, our model suggests that Interleukin-based therapies may not be effective for every patient, and that the piece-wise constant is the most effective delivery to stimulate the immune-response. For Adoptive Cellular Immunotherapies a metronomic delivery seems more effective, as it happens for other anti-angiogenesis therapies and chemotherapies, and the impulsive delivery seems more effective than the piece-wise constant. The expected synergistic

  18. Two RGD-independent alpha vbeta 3 integrin binding sites on tumstatin regulate distinct anti-tumor properties.

    PubMed

    Maeshima, Y; Colorado, P C; Kalluri, R

    2000-08-01

    Vascular basement membrane is an important regulator of angiogenesis and undergoes many alterations during angiogenesis and these changes are speculated to influence neovascularization. Recently, fragments of collagen molecules have been identified to possess anti-angiogenic activity. Tumstatin (alpha3(IV)NC1 domain) is one such novel molecule with distinct anti-tumor properties and possesses an N-terminal (amino acids 54-132) anti-angiogenic and a C-terminal (amino acids 185-203) anti-tumor cell activity (Maeshima, Y., et al. 2000) J. Biol. Chem. 275, 21340-21348). Previous studies have identified the 185-203 amino acid sequence as a ligand for alpha(v)beta(3) integrin (Shahan, T. A., et al. (1999) Cancer Res. 59, 4584-4590). In the present study, we found distinct additional RGD-independent alpha(v)beta(3) integrin binding site within 54-132 amino acids of tumstatin. This site is not essential for inhibition of tumor cell proliferation but necessary for the anti-angiogenic activity. A fragment of tumstatin containing 54-132 amino acid (tum-2) binds both endothelial cells and melanoma cells but only inhibited proliferation of endothelial cells, with no effect on tumor cell proliferation. A similar experiment with fragment of tumstatin containing the 185-203 amino acid (tum-4) demonstrates that it binds both endothelial cells and melanoma cells but only inhibits the proliferation of melanoma cells. The presence of cyclic RGD peptides did not affect the alpha(v)beta(3) integrin-mediated activity of tumstatin, although significant inhibition of endothelial cell binding to vitronectin was observed. The two distinct RGD-independent binding sites on tumstatin suggest unique alpha(v)beta(3) integrin-mediated mechanisms governing the two distinct anti-tumor properties of tumstatin. PMID:10837460

  19. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer.

    PubMed

    Xiang, Meixian; Su, Hanwen; Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

    2016-04-01

    Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

  20. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

    PubMed Central

    Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

    2016-01-01

    Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

  1. The anti-tumor effect and increased tregs infiltration mediated by rAAV-SLC vector.

    PubMed

    Li, Rilun; Hu, Heng; Ma, Huiying; Chen, Long; Zhou, Binbin; Liu, Yinkun; Liang, Chunmin

    2013-10-01

    To explore the anti-tumor effect and immune mechanism mediated by a new recombinant adeno-associated virus (rAAV) encoding secondary lymphoid tissue chemokine (SLC) mature peptide gene. AAV Helper-Free system was used for rAAV-SLC package. The anti-tumor effect of SLC was detected by bearing tumor established from Hepal-6 cells both in C57BL/6J and nude mice. Flow cytometry analysis and IHC for Tumor-infiltrating T cells and CD11c+DCs were also investigated to explore the immunological mechanism. rAAV-SLC was successfully packaged in AAV293 cells and transfected Hepal-6 tumor cells at high efficiency. The anti-tumor effect was demonstrated by less tumor weight and longer survival outcome. Coincident with the anti-tumor response, local elaboration of SLC within the tumor bed elicited a heavy infiltration of CD4+, CD8+T cells and CD11c+ dendritic cells into the tumor sites. More importantly, there was higher infiltration of Foxp3+ regulatory T cells (Tregs). Local elaboration of SLC mediated by rAAV-SLC has strong T cell mediated anti-tumor effect. The study also suggested that Tregs in the tumor microenvironment tampered the anti-tumor effect.

  2. Water-soluble extract of Saxifraga stolonifera has anti-tumor effects on Lewis lung carcinoma-bearing mice.

    PubMed

    Liu, Dong; Yang, Ping; Zhang, Yu-Qing

    2016-10-01

    Saxifraga stolonifera is an evergreen and herbaceous plant well known in Korea, Japan and western China, which has great potential applications in gardening and pharmacology. The aim of this study is to evaluate the anti-tumor effects of S. stolonifera extraction on lung tumors of Lewis mice. By the measurement of MS/MS, we found that there were four main bioactive components in methanol extract of S. stolonifera, including gallic acid, norbergenin, protocatechuic acid and bergenin, and the results of quantitative analysis showed that the contents of gallic acid, protocatechuic acid and bergenin in methanol extract of S. stolonifera were 5.150, 1.492, 24.559mg/g, respectively. Animal experiment showed that the mean tumor weight of Lewis lung carcinoma-bearing mice treated with water-soluble extract of S. stolonifera was obviously smaller than model group (cis-DDP), and its inhibition rate was 49.2%. In addition, histopathological evaluation and immunohistochemical assay confirmed the anti-tumor effects of S. stolonifera. Investigation of four haematological parameters revealed that the Lewis mice fed with S. stolonifera showed good resilience in the level of leukocyte, haemoglobin, blood platelets and red blood cell compared with the model group. In addition, RT-PCR suggested that the relative expression of pro-apoptosis gene p53, Sox and Bax was enhanced, while the relative expression of anti-apoptosis gene Bcl2 was diminished in comparison with model group. These results suggested that water-soluble extract of S. stolonifera has anti-tumor effects on Lewis lung tumors. PMID:27575479

  3. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies.

    PubMed

    Bamberger, Sarah; Martinez Vinson, Christine; Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients. PMID:27636201

  4. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies

    PubMed Central

    Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn’s disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn’s disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon’s signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients. PMID:27636201

  5. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies.

    PubMed

    Bamberger, Sarah; Martinez Vinson, Christine; Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients.

  6. Mechanisms Underlying the Anti-Tumoral Effects of Citrus bergamia Juice

    PubMed Central

    Delle Monache, Simona; Sanità, Patrizia; Trapasso, Elena; Ursino, Maria Rita; Dugo, Paola; Russo, Marina; Ferlazzo, Nadia; Calapai, Gioacchino; Angelucci, Adriano; Navarra, Michele

    2013-01-01

    Based on the growing deal of data concerning the biological activity of flavonoid-rich natural products, the aim of the present study was to explore in vitro the potential anti-tumoral activity of Citrus Bergamia (bergamot) juice (BJ), determining its molecular interaction with cancer cells. Here we show that BJ reduced growth rate of different cancer cell lines, with the maximal growth inhibition observed in neuroblastoma cells (SH-SY5Y) after 72 hs of exposure to 5% BJ. The SH-SY5Y antiproliferative effect elicited by BJ was not due to a cytotoxic action and it did not induce apoptosis. Instead, BJ stimulated the arrest in the G1 phase of cell cycle and determined a modification in cellular morphology, causing a marked increase of detached cells. The inhibition of adhesive capacity on different physiologic substrates and on endothelial cells monolayer were correlated with an impairment of actin filaments, a reduction in the expression of the active form of focal adhesion kinase (FAK) that in turn caused inhibition of cell migration. In parallel, BJ seemed to hinder the association between the neural cell adhesion molecule (NCAM) and FAK. Our data suggest a mechanisms through which BJ can inhibit important molecular pathways related to cancer-associated aggressive phenotype and offer new suggestions for further studies on the role of BJ in cancer treatment. PMID:23613861

  7. Cyclophosphamide augments the anti-tumor efficacy of uracil and tegafur by inhibiting dihydropyrimidine dehydrogenase.

    PubMed

    Nio, Yoshinori; Iguchi, Chikage; Kodama, Hiroshi; Itakura, Masayuki; Hashimoto, Koji; Koike, Makoto; Toga, Tomoko; Maruyama, Riruke; Fukushima, Masakazu

    2007-01-01

    The present study assesses the effects of neo-adjuvant chemotherapy (NAC) with uracil and tegafur (UFT) alone vs UFT plus cyclophosphamide (CPA), on the activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in breast cancer tissues. Breast cancer patients were randomly assigned to 3 groups; the control (no-treatment) group (n=13), the UFT (5-8 mg/kg/day) alone group (n=10) and the UFT plus CPA (1 mg/kg/one day interval) (UC) group (n=9), and they received NAC for 2-4 weeks. A total of 32 invasive ductal breast carcinomas were used to assay for TS and DPD activity. There were no statistically significant differences in tumor size or stage classification between the 3 groups. The DPD activity was inversely and significantly correlated with the tumor size and pT, but the TS activity was not correlated with these clinicopathological factors. The TS activity was decreased by NAC with UFT, and the addition of CPA resulted in an increased inhibition of TS activity. In contrast, DPD activity was increased by NAC with UFT administration, but its increased activity was significantly inhibited by the addition of CPA. Multiple regression analyses demonstrated that the total dose of UFT was a significant variable for inhibiting TS activity, and that CPA was a significant variable for inhibiting DPD activity. The DPD activity increased by UFT can be inhibited by CPA, and this may represent one of the possible mechanisms responsible for the anti-tumor activity of 5-FU or its derivatives as enhanced by CPA.

  8. Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase {alpha}

    SciTech Connect

    Maeda, Naoki; Kokai, Yasuo; Ohtani, Seiji; Sahara, Hiroeki; Kuriyama, Isoko; Kamisuki, Shinji; Takahashi, Shunya; Sakaguchi, Kengo; Sugawara, Fumio; Yoshida, Hiromi; Sato, Noriyuki; Mizushina, Yoshiyuki . E-mail: mizushin@nutr.kobegakuin.ac.jp

    2007-01-12

    In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol {alpha} from a fungus (Alternaria tennuis). We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited only mammalian pol {alpha} with IC{sub 50} value of 0.5 {mu}M, and did not influence the activities of other replicative pols such as pols {delta} and {epsilon}, but also showed no effect on pol {alpha} activity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. The compound also inhibited the proliferation of human cancer cells with LD{sub 50} values of 38.0-44.4 {mu}M. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, dehydroaltenusin was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that increased tumor necrosis and decreased mitotic index were apparently detected by the compound in vivo. Therefore, dehydroaltenusin could be of interest as not only a mammalian pol {alpha}-specific inhibitor, but also as a candidate drug for anti-cancer treatment.

  9. Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses

    PubMed Central

    Chiba, Shiho; Ikushima, Hiroaki; Ueki, Hiroshi; Yanai, Hideyuki; Kimura, Yoshitaka; Hangai, Sho; Nishio, Junko; Negishi, Hideo; Tamura, Tomohiko; Saijo, Shinobu; Iwakura, Yoichiro; Taniguchi, Tadatsugu

    2014-01-01

    The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications. DOI: http://dx.doi.org/10.7554/eLife.04177.001 PMID:25149452

  10. Melanoma differentiation associated gene-7 (mda-7): a novel anti-tumor gene for cancer gene therapy.

    PubMed Central

    Mhashilkar, A. M.; Schrock, R. D.; Hindi, M.; Liao, J.; Sieger, K.; Kourouma, F.; Zou-Yang, X. H.; Onishi, E.; Takh, O.; Vedvick, T. S.; Fanger, G.; Stewart, L.; Watson, G. J.; Snary, D.; Fisher, P. B.; Saeki, T.; Roth, J. A.; Ramesh, R.; Chada, S.

    2001-01-01

    BACKGROUND: The mda-7 gene (melanoma differentiation associated gene-7) is a novel tumor suppressor gene. The anti-proliferative activity of MDA-7 has been previously reported. In this report, we analyze the anti-tumor efficacy of Ad-mda7 in a broad spectrum of cancer lines. MATERIALS AND METHODS: Ad-mda7-transduced cancer or normal cell lines were assayed for cell proliferation (tritiated thymidine incorporation assay, Alamar blue assay, and trypan-blue exclusion assay), apoptosis (TUNEL, and Annexin V staining visualized by fluorescent microscopy or FACs analysis), and cell cycle regulation (Propidium Iodide staining and FACs analysis). RESULTS: Ad-mda7 treatment of tumor cells resulted in growth inhibition and apoptosis in a temporal and dose-dependent manner. The anti-tumor effects were independent of the genomic status of p53, RB, p16, ras, bax, and caspase 3 in these cells. In addition, normal cell lines did not show inhibition of proliferation or apoptotic response to Ad-mda7. Moreover, Ad-mda7-transduced cancer cells secreted a soluble form of MDA-7 protein. Thus, Ad-mda7 may represent a novel gene-therapeutic agent for the treatment of a variety of cancers. CONCLUSIONS: The potent and selective killing activity of Ad-mda7 in cancer cells but not in normal cells makes this vector a potential candidate for cancer gene therapy. PMID:11471572

  11. Modified chitosan thermosensitive hydrogel enables sustained and efficient anti-tumor therapy via intratumoral injection.

    PubMed

    Jiang, Yingchun; Meng, Xuanyu; Wu, Zhenghong; Qi, Xiaole

    2016-06-25

    Thermosensitive in situ hydrogels are potential candidates to achieve intratumoral administration, nevertheless their weak mechanical strength always lead to serious drug leakage and burst. Herein, we developed a chitosan based thermosensitive hydrogel of high mechanical strength, which was modified by glutaraldehyde (GA) and polyvinyl alcohol (PVA), for intratumoral delivery of paclitaxel (PTX). The modified hydrogel system could achieve sol-gel transition at 35.79±0.4°C and exhibit a 7.03-fold greater mechanical strength compared with simple chitosan hydrogel. Moreover, the drug release of PTX loaded modified hydrogel in PBS (pH 7.4) was found to be extended to 13 days. After intratumoral administration in mice bearing H22 tumors, PTX-loaded modified hydrogels exhibited a 3.72-fold greater antitumor activity compared with Taxol(®). Overall, these modified hydrogel systems demonstrated to be a promising way to achieve efficient sustained release and enhanced anti-tumor therapy efficiency of anticancer drugs through in situ tumor injectable administration. PMID:27083815

  12. Small structural differences of targeted anti-tumor toxins result in strong variation of protein expression.

    PubMed

    Gilabert-Oriol, Roger; Thakur, Mayank; Weise, Christoph; Dernedde, Jens; von Mallinckrodt, Benedicta; Fuchs, Hendrik; Weng, Alexander

    2013-09-01

    Targeted anti-tumor toxins consist of a toxic functional moiety that is chemically linked or recombinantly fused to a cell-directing ligand. Ribosome-inactivating proteins (RIPs), especially type I RIPs such as saporin or dianthin, are commonly used as toxin components. Although expression of type I RIP-based fusion proteins is well reported, the achievement of higher protein yields in heterologous expression systems through innovative strategies is of major interest. In the present study, the targeted toxins (his)saporin-EGF (SE) and (his)dianthin-EGF (DE) were expressed as fusion proteins under identical expression conditions. However, the total amount of DE was nearly two-times higher than SE. The identity of the heterologously expressed targeted toxins was confirmed by mass spectrometric studies. Their biological specific activity, monitored in real time, was almost equal. Sequence alignment shows 84% identity and a structural comparison revealed five major differences, two of which affect the secondary structure resulting in a loop (SE) to β-strand (DE) conversion and one introduces a gap in SE (after position 57). In conclusion, these structural variations resulted in different protein expression levels while codon usage and toxicity to bacteria were excluded as a cause. Minor structural differences identified in this study may be considered responsible for the protection of DE from bacterial proteases and therefore may serve as a lead to modify certain domains in type I RIP-based targeted toxins.

  13. Computational studies on DNA recognition of novel organic and copper anti-tumor compounds

    NASA Astrophysics Data System (ADS)

    Nascimento, Rafael R.; Gonçalves, Marcos B.; Petrilli, Helena M.; Ferreira, Ana M. D. C.; Ippoliti, Emiliano; Dreyer, Jens; Carloni, Paolo

    2013-03-01

    The ability of many organic and coordination compounds to bind to DNA and/or damage cellular structures has been largely exploited in anticancer research. Identifying DNA recognition mechanisms have thus important impact on the chemical biology of gene expression and the development of new drugs and therapies. Previous studies on copper(II) complexes with oxindole-Schiff base ligands have shown their potential anti-tumor activity towards different cells, inducing apoptosis through a preferential attack to DNA and/or mitochondria [SIL11]. The binding mechanism of the organic and copper(II) complexes [Cu(isaepy)2]2 + (1) and [Cu(isaenim)]2 + (2) and their modulation at DNA is investigated through theoretical studies. Here we adopted a multi-scale procedure to simulate this large system using molecular docking and classical molecular dynamics. Hybrid Car-Parrinello/Molecular Mechanics calculations were applied to parameterize the copper(II) complexes by using the force matching approach. Free energies of binding are investigated by metadynamics enhanced sampling methods[VAR08]. [SIL11] V. C. da Silveira et. al. JIB 105 (2011) 1692.[VAR08] A. V. Vargiu et. al. Nucl. Acids Res. 36 (2008) 5910.

  14. An evaluation of the anti-tumor efficacy of oleanolic acid-loaded PEGylated liposomes

    NASA Astrophysics Data System (ADS)

    Tang, Shengnan; Gao, Dawei; Zhao, Tingting; Zhou, Jing; Zhao, Xiaoning

    2013-06-01

    The effective delivery of oleanolic acid (OA) to the target site has several benefits in therapy for different pathologies. However, the delivery of OA is challenging due to its poor aqueous solubility. The study aims to evaluate the tumor inhibition effect of the PEGylated OA nanoliposome on the U14 cervical carcinoma cell line. In our previous study, OA was successfully encapsulated into PEGylated liposome with the modified ethanol injection method. Oral administration of PEGylated OA liposome was demonstrated to be more efficient in inhibiting xenograft tumors. The results of organ index indicated that PEG liposome exhibited higher anti-tumor activity and lower cytotoxicity. It was also found that OA and OA liposomes induced tumor cell apoptosis detected by flow cytometry. Furthermore, effects of OA on the morphology of tumor and other tissues were observed by hematoxylin and eosin staining. The histopathology sections did not show pathological changes in kidney or liver in tested mice. In contrast, there was a significant difference in tumor tissues between treatment groups and the negative control group. These observations imply that PEGylated liposomes seem to have advantages for cancer therapy in terms of effective delivery of OA.

  15. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation.

    PubMed

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X

    2016-01-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient's own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers. PMID:27256519

  16. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

    PubMed Central

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

    2016-01-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers. PMID:27256519

  17. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation.

    PubMed

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X

    2016-06-03

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient's own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.

  18. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

    NASA Astrophysics Data System (ADS)

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

    2016-06-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.

  19. The Potential of Intralesional Rose Bengal to Stimulate T-Cell Mediated Anti-Tumor Responses

    PubMed Central

    Maker, Ajay V; Prabhakar, Bellur; Pardiwala, Krunal

    2015-01-01

    Rose Bengal (RB) is a red synthetic dye that was initially used in the garment industry and has been used safely for decades as a corneal stain by ophthalmologists. Antineoplastic properties of RB have also been observed, though the mechanism of action remained to be elucidated. Recently, interest in RB as a therapeutic cancer treatment has increased due to significant anti-tumor responses with direct tumor injection in human clinical trials for metastatic melanoma. In these patients, there has been the implication that RB may mount a T-cell mediated anti-tumor response and impart antigen-specific responses in distant bystander lesions. This article serves to evaluate the potential of intralesional rose bengal to stimulate T-cell mediated anti-tumor responses in in-vitro, pre-clinical, and clinical studies. PMID:26618054

  20. TWEAK mediates anti-tumor effect of tumor-infiltrating macrophage

    SciTech Connect

    Kaduka, Yuki; Takeda, Kazuyoshi . E-mail: ktakeda@med.juntendo.ac.jp; Nakayama, Masafumi; Kinoshita, Katsuyuki; Yagita, Hideo; Okumura, Ko

    2005-06-03

    TWEAK induces diverse cellular responses, including pro-inflammatory chemokine production, migration, proliferation, and cell death through the TWEAK receptor, Fn14. In the present study, we examined the effect of TWEAK or Fn14 expression in tumor cells on tumor outgrowth in vivo. Administration of neutralizing anti-TWEAK mAb significantly reduced the frequency of tumor rejection and shortened the survival of mice intraperitoneally inoculated with TWEAK-sensitive Fn14-expressing tumor cells. Moreover, anti-TWEAK mAb treatment promoted the subcutaneous growth of TWEAK-sensitive Fn14-expressing tumor cells, and this promotion was abolished by the inhibition of macrophage infiltration but not NK cell depletion. In contrast, administration of anti-TWEAK mAb had no apparent effect on the growth of TWEAK-resistant tumor cells, even if tumor cells expressed Fn14. On the other hand, TWEAK expression in tumor cells had no significant effect on subcutaneous tumor growth. These results indicate that TWEAK mediates anti-tumor effect of macrophages in vivo.

  1. [Research advances of anti-tumor immune response induced by pulse electric field ablation].

    PubMed

    Cui, Guang-ying; Diao, Hong-yan

    2015-11-01

    As a novel tumor therapy, pulse electric field has shown a clinical perspective. This paper reviews the characteristics of tumor ablation by microsecond pulse and nanosecond pulse electric field, and the research advances of anti-tumor immune response induced by pulse electric field ablation. Recent researches indicate that the pulse electric field not only leads to a complete ablation of local tumor, but also stimulates a protective immune response, thereby inhibiting tumor recurrence and metastasis. These unique advantages will show an extensive clinical application in the future. However, the mechanism of anti-tumor immune response and the development of related tumor vaccine need further studies.

  2. HMGN2, a new anti-tumor effector molecule of CD8+ T cells

    PubMed Central

    2014-01-01

    Background Cytolytic T lymphocytes (CTL) and natural killer (NK) cells have been implicated as important cells in antitumor responses. Our previous research has shown that high mobility group nucleosomal-binding domain 2 (HMGN2) could be released by IL-2 and PHA stimulated peripheral blood mononuclear cells (PBMCs) and also induced tumor cells apoptosis at low doses. In this study, we isolated and cultured PBMCs and CD8+ T cells to analyze the expression and antitumor effects of HMGN2. Methods PBMCs from healthy donors were isolated using Human Lymphocyte Separation tube. CD8+ T cells were separated from the PBMCs using MoFlo XDP high-speed flow cytometry sorter. Activation of PBMCs and CD8+ T cells were achieved by stimulating with Phytohemagglutinin (PHA) or tumor antigen. In addition, the methods of ELISA, intracellular staining, and fluorescence-labeling assays were used. Results PHA induced PBMCs to release high levels of HMGN2, and CD8+ T cells was the major cell population in PBMCs that release HMGN2 after PHA activation. Tumor antigen-activated CD8+ T cells also released high levels of HMGN2. Supernatants of tumor antigen-activated CD8+ T cells were able to kill tumor cells in a dose-dependent manner. This antitumor effect could be significantly blocked by using an anti-HMGN2 antibody. Fluorescence-labeling assays showed that the supernatant proteins of activated CD8+ T cells could be transported into tumor cells, and the transport visibly decreased after HMGN2 was depleted by anti-HMGN2 antibody. Conclusions These results suggest that HMGN2 is an anti-tumor effector molecule of CD8+ T cells. PMID:25060707

  3. Optimizing production of asperolide A, a potential anti-tumor tetranorditerpenoid originally produced by the algal-derived endophytic fungus Aspergillus wentii EN-48

    NASA Astrophysics Data System (ADS)

    Xu, Rui; Li, Xiaoming; Xu, Gangming; Wang, Bingui

    2016-07-01

    The marine algal-derived endophytic fungus Aspergillus wentii EN-48 produces the potential anti-tumor agent asperolide A, a tetranorlabdane diterpenoid active against lung cancer. However, the fermentation yield of asperolide A was very low and only produced in static cultures. Static fermentation conditions of A. wentii EN-48 were optimized employing response surface methodology to enhance the production of asperolide A. The optimized conditions resulted in a 13.9-fold yield enhancement, which matched the predicted value, and the optimized conditions were successfully used in scale-up fermentation for the production of asperolide A. Exogenous addition of plant hormones (especially 10 μmol/L methyl jasmonate) stimulated asperolide A production. To our knowledge, this is first optimized production of an asperolide by a marine-derived fungus. The optimization is Effective and valuable to supply material for further anti-tumor mechanism studies and preclinical evaluation of asperolide A and other norditerpenoids.

  4. Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting Anti-Tumor Immunity

    NASA Astrophysics Data System (ADS)

    Dranoff, Glenn; Jaffee, Elizabeth; Lazenby, Audrey; Golumbek, Paul; Levitsky, Hyam; Brose, Katja; Jackson, Valerie; Hamada, Hirofumi; Pardoll, Drew; Mulligan, Richard C.

    1993-04-01

    To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4^+ and CD8^+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.

  5. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity.

    PubMed Central

    Dranoff, G; Jaffee, E; Lazenby, A; Golumbek, P; Levitsky, H; Brose, K; Jackson, V; Hamada, H; Pardoll, D; Mulligan, R C

    1993-01-01

    To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4+ and CD8+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines. PMID:8097319

  6. Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses

    PubMed Central

    Matsuzaki, Junko; Tsuji, Takemasa; Luescher, Immanuel F.; Shiku, Hiroshi; Mineno, Junichi; Okamoto, Sachiko; Old, Lloyd J.; Shrikant, Protul; Gnjatic, Sacha; Odunsi, Kunle

    2015-01-01

    Tumor antigen-specific CD4+ T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4+ T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4+ helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4+ T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8+ T cells by enhancing cytotoxic activity, and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8+ T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients. PMID:26447332

  7. The Elastin Receptor Complex: A Unique Matricellular Receptor with High Anti-tumoral Potential

    PubMed Central

    Scandolera, Amandine; Odoul, Ludivine; Salesse, Stéphanie; Guillot, Alexandre; Blaise, Sébastien; Kawecki, Charlotte; Maurice, Pascal; El Btaouri, Hassan; Romier-Crouzet, Béatrice; Martiny, Laurent; Debelle, Laurent; Duca, Laurent

    2016-01-01

    Elastin, one of the longest-lived proteins, confers elasticity to tissues with high mechanical constraints. During aging or pathophysiological conditions such as cancer progression, this insoluble polymer of tropoelastin undergoes an important degradation leading to the release of bioactive elastin-derived peptides (EDPs), named elastokines. EDP exhibit several biological functions able to drive tumor development by regulating cell proliferation, invasion, survival, angiogenesis, and matrix metalloproteinase expression in various tumor and stromal cells. Although, several receptors have been suggested to bind elastokines (αvβ3 and αvβ5 integrins, galectin-3), their main receptor remains the elastin receptor complex (ERC). This heterotrimer comprises a peripheral subunit, named elastin binding protein (EBP), associated to the protective protein/cathepsin A (PPCA). The latter is bound to a membrane-associated protein called Neuraminidase-1 (Neu-1). The pro-tumoral effects of elastokines have been linked to their binding onto EBP. Additionally, Neu-1 sialidase activity is essential for their signal transduction. Consistently, EDP-EBP interaction and Neu-1 activity emerge as original anti-tumoral targets. Interestingly, besides its direct involvement in cancer progression, the ERC also regulates diabetes outcome and thrombosis, an important risk factor for cancer development and a vascular process highly increased in patients suffering from cancer. In this review, we will describe ERC and elastokines involvement in cancer development suggesting that this unique receptor would be a promising therapeutic target. We will also discuss the pharmacological concepts aiming at blocking its pro-tumoral activities. Finally, its emerging role in cancer-associated complications and pathologies such as diabetes and thrombotic events will be also considered. PMID:26973522

  8. Epigallocatechin Gallate/Layered Double Hydroxide Nanohybrids: Preparation, Characterization, and In Vitro Anti-Tumor Study

    PubMed Central

    Shafiei, Seyedeh Sara; Solati-Hashjin, Mehran; Samadikuchaksaraei, Ali; Kalantarinejad, Reza; Asadi-Eydivand, Mitra; Abu Osman, Noor Azuan

    2015-01-01

    In recent years, nanotechnology in merging with biotechnology has been employed in the area of cancer management to overcome the challenges of chemopreventive strategies in order to gain promising results. Since most biological processes occur in nano scale, nanoparticles can act as carriers of certain drugs or agents to deliver it to specific cells or targets. In this study, we intercalated Epigallocatechin-3-Gallate (EGCG), the most abundant polyphenol in green tea, into Ca/Al-NO3 Layered double hydroxide (LDH) nanoparticles, and evaluated its efficacy compared to EGCG alone on PC3 cell line. The EGCG loaded LDH nanohybrids were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy (TEM) and nanosizer analyses. The anticancer activity of the EGCG-loaded LDH was investigated in prostate cancer cell line (PC3) while the release behavior of EGCG from LDH was observed at pH 7.45 and 4.25. Besides enhancing of apoptotic activity of EGCG, the results showed that intercalation of EGCG into LDH can improve the anti- tumor activity of EGCG over 5-fold dose advantages in in-vitro system. Subsequently, the in-vitro release data showed that EGCG-loaded LDH had longer release duration compared to physical mixture, and the mechanism of diffusion through the particle was rate-limiting step. Acidic attack was responsible for faster release of EGCG molecules from LDH at pH of 4.25 compared to pH of 7.4. The results showed that Ca/Al-LDH nanoparticles could be considered as an effective inorganic host matrix for the delivery of EGCG to PC3 cells with controlled release properties. PMID:26317853

  9. The Elastin Receptor Complex: A Unique Matricellular Receptor with High Anti-tumoral Potential.

    PubMed

    Scandolera, Amandine; Odoul, Ludivine; Salesse, Stéphanie; Guillot, Alexandre; Blaise, Sébastien; Kawecki, Charlotte; Maurice, Pascal; El Btaouri, Hassan; Romier-Crouzet, Béatrice; Martiny, Laurent; Debelle, Laurent; Duca, Laurent

    2016-01-01

    Elastin, one of the longest-lived proteins, confers elasticity to tissues with high mechanical constraints. During aging or pathophysiological conditions such as cancer progression, this insoluble polymer of tropoelastin undergoes an important degradation leading to the release of bioactive elastin-derived peptides (EDPs), named elastokines. EDP exhibit several biological functions able to drive tumor development by regulating cell proliferation, invasion, survival, angiogenesis, and matrix metalloproteinase expression in various tumor and stromal cells. Although, several receptors have been suggested to bind elastokines (αvβ3 and αvβ5 integrins, galectin-3), their main receptor remains the elastin receptor complex (ERC). This heterotrimer comprises a peripheral subunit, named elastin binding protein (EBP), associated to the protective protein/cathepsin A (PPCA). The latter is bound to a membrane-associated protein called Neuraminidase-1 (Neu-1). The pro-tumoral effects of elastokines have been linked to their binding onto EBP. Additionally, Neu-1 sialidase activity is essential for their signal transduction. Consistently, EDP-EBP interaction and Neu-1 activity emerge as original anti-tumoral targets. Interestingly, besides its direct involvement in cancer progression, the ERC also regulates diabetes outcome and thrombosis, an important risk factor for cancer development and a vascular process highly increased in patients suffering from cancer. In this review, we will describe ERC and elastokines involvement in cancer development suggesting that this unique receptor would be a promising therapeutic target. We will also discuss the pharmacological concepts aiming at blocking its pro-tumoral activities. Finally, its emerging role in cancer-associated complications and pathologies such as diabetes and thrombotic events will be also considered.

  10. Anti-tumor immunity generated by photodynamic therapy in a metastatic murine tumor model

    NASA Astrophysics Data System (ADS)

    Castano, Ana P.; Hamblin, Michael R.

    2005-04-01

    Photodynamic therapy (PDT) is a modality for the treatment of cancer involving excitation of photosensitizers with harmless visible light producing reactive oxygen species. The major biological effects of PDT are apoptosis of tumor cells, destruction of the blood supply and activation of the immune system. The objective of this study is to compare in an animal model of metastatic cancer, PDT alone and PDT combined with low-dose cyclophosphamide (CY). Since the tumor we used is highly metastatic, it is necessary to generate anti-tumor immunity using PDT to both cure the primary tumor and prevent death from metastasis. This immunity may be potentiated by low dose CY. In our model we used J774 cells (a Balb/c reticulum cell sarcoma line with the characteristics of macrophages) and the following PDT regimen: benzoporphyrin derivative monoacid ring A (BPD, 2mg/kg injected IV followed after 15 min by 150 J/cm2 of 690-nm light). CY (50 mg/kg i.p.) was injected 48 hours before light delivery. BPD-PDT led to complete regression of the primary tumor in more than half the mice but no permanent cures were obtained. BPD-PDT in combination with CY led to 60% permanent cures. CY alone gave no permanent cures but did provide a survival advantage. To probe permanent immunity cured animals were rechallenged with the same tumor cell line and the tumors were rejected in 71% of mice cured with BPD-PDT plus CY. We conclude that BPD-PDT in combination with CY gives best overall results and that this is attributable to immunological response activation in addition to PDT-mediated destruction of the tumor.

  11. Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1.

    PubMed

    Speyer, Cecilia L; Nassar, Mahdy A; Hachem, Ali H; Bukhsh, Miriam A; Jafry, Waris S; Khansa, Rafa M; Gorski, David H

    2016-06-01

    Riluzole, the only drug approved by the FDA for treating amyotrophic lateral sclerosis, inhibits melanoma proliferation through its inhibitory effect on glutamatergic signaling. We demonstrated that riluzole also inhibits the growth of triple-negative breast cancer (TNBC) and described a role for metabotropic glutamate receptor-1 (GRM1) in regulating TNBC cell growth and progression. However, the role of GRM1 in mediating riluzole's effects in breast cancer has not been fully elucidated. In this study, we seek to determine how much of riluzole's action in breast cancer is mediated through GRM1. We investigated anti-tumor properties of riluzole in TNBC and ER+ cells using cell growth, invasion, and soft-agar assays and compared riluzole activity with GRM1 levels. Using Lentiviral vectors expressing GRM1 or shGRM1, these studies were repeated in cells expressing high or low GRM1 levels where the gene was either silenced or overexpressed. Riluzole inhibited proliferation, invasion, and colony formation in both TNBC and ER+ cells. There was a trend between GRM1 expression in TNBC cells and their response to riluzole in both cell proliferation and invasion assays. However, silencing and overexpression studies had no effect on cell sensitivity to riluzole. Our results clearly suggest a GRM1-independent mechanism through which riluzole mediates its effects on breast cancer cells. Understanding the mechanism by which riluzole mediates breast cancer progression will be useful in identifying new therapeutic targets for treating TNBC and in facilitating stratification of patients in clinical trials using riluzole in conjunction with conventional therapy. PMID:27146584

  12. Promotion of initial anti-tumor effect via polydopamine modified doxorubicin-loaded electrospun fibrous membranes

    PubMed Central

    Yuan, Ziming; Zhao, Xin; Wang, Xiaohu; Qiu, Wangwang; Chen, Xinliang; Zheng, Qi; Cui, Wenguo

    2014-01-01

    Drug-loaded electrospun PLLA membranes are not conducive to adhesion between materials and tissues due to the strong hydrophobicity of PLLA, which possibly attenuate the drugs’ effect loaded on the materials. In the present work, we developed a facile method to improve the hydrophilicity of doxorubicin (DOX)-loaded electrospun PLLA fibrous membranes, which could enhance the anti-tumor effect at the early stage after implantation. A mussel protein, polydopamine (PDA), could be easily grafted on the surface of hydrophobic DOX-loaded electrospun PLLA membranes (PLLA-DOX/pDA) in water solution. The morphology analysis of PLLA-DOX/pDA fibers displayed that though the fiber diameter was slightly swollen, they still maintained a 3D fibrous structure, and the XPS analysis certified that pDA had successfully been grafted onto the surface of the fibers. The results of surface wettability analysis showed that the contact angle decreased from 136.7° to 0° after grafting. In vitro MTT assay showed that the cytotoxicity of PLLA-DOX/pDA fibers was the strongest, and the stereologic cell counting assay demonstrated that the adhesiveness of PLLA/pDA fiber was significantly better than PLLA fiber. In vivo tumor-bearing mice displayed that, after one week of implantation, the tumor apoptosis and necrosis of PLLA-DOX/pDA fibers were the most obvious from histopathology and TUNEL assay. The caspase-3 activity of PLLA-DOX/pDA group was the highest using biochemical techniques, and the Bax: Bcl-2 ratio increased significantly in PLLA-DOX/pDA group through qRT-PCR analysis. All the results demonstrated that pDA can improve the affinity of the electrospun PLLA membranes and enhance the drug effect on tumors. PMID:25337186

  13. Effect of anti-tumor necrosis factor alpha antibodies on histopathology of primary Salmonella infections.

    PubMed

    Mastroeni, P; Skepper, J N; Hormaeche, C E

    1995-09-01

    We reported that administration of anti-tumor necrosis factor alpha (anti-TNF-alpha) antibodies exacerbates the course of a Salmonella infection in both susceptible and resistant mice by preventing the suppression of bacterial growth in the reticuloendothelial system. In the present study, we evaluated the effect of in vivo neutralization of TNF-alpha on the histopathology of primary Salmonella infections. We show that in primary infections, the suppression of bacterial growth in the reticuloendothelial system coincides with granuloma formation in the spleen and liver. Administration of anti-TNF-alpha globulins on day -1 of salmonellosis affected neither the histological picture nor the course of the infection in the early stages of the disease (days 1 to 3), with splenic and hepatic lesions consisting mainly of polymorphonuclear leukocytes (PMNs); conversely, later in infection (days 3 to 7), the treatment inhibited the formation of granulomas. When the anti-TNF-alpha treatment was started well after the suppression of bacterial growth in the reticuloendothelial system and the formation of granulomatous lesions in the spleen and liver, a prompt relapse of the infection and regression of already established granulomas were seen. In anti-TNF-alpha-treated mice, salmonellae were found inside macrophages and PMNs and extracellularly in the necrotic tissue of the spleen, while in the liver the organisms were seen mainly in inflammatory mononuclear cells, resident Kupffer cells, and hepatocytes and occasionally in the extracellular compartment within necrotic lesions. The bacteria appeared most often in clusters, being morphologically intact when in the extracellular space or within hepatocytes, while undergoing various degrees of degeneration when inside phagocytes. The results suggest that TNF-alpha is required for granuloma formation in salmonellosis and that its neutralization does not completely abrogate the bactericidal activity of macrophages and PMNs

  14. Anti-tumor Effects of Exo- and Endo-biopolymers Produced from Submerged Cultures of Three Different Mushrooms

    PubMed Central

    Jeong, Yong-Tae; Yang, Byung-Keun; Li, Chun-ru

    2008-01-01

    The anti-tumor effects of exo- (EX) and endo-biopolymers (EN) produced from submerged mycelial cultures of Ganoderma applanatum (GA), Collybia confluens (CC), and Pleurotus eryngii (PE) were studied using Sarcoma 180 bearing mice. Solid tumor growth was inhibited most effectively when 40 mg/kg body weight (BW) of GA-EX or PE-EN was administered to the intraperitoneal (i.p.) cavity of BALB/c mice. The spleen and liver indexes were increased in mice following i.p. administration of GA-EX and PE-EN fractions. GA-EX and PE-EN reduced the tumor formation by 30.7% and 29.4%, respectively. GA-EX and PE-EN increased the natural killer (NK) cell activity of splenocytes by 41.3% and 28.9%, respectively. PMID:23990743

  15. Improved local and systemic anti-tumor efficacy for irreversible electroporation in immunocompetent versus immunodeficient mice.

    PubMed

    Neal, Robert E; Rossmeisl, John H; Robertson, John L; Arena, Christopher B; Davis, Erica M; Singh, Ravi N; Stallings, Jonathan; Davalos, Rafael V

    2013-01-01

    Irreversible electroporation (IRE) is a non-thermal focal ablation technique that uses a series of brief but intense electric pulses delivered into a targeted region of tissue, killing the cells by irrecoverably disrupting cellular membrane integrity. This study investigates if there is an improved local anti-tumor response in immunocompetent (IC) BALB/c versus immunodeficient (ID) nude mice, including the potential for a systemic protective effect against rechallenge. Subcutaneous murine renal carcinoma tumors were treated with an IRE pulsing protocol that used 60% of the predicted voltage required to invoke complete regressions in the ID mice. Tumors were followed for 34 days following treatment for 11 treated mice from each strain, and 7 controls from each strain. Mouse survival based on tumor burden and the progression-free disease period was substantially longer in the treated IC mice relative to the treated ID mice and sham controls for both strains. Treated IC mice were rechallenged with the same cell line 18 days after treatment, where growth of the second tumors was shown to be significantly reduced or prevented entirely. There was robust CD3+ cell infiltration in some treated BALB/C mice, with immunocytes focused at the transition between viable and dead tumor. There was no difference in the low immunocyte presence for untreated tumors, nude mice, and matrigel-only injections in both strains. These findings suggest IRE therapy may have greater therapeutic efficacy in immunocompetent patients than what has been suggested by immunodeficient models, and that IRE may invoke a systemic response beyond the targeted ablation region. PMID:23717630

  16. Improved Local and Systemic Anti-Tumor Efficacy for Irreversible Electroporation in Immunocompetent versus Immunodeficient Mice

    PubMed Central

    Neal, Robert E.; Rossmeisl, John H.; Robertson, John L.; Arena, Christopher B.; Davis, Erica M.; Singh, Ravi N.; Stallings, Jonathan; Davalos, Rafael V.

    2013-01-01

    Irreversible electroporation (IRE) is a non-thermal focal ablation technique that uses a series of brief but intense electric pulses delivered into a targeted region of tissue, killing the cells by irrecoverably disrupting cellular membrane integrity. This study investigates if there is an improved local anti-tumor response in immunocompetent (IC) BALB/c versus immunodeficient (ID) nude mice, including the potential for a systemic protective effect against rechallenge. Subcutaneous murine renal carcinoma tumors were treated with an IRE pulsing protocol that used 60% of the predicted voltage required to invoke complete regressions in the ID mice. Tumors were followed for 34 days following treatment for 11 treated mice from each strain, and 7 controls from each strain. Mouse survival based on tumor burden and the progression-free disease period was substantially longer in the treated IC mice relative to the treated ID mice and sham controls for both strains. Treated IC mice were rechallenged with the same cell line 18 days after treatment, where growth of the second tumors was shown to be significantly reduced or prevented entirely. There was robust CD3+ cell infiltration in some treated BALB/C mice, with immunocytes focused at the transition between viable and dead tumor. There was no difference in the low immunocyte presence for untreated tumors, nude mice, and matrigel-only injections in both strains. These findings suggest IRE therapy may have greater therapeutic efficacy in immunocompetent patients than what has been suggested by immunodeficient models, and that IRE may invoke a systemic response beyond the targeted ablation region. PMID:23717630

  17. A Novel Copper Chelate Modulates Tumor Associated Macrophages to Promote Anti-Tumor Response of T Cells

    PubMed Central

    Chakraborty, Paramita; Ganguly, Avishek; Adhikary, Arghya; Mukhopadhyay, Debanjan; Ganguli, Sudipta; Banerjee, Rajdeep; Ashraf, Mohammad; Biswas, Jaydip; Das, Pradeep K.; Sa, Gourisankar; Chatterjee, Mitali; Das, Tanya; Choudhuri, Soumitra Kumar

    2009-01-01

    Background At the early stages of carcinogenesis, the induction of tumor specific T cell mediated immunity seems to block the tumor growth and give protective anti-tumor immune response. However, tumor associated macrophages (TAMs) might play an immunosuppressive role and subvert this anti tumor immunity leading to tumor progression and metastasis. Methodology/Principal Findings The Cu (II) complex, (chelate), copper N-(2-hydroxy acetophenone) glycinate (CuNG), synthesized by us, has previously been shown to have a potential usefulness in immunotherapy of multiple drug resistant cancers. The current study demonstrates that CuNG treatment of TAMs modulates their status from immunosuppressive to proimmunogenic nature. Interestingly, these activated TAMs produced high levels of IL-12 along with low levels of IL-10 that not only allowed strong Th1 response marked by generation of high levels of IFN-γ but also reduced activation induced T cell death. Similarly, CuNG treatment of peripheral blood monocytes from chemotherapy and/or radiotherapy refractory cancer patients also modulated their cytokine status. Most intriguingly, CuNG treated TAMs could influence reprogramming of TGF-β producing CD4+CD25+ T cells toward IFN-γ producing T cells. Conclusion/Significance Our results show the potential usefulness of CuNG in immunotherapy of drug-resistant cancers through reprogramming of TAMs that in turn reprogram the T cells and reeducate the T helper function to elicit proper anti-tumorogenic Th1 response leading to effective reduction in tumor growth. PMID:19756150

  18. Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy

    PubMed Central

    Kwong, Brandon; Liu, Haipeng; Irvine, Darrell J.

    2011-01-01

    Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical use even as monotherapies is hampered by dose-limiting inflammatory toxicity provoked upon systemic exposure. We hypothesized that by anchoring immuno-agonist compounds to lipid nanoparticles we could retain the bio-activity of therapeutics in the local tumor tissue and tumor-draining lymph node, but limit systemic exposure to these potent molecules. We prepared PEGylated liposomes bearing surface-conjugated anti-CD40 and CpG and assessed their therapeutic efficacy and systemic toxicity compared to soluble versions of the same immuno-agonists, injected intratumorally in the B16F10 murine model of melanoma. Anti-CD40/CpG-liposomes significantly inhibited tumor growth and induced a survival benefit similar to locally injected soluble anti-CD40+CpG. Biodistribution analyses following local delivery showed that the liposomal carriers successfully sequestered anti-CD40 and CpG in vivo, reducing leakage into systemic circulation while allowing draining to the tumor-proximal lymph node. Contrary to locally administered soluble immunotherapy, anti-CD40/CpG liposomes did not elicit significant increases in serum levels of ALT enzyme, systemic inflammatory cytokines, or overall weight loss, confirming that off-target inflammatory effects had been minimized. The development of a delivery strategy capable of inducing robust anti-tumor responses concurrent with minimal systemic side effects is crucial for the continued progress of potent immunotherapies toward widespread clinical translation. PMID:21514665

  19. Nonsense-Mediated mRNA Decay Impacts MSI-Driven Carcinogenesis and Anti-Tumor Immunity in Colorectal Cancers

    PubMed Central

    El-Bchiri, Jamila; Guilloux, Agathe; Dartigues, Peggy; Loire, Etienne; Mercier, Dominique; Buhard, Olivier; Sobhani, Iradj; de la Grange, Pierre; Auboeuf, Didier; Praz, Françoise; Fléjou, Jean-François; Duval, Alex

    2008-01-01

    Nonsense-mediated mRNA Decay (NMD) degrades mutant mRNAs containing premature termination codon (PTC-mRNAs). Here we evaluate the consequence of NMD activity in colorectal cancers (CRCs) showing microsatellite instability (MSI) whose progression is associated with the accumulation of PTC-mRNAs encoding immunogenic proteins due to frameshift mutations in coding repeat sequences. Inhibition of UPF1, one of the major NMD factors, was achieved by siRNA in the HCT116 MSI CRC cell line and the resulting changes in gene expression were studied using expression microarrays. The impact of NMD activity was also investigated in primary MSI CRCs by quantifying the expression of several mRNAs relative to their mutational status and to endogenous UPF1 and UPF2 expression. Host immunity developed against MSI cancer cells was appreciated by quantifying the number of CD3ε-positive tumor-infiltrating lymphocytes (TILs). UPF1 silencing led to the up-regulation of 1251 genes in HCT116, among which a proportion of them (i.e. 38%) significantly higher than expected by chance contained a coding microsatellite (P<2×10−16). In MSI primary CRCs, UPF1 was significantly over-expressed compared to normal adjacent mucosa (P<0.002). Our data provided evidence for differential decay of PTC-mRNAs compared to wild-type that was positively correlated to UPF1 endogenous expression level (P = 0.02). A negative effect of UPF1 and UPF2 expression on the host's anti-tumor response was observed (P<0.01). Overall, our results show that NMD deeply influences MSI-driven tumorigenesis at the molecular level and indicate a functional negative impact of this system on anti-tumor immunity whose intensity has been recurrently shown to be an independent factor of favorable outcome in CRCs. PMID:18612427

  20. Molecularly Characterized Solvent Extracts and Saponins from Polygonum hydropiper L. Show High Anti-Angiogenic, Anti-Tumor, Brine Shrimp, and Fibroblast NIH/3T3 Cell Line Cytotoxicity.

    PubMed

    Ayaz, Muhammad; Junaid, Muhammad; Ullah, Farhat; Sadiq, Abdul; Subhan, Fazal; Khan, Mir Azam; Ahmad, Waqar; Ali, Gowhar; Imran, Muhammad; Ahmad, Sajjad

    2016-01-01

    Polygonum hydropiper is used as anti-cancer and anti-rheumatic agent in folk medicine. This study was designed to investigate the anti-angiogenic, anti-tumor, and cytotoxic potentials of different solvent extracts and isolated saponins. Samples were analyzed using GC, Gas Chromatography-Mass Spectrometry (GC-MS) to identify major and bioactive compounds. Quantitation of antiangiogenesis for the plant's samples including methanolic extract (Ph.Cr), its subsequent fractions; n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq), saponins (Ph.Sp) were performed using the chick embryo chorioallantoic membrane (CAM) assay. Potato disc anti-tumor assay was performed on Agrobacterium tumefaciens containing tumor inducing plasmid. Cytotoxicity was performed against Artemia salina and mouse embryonic fibroblast NIH/3T3 cell line following contact toxicity and MTT cells viability assays, respectively. The GC-MS analysis of Ph.Cr, Ph.Hex, Ph.Chf, Ph.Bt, and Ph.EtAc identified 126, 124, 153, 131, and 164 compounds, respectively. In anti-angiogenic assay, Ph.Chf, Ph.Sp, Ph.EtAc, and Ph.Cr exhibited highest activity with IC50 of 28.65, 19.21, 88.75, and 461.53 μg/ml, respectively. In anti-tumor assay, Ph.Sp, Ph.Chf, Ph.EtAc, and Ph.Cr were most potent with IC50 of 18.39, 73.81, 217.19, and 342.53 μg/ml, respectively. In MTT cells viability assay, Ph.Chf, Ph.EtAc, Ph.Sp were most active causing 79.00, 72.50, and 71.50% cytotoxicity, respectively, at 1000 μg/ml with the LD50 of 140, 160, and 175 μg/ml, respectively. In overall study, Ph.Chf and Ph.Sp have shown overwhelming results which signifies their potentials as sources of therapeutic agents against cancer. PMID:27065865

  1. Molecularly Characterized Solvent Extracts and Saponins from Polygonum hydropiper L. Show High Anti-Angiogenic, Anti-Tumor, Brine Shrimp, and Fibroblast NIH/3T3 Cell Line Cytotoxicity.

    PubMed

    Ayaz, Muhammad; Junaid, Muhammad; Ullah, Farhat; Sadiq, Abdul; Subhan, Fazal; Khan, Mir Azam; Ahmad, Waqar; Ali, Gowhar; Imran, Muhammad; Ahmad, Sajjad

    2016-01-01

    Polygonum hydropiper is used as anti-cancer and anti-rheumatic agent in folk medicine. This study was designed to investigate the anti-angiogenic, anti-tumor, and cytotoxic potentials of different solvent extracts and isolated saponins. Samples were analyzed using GC, Gas Chromatography-Mass Spectrometry (GC-MS) to identify major and bioactive compounds. Quantitation of antiangiogenesis for the plant's samples including methanolic extract (Ph.Cr), its subsequent fractions; n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq), saponins (Ph.Sp) were performed using the chick embryo chorioallantoic membrane (CAM) assay. Potato disc anti-tumor assay was performed on Agrobacterium tumefaciens containing tumor inducing plasmid. Cytotoxicity was performed against Artemia salina and mouse embryonic fibroblast NIH/3T3 cell line following contact toxicity and MTT cells viability assays, respectively. The GC-MS analysis of Ph.Cr, Ph.Hex, Ph.Chf, Ph.Bt, and Ph.EtAc identified 126, 124, 153, 131, and 164 compounds, respectively. In anti-angiogenic assay, Ph.Chf, Ph.Sp, Ph.EtAc, and Ph.Cr exhibited highest activity with IC50 of 28.65, 19.21, 88.75, and 461.53 μg/ml, respectively. In anti-tumor assay, Ph.Sp, Ph.Chf, Ph.EtAc, and Ph.Cr were most potent with IC50 of 18.39, 73.81, 217.19, and 342.53 μg/ml, respectively. In MTT cells viability assay, Ph.Chf, Ph.EtAc, Ph.Sp were most active causing 79.00, 72.50, and 71.50% cytotoxicity, respectively, at 1000 μg/ml with the LD50 of 140, 160, and 175 μg/ml, respectively. In overall study, Ph.Chf and Ph.Sp have shown overwhelming results which signifies their potentials as sources of therapeutic agents against cancer.

  2. Molecularly Characterized Solvent Extracts and Saponins from Polygonum hydropiper L. Show High Anti-Angiogenic, Anti-Tumor, Brine Shrimp, and Fibroblast NIH/3T3 Cell Line Cytotoxicity

    PubMed Central

    Ayaz, Muhammad; Junaid, Muhammad; Ullah, Farhat; Sadiq, Abdul; Subhan, Fazal; Khan, Mir Azam; Ahmad, Waqar; Ali, Gowhar; Imran, Muhammad; Ahmad, Sajjad

    2016-01-01

    Polygonum hydropiper is used as anti-cancer and anti-rheumatic agent in folk medicine. This study was designed to investigate the anti-angiogenic, anti-tumor, and cytotoxic potentials of different solvent extracts and isolated saponins. Samples were analyzed using GC, Gas Chromatography–Mass Spectrometry (GC–MS) to identify major and bioactive compounds. Quantitation of antiangiogenesis for the plant's samples including methanolic extract (Ph.Cr), its subsequent fractions; n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq), saponins (Ph.Sp) were performed using the chick embryo chorioallantoic membrane (CAM) assay. Potato disc anti-tumor assay was performed on Agrobacterium tumefaciens containing tumor inducing plasmid. Cytotoxicity was performed against Artemia salina and mouse embryonic fibroblast NIH/3T3 cell line following contact toxicity and MTT cells viability assays, respectively. The GC–MS analysis of Ph.Cr, Ph.Hex, Ph.Chf, Ph.Bt, and Ph.EtAc identified 126, 124, 153, 131, and 164 compounds, respectively. In anti-angiogenic assay, Ph.Chf, Ph.Sp, Ph.EtAc, and Ph.Cr exhibited highest activity with IC50 of 28.65, 19.21, 88.75, and 461.53 μg/ml, respectively. In anti-tumor assay, Ph.Sp, Ph.Chf, Ph.EtAc, and Ph.Cr were most potent with IC50 of 18.39, 73.81, 217.19, and 342.53 μg/ml, respectively. In MTT cells viability assay, Ph.Chf, Ph.EtAc, Ph.Sp were most active causing 79.00, 72.50, and 71.50% cytotoxicity, respectively, at 1000 μg/ml with the LD50 of 140, 160, and 175 μg/ml, respectively. In overall study, Ph.Chf and Ph.Sp have shown overwhelming results which signifies their potentials as sources of therapeutic agents against cancer. PMID:27065865

  3. Combination of sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy.

    PubMed

    Jaini, Ritika; Rayman, Patricia; Cohen, Peter A; Finke, James H; Tuohy, Vincent K

    2014-04-01

    Sunitinib, a protein tyrosine kinase inhibitor is the frontline therapy for renal and gastrointestinal cancers. We hypothesized that by virtue of its well documented tumor apoptosis and immune adjuvant properties, combination of Sunitinib with anti-tumor immunotherapeutics will provide synergistic inhibition of tumor growth. Our study was designed to evaluate the impact of Sunitinib on immunotherapy mediated anti-tumor immune responses and evaluate its efficacy as a combinatorial therapy with tumor targeted immunotherapeutic vaccination. Mice immunized with recombinant α-lactalbumin, a lactation protein expressed on majority of breast tumors were treated with 1 mg of Sunitinib for seven consecutive days beginning (1) concurrently, on the day of α-lactalbumin immunization or (2) sequentially, on day 9 after immunization. Ten-day lymph nodes or 21 day spleens were tested by ELISPOT assays and flow cytometry to evaluate responsiveness to α-lactalbumin immunization in presence of Sunitinib and distribution of cells involved in T cell antigen priming and proliferation in different lymphoid compartments. In addition, therapeutic efficacy of the α-lactalbumin/ Sunitinib combination was evaluated by monitoring tumor growth in the 4T1 transplanted tumor model. Our studies reveal that concurrent administration of Sunitinib with active vaccination against a targeted tumor antigen inhibits priming to the immunogen due to a drastic decrease in CD11b+CD11c+ antigen presenting cells, leading to failure of vaccination. However, sequential delivery of Sunitinib timed to avoid the priming phase of vaccination results in the desired vaccination mediated boost in immune responses.

  4. Localized expression of GITR-L in the tumor microenvironment promotes CD8+ T cell dependent anti-tumor immunity

    PubMed Central

    Cho, John S.; Hsu, Jeffrey V.; Morrison, Sherie L.

    2009-01-01

    The systemic administration of an agonist antibody against glucocorticoid-induced tumor necrosis factor receptor related (GITR) protein has been shown to be effective in overcoming immune tolerance and promoting tumor rejection in a variety of murine tumor models. However, little is known regarding the functional consequence of ligation of GITR with its natural ligand (GITR-L) in the context of regulatory T cell (Treg) suppression in vivo. To determine the mechanism of GITR-L action in vivo, we generated a panel of tumor cell clones that express varying levels of GITR-L. The ectopic expression of GITR-L on the tumor cell surface was sufficient to enhance anti-tumor immunity and delay tumor growth in syngeneic BALB/c mice. Within the range examined, the extent of anti-tumor activity in vivo did not correlate with the level of GITR-L expression, as all clones tested exhibited a similar delay in tumor growth. The localized expression of GITR-L on the tumor cells led to a significant increase in CD8+ T cell infiltration into the tumor compared to control tumors. The increased proportion of CD8+ T cells was only observed locally at the tumor site and was not seen in the tumor draining lymph node. Depletion studies showed that CD8+ T cells, but not CD4+ T cells, were required for GITR-L mediated protection against tumor growth. These studies demonstrate that signaling between GITR-L and GITR in the tumor microenvironment promotes the infiltration of CD8+ T cells, which are essential for controlling tumor growth. PMID:19018533

  5. The dual role of complement in cancer and its implication in anti-tumor therapy

    PubMed Central

    2016-01-01

    Chronic inflammation has been linked to the initiation of carcinogenesis, as well as the advancement of established tumors. The polarization of the tumor inflammatory microenvironment can contribute to either the control, or the progression of the disease. The emerging participation of members of the complement cascade in several hallmarks of cancer, renders it a potential target for anti-tumor treatment. Moreover, the presence of complement regulatory proteins (CRPs) in most types of tumor cells is known to impede anti-tumor therapies. This review focuses on our current knowledge of complement’s potential involvement in shaping the inflammatory tumor microenvironment and its role on the regulation of angiogenesis and hypoxia. Furthermore, we discuss approaches using complement-based therapies as an adjuvant in tumor immunotherapy. PMID:27563652

  6. Green synthesis and characterization of gold nanoparticles using extract of anti-tumor potent Crocus sativus

    NASA Astrophysics Data System (ADS)

    Vijayakumar, R.; Devi, V.; Adavallan, K.; Saranya, D.

    2011-12-01

    In the present study, we have explored anti-tumor potent Crocus sativus (saffron) as a reducing agent for one pot size controlled green synthesis of gold nanoparticles (AuNps) at ambient conditions. The nanoparticles were characterized using UV-vis, scanning electron microscope (SEM), high resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD) and FTIR analysis. The prepared AuNPs showed surface Plasmon resonance centered at 549 nm with average particle size of 15±5 nm. Stable, spherical and triangular crystalline AuNPs with well-defined dimensions were synthesized using anti-tumor potent Crocus sativus (saffron). Crystalline nature of the nanoparticles is confirmed from the HR-TEM, SAED and SEM images, and XRD patterns. From the FTIR spectra it is found that the biomolecules are responsible for capping in gold nanoparticles.

  7. Gemella morbillorum Bacteremia after Anti-Tumor Necrosis Factor Alpha as Acne Inversa Therapy

    PubMed Central

    Vossen, Matthias G.; Gattringer, Klaus B.; Khalifeh, Neda; Koreny, Maria; Spertini, Verena; Mallouhi, Ammar; Willeit, Markus; Volc-Platzer, Beatrix; Asboth, Friederike; Graninger, Wolfgang; Thalhammer, Florian

    2012-01-01

    We present a case of fever, brain abscesses, and Gemella morbillorum bacteremia after anti-tumor necrosis factor alpha (TNF-α) therapy in a 21-year-old acne inversa patient currently taking long-term dapsone. To the best of our knowledge, this is the first report describing such a case. During antimicrobial therapy, the patient developed systemic varicella infection with severe thrombocytopenia. PMID:22189120

  8. BPIC: A novel anti-tumor lead capable of inhibiting inflammation and scavenging free radicals.

    PubMed

    Li, Shan; Wang, Yuji; Zhao, Ming; Wu, Jianhui; Peng, Shiqi

    2015-03-01

    Inflammation has a critical role in the tumor progression, free radical damage can worse the status of patients in cancer condition. The anti-cancer agents capable of inhibiting inflammation and scavenging free radicals attract a lot of our interest. Aimed at the discovery of such anti-tumor agent, a novel intercalator, benzyl 1-[4-hydroxy-3-(methoxycarbonyl)-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate (BPIC) was presented. The docking investigation of BPIC and doxorubicin towards the DNA (PDB ID: 1NAB) gave equal score and similar feature. The anti-proliferation assay of 8 cancer cells identified S180 cells had equal sensitivity to BPIC and doxorubicin. The anti-tumor assay defined the efficacy of BPIC been 2 folds higher than that of doxorubicin. At 1μmol/kg of dose BPIC effectively inhibited xylene-induced ear edema and decreased the plasma TNF-α and IL-8 of the mice. BPIC scavenged ∙OH, ∙O2(-) and NO free radicals in a concentration dependent manner and NO free radicals had the highest sensitivity. BPIC could be a novel anti-tumor lead capable of simultaneously inhibiting inflammation and scavenging free radicals.

  9. Anti-Tumor Effects From Dendritic Cell-Based Cancer Immunotherapy Using Liposomal Bubbles and Ultrasound

    NASA Astrophysics Data System (ADS)

    Oda, Yusuke; Suzuki, Ryo; Hirata, Keiichi; Nomura, Tetsuya; Utoguchi, Naoki; Maruyama, Kazuo

    2011-09-01

    Dendritic cell (DC)-based cancer immunotherapy has the potential to be a minimally invasive therapy that could prevent cancer metastasis and recurrence. Recently, in order to induce effective anti-tumor immunity, we developed a novel antigen delivery system for DCs by the combination of ultrasound (US) and liposomal bubbles (Bubble Liposomes: BLs) with entrapped perfluoropropane gas. In this study, we investigated the induction of antigen specific immune responses in vivo and the anti-tumor effect caused by immunization of DCs treated with BLs and US. For the immunization of DCs which had delivered antigen, using BLs and US, the mice induced antigen specific cytotoxic T lymphocytes (CTLs) were found to be the main effector cells in DC-based cancer immunotherapy. In addition, immunization with DCs that had been pulsed with antigen using BLs and US completely suppressed tumor growth Therefore, immunization of DCs with this antigen delivery system has promise for the efficient induction of anti-tumor immune responses.

  10. Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model.

    PubMed

    Kuryk, Lukasz; Haavisto, Elina; Garofalo, Mariangela; Capasso, Cristian; Hirvinen, Mari; Pesonen, Sari; Ranki, Tuuli; Vassilev, Lotta; Cerullo, Vincenzo

    2016-10-15

    Malignant mesothelioma (MM) is a rare cancer type caused mainly by asbestos exposure. The median overall survival time of a mesothelioma cancer patient is less than 1-year from diagnosis. Currently there are no curative treatment modalities for malignant mesothelioma, however treatments such as surgery, chemotherapy and radiotherapy can help to improve patient prognosis and increase life expectancy. Pemetrexed-Cisplatin is the only standard of care (SoC) chemotherapy for malignant mesothelioma, but the median PFS/OS (progression-free survival/overall survival) from the initiation of treatment is only up to 12 months. Therefore, new treatment strategies against malignant mesothelioma are in high demand. ONCOS-102 is a dual targeting, chimeric oncolytic adenovirus, coding for human GM-CSF. The safety and immune activating properties of ONCOS-102 have already been assessed in phase 1 study (NCT01598129). In this preclinical study, we evaluated the antineoplastic activity of combination treatment with SoC chemotherapy (Pemetrexed, Cisplatin, Carboplatin) and ONCOS-102 in xenograft BALB/c model of human malignant mesothelioma. We demonstrated that ONCOS-102 is able to induce immunogenic cell death of human mesothelioma cell lines in vitro and showed anti-tumor activity in the treatment of refractory H226 malignant pleural mesothelioma (MPM) xenograft model. While chemotherapy alone showed no anti-tumor activity in the mesothelioma mouse model, ONCOS-102 was able to slow down tumor growth. Interestingly, a synergistic anti-tumor effect was seen when ONCOS-102 was combined with chemotherapy regimens. These findings give a rationale for the clinical testing of ONCOS-102 in combination with first-line chemotherapy in patients suffering from malignant mesothelioma. PMID:27287512

  11. Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers.

    PubMed

    Krzywinska, Ewelina; Allende-Vega, Nerea; Cornillon, Amelie; Vo, Dang-Nghiem; Cayrefourcq, Laure; Panabieres, Catherine; Vilches, Carlos; Déchanet-Merville, Julie; Hicheri, Yosr; Rossi, Jean-François; Cartron, Guillaume; Villalba, Martin

    2015-10-01

    Natural killer (NK) cells, a cytotoxic lymphocyte lineage, are able to kill tumor cells in vitro and in mouse models. However, whether these cells display an anti-tumor activity in cancer patients has not been demonstrated. Here we have addressed this issue in patients with several hematological cancers. We found a population of highly activated CD56(dim)CD16(+) NK cells that have recently degranulated, evidence of killing activity, and it is absent in healthy donors. A high percentage of these cells expressed natural killer cell p46-related protein (NKp46), natural-killer group 2, member D (NKG2D) and killer inhibitory receptors (KIRs) and a low percentage expressed NKG2A and CD94. They are also characterized by a high metabolic activity and active proliferation. Notably, we found that activated NK cells from hematological cancer patients have non-NK tumor cell antigens on their surface, evidence of trogocytosis during tumor cell killing. Finally, we found that these activated NK cells are distinguished by their CD45RA(+)RO(+) phenotype, as opposed to non-activated cells in patients or in healthy donors displaying a CD45RA(+)RO(-) phenotype similar to naïve T cells. In summary, we show that CD45RA(+)RO(+) cells, which resemble a unique NK population, have recognized tumor cells and degranulate in patients with hematological neoplasias.

  12. Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers

    PubMed Central

    Krzywinska, Ewelina; Allende-Vega, Nerea; Cornillon, Amelie; Vo, Dang-Nghiem; Cayrefourcq, Laure; Panabieres, Catherine; Vilches, Carlos; Déchanet-Merville, Julie; Hicheri, Yosr; Rossi, Jean-François; Cartron, Guillaume; Villalba, Martin

    2015-01-01

    Natural killer (NK) cells, a cytotoxic lymphocyte lineage, are able to kill tumor cells in vitro and in mouse models. However, whether these cells display an anti-tumor activity in cancer patients has not been demonstrated. Here we have addressed this issue in patients with several hematological cancers. We found a population of highly activated CD56dimCD16+ NK cells that have recently degranulated, evidence of killing activity, and it is absent in healthy donors. A high percentage of these cells expressed natural killer cell p46-related protein (NKp46), natural-killer group 2, member D (NKG2D) and killer inhibitory receptors (KIRs) and a low percentage expressed NKG2A and CD94. They are also characterized by a high metabolic activity and active proliferation. Notably, we found that activated NK cells from hematological cancer patients have non-NK tumor cell antigens on their surface, evidence of trogocytosis during tumor cell killing. Finally, we found that these activated NK cells are distinguished by their CD45RA+RO+ phenotype, as opposed to non-activated cells in patients or in healthy donors displaying a CD45RA+RO− phenotype similar to naïve T cells. In summary, we show that CD45RA+RO+ cells, which resemble a unique NK population, have recognized tumor cells and degranulate in patients with hematological neoplasias. PMID:26629531

  13. Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: novel anti-tumor mechanisms of Cannabidiol in breast cancer.

    PubMed

    Elbaz, Mohamad; Nasser, Mohd W; Ravi, Janani; Wani, Nissar A; Ahirwar, Dinesh K; Zhao, Helong; Oghumu, Steve; Satoskar, Abhay R; Shilo, Konstantin; Carson, William E; Ganju, Ramesh K

    2015-04-01

    The anti-tumor role and mechanisms of Cannabidiol (CBD), a non-psychotropic cannabinoid compound, are not well studied especially in triple-negative breast cancer (TNBC). In the present study, we analyzed CBD's anti-tumorigenic activity against highly aggressive breast cancer cell lines including TNBC subtype. We show here -for the first time-that CBD significantly inhibits epidermal growth factor (EGF)-induced proliferation and chemotaxis of breast cancer cells. Further studies revealed that CBD inhibits EGF-induced activation of EGFR, ERK, AKT and NF-kB signaling pathways as well as MMP2 and MMP9 secretion. In addition, we demonstrated that CBD inhibits tumor growth and metastasis in different mouse model systems. Analysis of molecular mechanisms revealed that CBD significantly inhibits the recruitment of tumor-associated macrophages in primary tumor stroma and secondary lung metastases. Similarly, our in vitro studies showed a significant reduction in the number of migrated RAW 264.7 cells towards the conditioned medium of CBD-treated cancer cells. The conditioned medium of CBD-treated cancer cells also showed lower levels of GM-CSF and CCL3 cytokines which are important for macrophage recruitment and activation. In summary, our study shows -for the first time-that CBD inhibits breast cancer growth and metastasis through novel mechanisms by inhibiting EGF/EGFR signaling and modulating the tumor microenvironment. These results also indicate that CBD can be used as a novel therapeutic option to inhibit growth and metastasis of highly aggressive breast cancer subtypes including TNBC, which currently have limited therapeutic options and are associated with poor prognosis and low survival rates.

  14. Electrotransfer of Plasmid DNA Encoding an Anti-Mouse Endoglin (CD105) shRNA to B16 Melanoma Tumors with Low and High Metastatic Potential Results in Pronounced Anti-Tumor Effects

    PubMed Central

    Dolinsek, Tanja; Sersa, Gregor; Prosen, Lara; Bosnjak, Masa; Stimac, Monika; Razborsek, Urska; Cemazar, Maja

    2015-01-01

    Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing by electrotransfer of plasmid DNA encoding short hairpin RNA against endoglin in two murine B16 melanoma variants with different metastatic potential on cells, spheroids and subcutaneous tumors in mice. The results demonstrate that endoglin silencing with gene electrotransfer reduces the proliferation, survival and migration of melanoma cells and also has anti-tumor effectiveness, as the therapy resulted in a high percentage of tumor cures (23% and 58% on B16F1 and B16F10 tumors, respectively). The effectiveness of the therapy correlated with endoglin expression in melanoma cells; in vitro the effects were more pronounced in B16F1 cells, which express more endoglin than B16F10. However, the opposite was observed in vivo in tumors, where there was a higher expression of endoglin and better anti-tumor effectiveness in the B16F10 tumor. In conclusion, targeting endoglin for the treatment of melanoma seems to be a concept worthy of further exploration due to the increased therapeutic effect of the therapy based on simultaneous vascular targeting and its direct effect on tumor cells. PMID:26712792

  15. Bortezomib enhances expression of effector molecules in anti-tumor CD8+ T lymphocytes by promoting Notch-nuclear factor-κB crosstalk

    PubMed Central

    Thounaojam, Menaka C.; Dudimah, Duafalia F.; Pellom, Samuel T.; Uzhachenko, Roman V.; Carbone, David P.; Dikov, Mikhail M.; Shanker, Anil

    2015-01-01

    The immunosuppressive tumor microenvironment usurps host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various metazoan cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with the proteasome inhibitor bortezomib in mice bearing various solid tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues, thereby increasing CD8+T-lymphocyte IFNγ secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Bortezomib also neutralized TGFβ-mediated suppression of IFNγ and granzyme B expression in activated CD8+T-cells. Of note, bortezomib reversed tumor-induced downregulation of Notch receptors, Notch1 and Notch2, as well as increased the levels of cleaved Notch intracellular domain (NICD) and downstream targets Hes1 and Hey1 in tumor-draining CD8+T-cells. Moreover, bortezomib promoted CD8+T-cell nuclear factor-κB (NFκB) activity by increasing the total and phosphorylated levels of the IκB kinase and IκBα as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NFκB activity by Bay-11-7082, or NICD cleavage by γ-secretase inhibitor, bortezomib significantly increased expression of Notch Hes1 and Hey1 genes as well as perforin, granzyme B and eomesodermin in activated CD8+T-cells. Data suggest that bortezomib can rescue tumor-induced dysfunction of CD8+T-cells by its intrinsic stimulatory effects promoting NICD-NFκB crosstalk. These findings provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death but also to provide lymphocyte-stimulatory effects, thereby overcoming immunosuppressive actions of tumor on anti-tumor T-cell functions. PMID:26431276

  16. Bortezomib enhances expression of effector molecules in anti-tumor CD8+ T lymphocytes by promoting Notch-nuclear factor-κB crosstalk.

    PubMed

    Thounaojam, Menaka C; Dudimah, Duafalia F; Pellom, Samuel T; Uzhachenko, Roman V; Carbone, David P; Dikov, Mikhail M; Shanker, Anil

    2015-10-20

    The immunosuppressive tumor microenvironment usurps host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various metazoan cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with the proteasome inhibitor bortezomib in mice bearing various solid tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues, thereby increasing CD8+T-lymphocyte IFNγ secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Bortezomib also neutralized TGFβ-mediated suppression of IFNγ and granzyme B expression in activated CD8+T-cells. Of note, bortezomib reversed tumor-induced downregulation of Notch receptors, Notch1 and Notch2, as well as increased the levels of cleaved Notch intracellular domain (NICD) and downstream targets Hes1 and Hey1 in tumor-draining CD8+T-cells. Moreover, bortezomib promoted CD8+T-cell nuclear factor-κB (NFκB) activity by increasing the total and phosphorylated levels of the IκB kinase and IκBα as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NFκB activity by Bay-11-7082, or NICD cleavage by γ-secretase inhibitor, bortezomib significantly increased expression of Notch Hes1 and Hey1 genes as well as perforin, granzyme B and eomesodermin in activated CD8+T-cells. Data suggest that bortezomib can rescue tumor-induced dysfunction of CD8+T-cells by its intrinsic stimulatory effects promoting NICD-NFκB crosstalk. These findings provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death but also to provide lymphocyte-stimulatory effects, thereby overcoming immunosuppressive actions of tumor on anti-tumor T-cell functions.

  17. Everglades National Park Including Biscayne National Park. Activity Book.

    ERIC Educational Resources Information Center

    Ruehrwein, Dick

    Intended to help elementary school children learn about the resources of the Everglades and Biscayne National Parks, this activity book includes information, puzzles, games, and quizzes. The booklet deals with concepts related to: (1) the seasons; (2) fire ecology; (3) water; (4) fish; (5) mammals; (6) mosquitos; (7) birds; (8) venomous snakes;…

  18. Efficient Double Suzuki Cross-Coupling Reactions of 2,5-Dibromo-3-hexylthiophene: Anti-Tumor, Haemolytic, Anti-Thrombolytic and Biofilm Inhibition Studies.

    PubMed

    Ikram, Hafiz Mansoor; Rasool, Nasir; Zubair, Muhammad; Khan, Khalid Mohammed; Abbas Chotana, Ghayoor; Akhtar, Muhammad Nadeem; Abu, Nadiah; Alitheen, Noorjahan Banu; Elgorban, Abdallah Mohamed; Rana, Usman Ali

    2016-01-01

    The present study describes several novel 2,5-biaryl-3-hexylthiophene derivatives (3a-i) synthesized via a Pd(0)-catalyzed Suzuki cross-coupling reaction in moderate to good yields. The novel compounds were also analyzed for their anti-thrombolytic, haemolytic, and biofilm inhibition activities. In addition, the anti-tumor activity was also evaluated in vitro for newly-synthesized compounds, where 3-hexyl-2,5-bis(4-(methylthio)phenyl)thiophene exhibited the best anti-tumor activity against 4T1 cells with IC50 value of 16 μM. Moreover, 2,5-bis(4-methylphenyl)-3-hexylthiophene showed the highest activity against MCF-7 cells with an IC50 value of 26.2 μM. On the other hand, the compound 2,5-bis(4-chloropheny)-3-hexylthiophene exhibited excellent biofilm inhibition activity. Furthermore, the compound 2,5-bis(3-chloro-4-fluorophenyl)-3-hexylthiophene also exhibited better anti-thrombolytic and hemolytic activity results as compared to the other newly-synthesized compounds. PMID:27472312

  19. Rheumatoid arthritis patients fulfilling Korean National Health Insurance reimbursement guidelines for anti-tumor necrosis factor-α treatment and comparison to other guidelines.

    PubMed

    Hur, Jin-Wuk; Choe, Jung-Yoon; Kim, Dong-Wook; Kim, Hyun Ah; Kim, Sang-Hyon; Kim, Wan-Uk; Kim, Yun Sung; Lee, Hye-Soon; Lee, Sang-Heon; Park, Sung-Hwan; Park, Won; Park, Yong-Beom; Suh, Chang-Hee; Shim, Seung-Cheol; Song, Yeong-Wook; Yoon, Bo Young; Yu, Dae Young; Yoo, Dae Hyun

    2015-11-01

    The aim of this study was to compare anti-tumor necrosis factor-α (TNFα) treatment status in rheumatoid arthritis (RA) patients with the Korean National Health Insurance (KNHI) reimbursement eligibility criteria and with American College of Rheumatology (ACR) recommendations, Japan College of Rheumatology (JCR) guidelines and British Society for Rheumatology (BSR) guidelines. Between December 2011 and August 2012, outpatients from 17 South Korean general hospitals diagnosed with RA according to the 1987 ACR criteria were enrolled into a noninterventional, cross-sectional, observational study. Of 1700 patients (1414 female (83.2 %), mean age of 56.6 ± 12.0, mean disease duration 97.9 ± 91.8 months), 306 (18.0 %) had used anti-TNFα agents, and 224 (13.2 %) were currently using an anti-TNFα agent. Of 1394 anti-TNFα-naive patients, 32 (2.3 %) met KNHI reimbursement guidelines, 148 (10.6 %) met ACR recommendations, and 127 (9.1 %) and 126 (9.0 %) were considered eligible for anti-TNFα agents according to JCR and BSR guidelines, respectively. The main discrepancy was the higher active joint count required by the KNHI eligibility criteria. In the opinion of treating rheumatologists, the KNHI reimbursement criteria ineligibility accounted for 15.3 % (n = 213) of the reasons for not initiating anti-TNFα agents in anti-TNFα-naive group. The anti-TNFα user group showed significantly higher disease activity than the anti-TNFα-naive group based on DAS28 score. In comparison with the ACR recommendations and JCR and BSR guidelines, fewer patients met KNHI reimbursement eligibility criteria for anti-TNFα agents. The current amendment of the KNHI criteria based on DAS28 score will improve an access to biologic agents including anti-TNFα treatment for South Korean patients with active RA.

  20. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.

    PubMed

    Dumble, Melissa; Crouthamel, Ming-Chih; Zhang, Shu-Yun; Schaber, Michael; Levy, Dana; Robell, Kimberly; Liu, Qi; Figueroa, David J; Minthorn, Elisabeth A; Seefeld, Mark A; Rouse, Meagan B; Rabindran, Sridhar K; Heerding, Dirk A; Kumar, Rakesh

    2014-01-01

    Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.

  1. High intensity focused ultrasound enhances anti-tumor immunity by inhibiting the negative regulatory effect of miR-134 on CD86 in a murine melanoma model

    PubMed Central

    Yang, Min; Zha, He; Sun, Hui; Li, Xue-Ru; Li, Ai-Fang; Gu, Yue; Duan, Liang; Luo, Jin-Yong; Li, Chong-Yan; Wang, Yan; Wang, Zhi-Biao; He, Tong-Chuan; Zhou, Lan

    2015-01-01

    HIFU has been demonstrated to enhance anti-tumor immunity, however, the mechanism of which has not been well elucidated. Emerging evidence indicates that miRNAs play important roles in immune response. In this study, we used the B16F10 melanoma allograft mouse model to investigate the role of miRNAs in HIFU-enhanced anti-tumor immunity. We found that HIFU treatment decreased circulating B16F10 cells and pulmonary metastasis nodules while increased IFN-γ and TNF-α in the peripheral blood and cumulative mouse survival, which was associated with inhibition of miR-134 expression and activation of CD86 expression in tumor tissues. Further, we determined that miR-134 directly binds to the 3′UTR of CD86 mRNA to suppress its expression in B16F10 cells. When B16F10 cells transfected with miR-134 were co-cultured with normal splenic lymphocytes, the secretion of IFN-γ and TNF-α from lymphocytes was reduced and B16F10 cell survival was increased. HIFU exposure efficiently decreased miR-134 while increased CD86 expression in B16F10 cells in vitro. CD86 knockdown with siRNA markedly rescued the viability of HIFU-treated B16F10 cells that co-cultured with lymphocytes. Altogether, our results suggest that HIFU down-regulates miR-134 to release the inhibition of miR-134 on CD86 in melanoma cells, thereby enhancing anti-tumor immune response. PMID:26485753

  2. Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles.

    PubMed

    Wang, Hai; Zhao, Ying; Wu, Yan; Hu, Yu-lin; Nan, Kaihui; Nie, Guangjun; Chen, Hao

    2011-11-01

    The use of single chemotherapeutic drug has shown some limitations in anti-tumor treatment, such as development of drug resistance, high toxicity and limited regime of clinical uses. The combination of two or more therapeutic drugs is feasible means to overcome the limitations. Co-delivery strategy has been proposed to minimize the amount of each drug and to achieve the synergistic effect for cancer therapies. Attempts have been made to deliver chemotherapeutic drugs simultaneously using drug carriers, such as micelles, liposomes, and inorganic nanoparticles (NPs). Here we reported core-shell NPs that were doubly emulsified from an amphiphilic copolymer methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA). These NPs offered advantages over other nanocarriers, as they were easy to fabricate by improved double emulsion method, biocompatible, and showed high loading efficacy. More importantly, these NPs could co-deliver hydrophilic doxorubicin (DOX) and hydrophobic paclitaxel (TAX). The drug-loaded NPs possessed a better polydispersity, indicating that they are more readily subject to controlled size distribution. Studies on drug release and cellular uptake of the co-delivery system demonstrated that both drugs were effectively taken up by the cells and released simultaneously. Furthermore, the co-delivery nanocarrier suppressed tumor cells growth more efficiently than the delivery of either DOX or TAX at the same concentrations, indicating a synergistic effect. Moreover, the NPs loading drugs with a DOX/TAX concentration ratio of 2:1 showed the highest anti-tumor activity to three different types of tumor cells. This nanocarrier might have important potential in clinical implications for co-delivery of multiple anti-tumor drugs with different properties. PMID:21807411

  3. Synthesis and biological evaluation of 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives as hypoxic selective anti-tumor agents.

    PubMed

    Hu, Yunzhen; Xia, Qing; Shangguan, Shihao; Liu, Xiaowen; Hu, Yongzhou; Sheng, Rong

    2012-08-13

    A series of 3-aryl-2-quinoxaline-carbonitrile 1,4-di-N-oxide derivatives were designed, synthesized and evaluated for hypoxic and normoxic cytotoxic activity against human SMMC-7721, K562, KB, A549 and PC-3 cell lines. Many of these new compounds displayed more potent hypoxic cytotoxic activity compared with TX-402 and TPZ in the tumor cells based evaluation, which confirmed our hypothesis that the replacement of the 3-amine with the substituted aryl ring of TX-402 increases the hypoxic anti-tumor activity. The preliminary SAR revealed that 3-chloro was a favorable substituent in the phenyl ring for hypoxic cytotoxicity and 7-methyl or 7-methoxy substituted derivatives exhibited better hypoxic selectivity against most of the tested cell lines. The most potent compound, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (9h) was selected for further anti-tumor evaluation and mechanistic study. It also exhibited significant cytotoxic activity against BEL-7402, HepG2, HL-60, NCI-H460, HCT-116 and CHP126 cell lines in hypoxia with IC₅₀ values ranging from 0.31 to 3.16 μM, and preliminary mechanism study revealed that 9h induced apoptosis in a caspase-dependent pathway.

  4. Anti-tumor effect of bevacizumab on a xenograft model of feline mammary carcinoma

    PubMed Central

    MICHISHITA, Masaki; OHTSUKA, Aya; NAKAHIRA, Rei; TAJIMA, Tsuyoshi; NAKAGAWA, Takayuki; SASAKI, Nobuo; ARAI, Toshiro; TAKAHASHI, Kimimasa

    2015-01-01

    Feline mammary carcinomas are characterized by rapid progression and metastases. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, proliferation and metastasis. The present study aimed to investigate the effects of a single drug therapy of bevacizumab on a xenograft model of feline mammary carcinoma expressing VEGF protein. Bevacizumab treatment suppressed tumor growth by inhibiting angiogenesis and enhancing apoptosis; however, it did not affect the tumor proliferation index. Thus, bevacizumab had anti-tumor effects on a xenograft model, and this may be useful for the treatment of feline mammary carcinoma. PMID:26616000

  5. Tumor-associated macrophages and anti-tumor therapies: complex links.

    PubMed

    Belgiovine, Cristina; D'Incalci, Maurizio; Allavena, Paola; Frapolli, Roberta

    2016-07-01

    Myeloid cells infiltrating the tumor microenvironment, especially tumor-associated macrophages (TAMs), are essential providers of cancer-related inflammation, a condition known to accelerate tumor progression and limit the response to anti-tumor therapies. As a matter of fact, TAMs may have a dual role while interfering with cancer treatments, as they can either promote or impair their functionality. Here we review the connection between macrophages and anticancer therapies; moreover, we provide an overview of the different strategies to target or re-program TAMs for therapeutic purposes. PMID:26956893

  6. Mechanical Disruption of Tumors by Iron Particles and Magnetic Field Application Results in Increased Anti-Tumor Immune Responses

    PubMed Central

    Bouchlaka, Myriam N.; Sckisel, Gail D.; Wilkins, Danice; Maverakis, Emanual; Monjazeb, Arta M.; Fung, Maxwell; Welniak, Lisbeth; Redelman, Doug; Fuchs, Alan; Evrensel, Cahit A.; Murphy, William J.

    2012-01-01

    The primary tumor represents a potential source of antigens for priming immune responses for disseminated disease. Current means of debulking tumors involves the use of cytoreductive conditioning that impairs immune cells or removal by surgery. We hypothesized that activation of the immune system could occur through the localized release of tumor antigens and induction of tumor death due to physical disruption of tumor architecture and destruction of the primary tumor in situ. This was accomplished by intratumor injection of magneto-rheological fluid (MRF) consisting of iron microparticles, in Balb/c mice bearing orthotopic 4T1 breast cancer, followed by local application of a magnetic field resulting in immediate coalescence of the particles, tumor cell death, slower growth of primary tumors as well as decreased tumor progression in distant sites and metastatic spread. This treatment was associated with increased activation of DCs in the draining lymph nodes and recruitment of both DCs and CD8(+)T cells to the tumor. The particles remained within the tumor and no toxicities were observed. The immune induction observed was significantly greater compared to cryoablation. Further anti-tumor effects were observed when MRF/magnet therapy was combined with systemic low dose immunotherapy. Thus, mechanical disruption of the primary tumor with MRF/magnetic field application represents a novel means to induce systemic immune activation in cancer. PMID:23133545

  7. Up-Regulation of GITRL on Dendritic Cells by WGP Improves Anti-Tumor Immunity in Murine Lewis Lung Carcinoma

    PubMed Central

    Tian, Jie; Ma, Jie; Ma, Ke; Ma, Bin; Tang, Xinyi; Baidoo, Samuel Essien; Tong, Jia; Yan, Jun; Lu, Liwei; Xu, Huaxi; Wang, Shengjun

    2012-01-01

    Background β-Glucans have been shown to function as a potent immunomodulator to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Glucocorticoid-induced TNF receptor ligand (GITRL), a member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells, generates a positive co-stimulatory signal implicated in a wide range of T cell functions, which is important for the development of immune responses. Methodology/Principal Findings In this study, we found that whole β-glucan particles (WGPs) could activate dendritic cells (DCs) via dectin-1 receptor, and increase the expression of GITRL on DCs in vitro and in vivo. Furthermore, we demonstrated that the increased GITRL on DCs could impair the regulartory T cell (Treg)-mediated suppression and enhance effector T cell proliferation in a GITR/GITRL dependent way. In tumor models, DCs with high levels of GITRL were of great potential to prime cytotoxic T lymphocyte (CTL) responses and down-regulate the suppressive activity of Treg cells, thereby leading to the delayed tumor progression. Conclusions/Significance These findings suggest that particulate β-glucans can be used as an immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate suppressive immune activity via GITR/GITRL interaction, leading to a more efficient defense mechanism against tumor development. PMID:23077535

  8. Encapsulated paclitaxel nanoparticles exhibit enhanced anti-tumor efficacy in A549 non-small lung cancer cells.

    PubMed

    Huang, Guojin; Zang, Bao; Wang, Xiaowei; Liu, Gang; Zhao, Jianqiang

    2015-12-01

    In the present study, paclitaxel (PTX) were encapsulated with polyethylene glycol (PEG)-polylactide (PLA)/D-α tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-PLA/TPGS) and the enhanced anti-tumor activity of this PTX mixed micelles (PTX-MM) was evaluated in lung cancer cells. The PTX-MM prepared by a solvent evaporation method was demonstrated to have high drug-loading efficiency (23.2%), high encapsulation efficiency (76.4%), and small size (59 nm). In vitro release assay showed the slow release behavior of PTX-MM, suggesting the good stability of the PTX-MM essential for long circulation time. In vitro kinetics assay demonstrated that PTX-MM could promote absorption and increase relative bioavailability. The anti-cancer efficiency of PTX-MM was also examined by both in vitro and in vivo studies. PTX-MM exhibits obvious cytotoxicity against lung cancer cells with much lower IC50 value when compared with commercial formulated PTX or PTX + TPGS. The xenograft tumor model studies on nude mice indicated that PTX-MM inhibits tumor growth more effectively than other formulations. It was also found that most of mixed micelles were integral in tumor site to exhibit anti-cancer activity. Our results suggested that the use of PTX-MM as an anti-cancer drug may be an effective approach to treat lung cancer. PMID:26525950

  9. Synthesis and Characterization of Some New Bis-Pyrazolyl-Thiazoles Incorporating the Thiophene Moiety as Potent Anti-Tumor Agents

    PubMed Central

    Gomha, Sobhi M.; Edrees, Mastoura M.; Altalbawy, Farag M. A.

    2016-01-01

    A new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)benzenes 3a–i were synthesized via reaction of 5,5′-(1,4-phenylene)bis(3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide) (1) with hydrazonoyl halides 2a–i. In addition, reaction of 1 with ethyl chloroacetate afforded bis-thiazolone derivative 8 as the end product. Reaction of compound 8 with methyl glyoxalate gave bis-thiazolone derivative 10. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. All the synthesized compounds were evaluated for their anti-tumor activities against hepatocellular carcinoma (HepG2) cell lines, and the results revealed promising activities of compounds 3g, 5e, 3e, 10, 5f, 3i, and 3f with IC50 equal 1.37 ± 0.15, 1.41 ± 0.17, 1.62 ± 0.20, 1.86 ± 0.20, 1.93 ± 0.08, 2.03 ± 0.25, and 2.09 ± 0.19 μM, respectively. PMID:27618013

  10. Synthesis and Characterization of Some New Bis-Pyrazolyl-Thiazoles Incorporating the Thiophene Moiety as Potent Anti-Tumor Agents.

    PubMed

    Gomha, Sobhi M; Edrees, Mastoura M; Altalbawy, Farag M A

    2016-01-01

    A new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)benzenes 3a-i were synthesized via reaction of 5,5'-(1,4-phenylene)bis(3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide) (1) with hydrazonoyl halides 2a-i. In addition, reaction of 1 with ethyl chloroacetate afforded bis-thiazolone derivative 8 as the end product. Reaction of compound 8 with methyl glyoxalate gave bis-thiazolone derivative 10. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. All the synthesized compounds were evaluated for their anti-tumor activities against hepatocellular carcinoma (HepG2) cell lines, and the results revealed promising activities of compounds 3g, 5e, 3e, 10, 5f, 3i, and 3f with IC50 equal 1.37 ± 0.15, 1.41 ± 0.17, 1.62 ± 0.20, 1.86 ± 0.20, 1.93 ± 0.08, 2.03 ± 0.25, and 2.09 ± 0.19 μM, respectively. PMID:27618013

  11. Type I Interferons as Stimulators of DC-Mediated Cross-Priming: Impact on Anti-Tumor Response

    PubMed Central

    Schiavoni, Giovanna; Mattei, Fabrizio; Gabriele, Lucia

    2013-01-01

    Induction of potent tumor-specific cytotoxic T-cell responses is a fundamental objective in anticancer therapeutic strategies. This event requires that antigen-presenting cells present tumor-associated antigens (Ag) on their MHC class-I molecule, in a process termed cross-presentation. Dendritic cells (DC) are particularly keen on this task and can induce the cross-priming of CD8+ T cells, when exposed to danger or inflammatory signals that stimulate their activation. Type I interferons (IFN-I), a family of long-known immunostimulatory cytokines, have been proven to produce optimal activation signal for DC-induced cross-priming. Recent in vitro and in vivo evidences have suggested that IFN-I-stimulated cross-priming by DC against tumor-associated Ag is a key mechanism for cancer immunosurveillance and may be usefully exploited to boost anti-tumor CD8+ T-cell responses. Here, we will review the cross-presentation properties of different DC subsets, with special focus on cell-associated and tumor Ag, and discuss how IFN-I can modify this function, with the aim of identifying more specific and effective strategies for improving anticancer responses. PMID:24400008

  12. Type I Interferons as Stimulators of DC-Mediated Cross-Priming: Impact on Anti-Tumor Response.

    PubMed

    Schiavoni, Giovanna; Mattei, Fabrizio; Gabriele, Lucia

    2013-01-01

    Induction of potent tumor-specific cytotoxic T-cell responses is a fundamental objective in anticancer therapeutic strategies. This event requires that antigen-presenting cells present tumor-associated antigens (Ag) on their MHC class-I molecule, in a process termed cross-presentation. Dendritic cells (DC) are particularly keen on this task and can induce the cross-priming of CD8(+) T cells, when exposed to danger or inflammatory signals that stimulate their activation. Type I interferons (IFN-I), a family of long-known immunostimulatory cytokines, have been proven to produce optimal activation signal for DC-induced cross-priming. Recent in vitro and in vivo evidences have suggested that IFN-I-stimulated cross-priming by DC against tumor-associated Ag is a key mechanism for cancer immunosurveillance and may be usefully exploited to boost anti-tumor CD8(+) T-cell responses. Here, we will review the cross-presentation properties of different DC subsets, with special focus on cell-associated and tumor Ag, and discuss how IFN-I can modify this function, with the aim of identifying more specific and effective strategies for improving anticancer responses. PMID:24400008

  13. [Study of anti-tumor effects of hyperthermia combined with hydralazine on experimental tumor].

    PubMed

    Aoki, Y; Akagi, K; Kitada, N; Tanaka, Y; Fritz-Zieroth, B

    1995-11-01

    We analyzed tumor growth delay in experimental tumors after hyperthermia alone, hydralazine (HDZ) injection alone and the combination of these modalities. We also analyzed the energy parameter (ATP/Pi ratio) obtained by 31P-MRS (magnetic resonance spectroscopy). The purpose of this study was to evaluate the usefulness of 31P-MRS as an index of anti-tumor effect. FM3A tumor cells were transplanted subcutaneously in the hind legs of C3H/He mice. We dipped the tumors into a heated circulating water bath. 31P-MRS was performed with a CSI spectrometer. The anti-tumor effect obtained with HDZ alone was insignificant, but combined treatment with hyperthermia and HDZ had a significant synergistic effect. The ATP/Pi ratios for all groups treated separately with HDZ or hyperthermia were not different from the control, but the ATP/Pi ratio decreased after combined use of these agents. There was a significant correlation between the decrease in ATP/Pi ratio and tumor growth delay. We observed a direct relation between the delay in tumor growth and the decline in ATP/Pi ratio after combined treatment with HDZ and hyperthermia. The ATP/Pi ratio 24 hr after treatment may be useful in predicting the efficacy of the combined use of HDZ and hyperthermia.

  14. Microencapsulation of anti-tumor, antibiotic and thrombolytic drugs in microgravity

    NASA Technical Reports Server (NTRS)

    Morrison, Dennis R.; Mosier, Benjamin; Cassanto, John

    1994-01-01

    Encapsulation of cytotoxic or labile drugs enables targeted delivery and sustained release kinetics that are not available with intravenous injection. A new liquid-liquid diffusion process has been developed for forming unique microcapsules that contain both aqueous and hydrocarbon soluble drugs. Microgravity experiments, on sounding rockets (1989-92) and Shuttle missions STS-52 (1992) and STS-56 (1993) using an automated Materials Dispersion Apparatus, produced multi-lamellar microcapsules containing both Cis-platinum (anti-tumor drug) and iodinated poppy seed oil (a radiocontrast medium), surrounded by a polyglyceride skin. Microcapsules formed with amoxicillin (antibiotic) or urokinase (a clot dissolving enzyme), co-encapsulated with IPO, are still intact after two years. Microcapsules were formed with the drug so concentrated that crystals formed inside. Multi-layered microspheres, with both hydrophobic drug compartments, can enable diffusion of complementary drugs from the same microcapsule, e.g. antibiotics and immuno-stimulants to treat resistant infections or multiple fibrinolytic drugs to dissolve emboli. Co-encapsulation of enough radio-contrast medium enables oncologists to monitor the delivery of anti-tumor microcapsules to target tumors using computerized tomography and radiography that would track the distribution of microcapsules after release from the intra-arterial catheter. These microcapsules could have important applications in chemotheraphy of certain liver, kidney, brain and other tumors.

  15. Lenalidomide Polarizes Th1-specific Anti-tumor Immune Response and Expands XBP1 Antigen-Specific Central Memory CD3+CD8+ T cells against Various Solid Tumors

    PubMed Central

    Bae, Jooeun; Keskin, Derin B; Cowens, Kristen; Lee, Ann-Hwee; Dranoff, Glen; Munshi, Nikhil C; Anderson, Kenneth C

    2016-01-01

    Introduction Effective combination immunotherapeutic strategies may be required to enhance effector cells’ anti-tumor activities and improve clinical outcomes. Methods XBP1 antigen-specific cytotoxic T lymphocytes (XBP1-CTL) generated using immunogenic heteroclitic XBP1 US184-192 (YISPWILAV) and XBP1 SP367-375 (YLFPQLISV) peptides or various solid tumor cells over-expressing XBP1 target antigen were evaluated, either alone or in combination with lenalidomide, for phenotype and immune functional activity. Results Lenalidomide treatment of XBP1-CTL increased the proportion of CD45RO+ memory CD3+CD8+ T cells, but not the total CD3+CD8+ T cells. Lenalidomide upregulated critical T cell activation markers and costimulatory molecules (CD28, CD38, CD40L, CD69, ICOS), especially within the central memory CTL subset of XBP1-CTL, while decreasing TCRαβ and T cell checkpoint blockade (CTLA-4, PD-1). Lenalidomide increased the anti-tumor activities of XBP1-CTL memory subsets, which were associated with expression of Th1 transcriptional regulators (T-bet, Eomes) and Akt activation, thereby resulting in enhanced IFN-γ production, granzyme B upregulation and specific CD28/CD38-positive and CTLA-4/PD-1-negative cell proliferation. Conclusions These studies suggest the potential benefit of lenalidomide treatment to boost anti-tumor activities of XBP1-specific CTL against a variety of solid tumors and enhance response to an XBP1-directing cancer vaccine regime.

  16. An increase of B cells in the tumor-bearing state has the potential to induce anti-tumor immunity.

    PubMed

    Ito, O; Harada, M; Takenoyama, M; Sumichika, H; Matsuzaki, G; Nomoto, K

    1996-01-01

    We investigated the role of an increased amount of B cells in the tumor-bearing state. The proportion of B cells increased concomitantly with tumor development in the regional lymph nodes (LN) of BALB/c mice bearing Meth A fibrosarcoma (Meth A). Tumor development was accompanied by an increased level of IgG antibodies against Meth A. CD4+ T cells of the regional LN in the early tumor-bearing stage produced significant levels of interferon-gamma and interleukin-4 in response to in vitro stimulation with coated anti-CD3 monoclonal antibody, whereas such capacities decreased in the late tumor-bearing stage. In a tumor-neutralizing assay, the growth of Meth A was significantly suppressed by a co-inoculation with splenic B cells from BALB/c mice in the late tumor-bearing state. This suppression of Meth A growth was tumor-specific and was abolished by the in vivo depletion of either CD4+ or CD8+ T cells. These findings thus suggest that tumor development was accompanied by an increase of B cells and tumor-specific IgG production, but such kinetic changes were not the result of a preferential activation of Th2 type CD4+ T cells. Furthermore, our results indicate that the increase of B cells in the tumor-bearing state has the potential to induce anti-tumor-specific T cell immunity.

  17. Triterpenoids Amplify Anti-Tumoral Effects of Mistletoe Extracts on Murine B16.F10 Melanoma In Vivo

    PubMed Central

    Strüh, Christian M.; Jäger, Sebastian; Kersten, Astrid; Schempp, Christoph M.; Scheffler, Armin; Martin, Stefan F.

    2013-01-01

    Purpose Mistletoe extracts are often used in complementary cancer therapy although the efficacy of that therapy is controversially discussed. Approved mistletoe extracts contain mainly water soluble compounds of the mistletoe plant, i.e. mistletoe lectins. However, mistletoe also contains water-insoluble triterpenoids (mainly oleanolic acid) that have anti-tumorigenic effects. To overcome their loss in watery extracts we have solubilized mistletoe triterpenoids with cyclodextrins, thus making them available for in vivo cancer experiments. Experimental design B16.F10 subcutaneous melanoma bearing C57BL/6 mice were treated with new mistletoe extracts containing both water soluble compounds and solubilized triterpenoids. Tumor growth and survival was monitored. In addition, histological examinations of the tumor material and tumor surrounding tissue were performed. Results Addition of solubilized triterpenoids increased the anti-tumor effects of the mistletoe extracts, resulting in reduced tumor growth and prolonged survival of the mice. Histological examination of the treated tumors showed mainly tumor necrosis and some apoptotic cells with active caspase-3 and TUNEL staining. A significant decrease of CD31-positive tumor blood vessels was observed after treatment with solubilized triterpenoids and different mistletoe extracts. Conclusion We conclude that the addition of solubilized mistletoe triterpenoids to conventional mistletoe extracts improves the efficacy of mistletoe treatment and may represent a novel treatment option for malignant melanoma. PMID:23614029

  18. Anti-tumoral effect of the mitochondrial target domain of Noxa delivered by an engineered Salmonella typhimurium.

    PubMed

    Jeong, Jae-Ho; Kim, Kwangsoo; Lim, Daejin; Jeong, Kwangjoon; Hong, Yeongjin; Nguyen, Vu H; Kim, Tae-Hyoung; Ryu, Sangryeol; Lim, Jeong-A; Kim, Jae Il; Kim, Geun-Joong; Kim, Sun Chang; Min, Jung-Joon; Choy, Hyon E

    2014-01-01

    Bacterial cancer therapy relies on the fact that several bacterial species are capable of targeting tumor tissue and that bacteria can be genetically engineered to selectively deliver therapeutic proteins of interest to the targeted tumors. However, the challenge of bacterial cancer therapy is the release of the therapeutic proteins from the bacteria and entry of the proteins into tumor cells. This study employed an attenuated Salmonella typhimurium to selectively deliver the mitochondrial targeting domain of Noxa (MTD) as a potential therapeutic cargo protein, and examined its anti-cancer effect. To release MTD from the bacteria, a novel bacterial lysis system of phage origin was deployed. To facilitate the entry of MTD into the tumor cells, the MTD was fused to DS4.3, a novel cell-penetrating peptide (CPP) derived from a voltage-gated potassium channel (Kv2.1). The gene encoding DS4.3-MTD and the phage lysis genes were placed under the control of PBAD , a promoter activated by L-arabinose. We demonstrated that DS4.3-MTD chimeric molecules expressed by the Salmonellae were anti-tumoral in cultured tumor cells and in mice with CT26 colon carcinoma.

  19. In vivo gold nanoparticle delivery of peptide vaccine induces anti-tumor immune response in prophylactic and therapeutic tumor models

    PubMed Central

    Almeida, Joao Paulo Mattos; Lin, Adam Yuh; Figueroa, Elizabeth Raquel

    2015-01-01

    Gold nanoparticles (AuNPs) are promising vehicles for cancer immunotherapy, with demonstrated efficacy in immune delivery and innate cell stimulation. Nevertheless, their potential has yet to be assessed in the in vivo application of peptide cancer vaccines. In this study, we hypothesized that the immune distribution and adjuvant qualities of AuNPs could be leveraged to facilitate delivery of the ovalbumin (OVA) peptide antigen and the CpG adjuvant and enhance their therapeutic effect in a B16-OVA tumor model. AuNP delivery of OVA (AuNP-OVA) and of CpG (AuNP-CpG) enhanced the efficacy of both agents and induced strong antigen-specific responses. In addition, we found that AuNP-OVA delivery alone, without CpG, was sufficient to promote significant antigen-specific responses, leading to subsequent anti-tumor activity and prolonged survival in both prophylactic and therapeutic in vivo tumor models. This enhanced therapeutic efficacy was likely due to the adjuvant effect of peptide coated AuNPs, as they induced inflammatory cytokine release when cultured with bone marrow dendritic cells. Overall, we demonstrate that AuNP mediated OVA peptide delivery can produce significant therapeutic benefit without the need of adjuvant, indicating that AuNPs are effective peptide vaccine carriers with the potential to permit the use of lower and safer adjuvant doses during vaccination. PMID:25354691

  20. Synthesis and pharmacological evaluation of a novel AT1 angiotensin II receptor antagonist with anti-hypertension and anti-tumor effects.

    PubMed

    Bao, Xiaolu; Zhu, Weibo; Da, Yajing; Zhu, Linfeng; Qie, Li; Yan, Yijia; Wang, Li; Tang, Hesheng; Chen, Zhi-long

    2015-01-01

    A new compound 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl) benzamide (1) was designed, synthesized and evaluated as a novel AT1 receptor antagonist. Compound 1 displayed high affinity to AT1 receptor with an IC50 value of 1.65 ± 0.2 nM in radio-ligand binding assays. It had an efficient and long-lasting effect in reducing blood pressure which could last for more than 12 h at the dose of 10 mg/kg in spontaneously hypertensive rats. Acute toxicity tests suggested that compound 1 was safe with the LD50 value of 2519.81 mg/kg. Besides, in vitro and in vivo tests suggested its anti-proliferative and anti-tumor activities, respectively. So compound 1 could be considered as a novel anti-hypertension, anti-tumor candidate and deserved further investigation. PMID:25919352

  1. Enhancement of anti-tumor effect of particulate vaccine delivery system by ‘Bacteriomimetic’ CpG functionalization of poly-lactic-co-glycolic acid nanoparticles

    PubMed Central

    Kokate, Rutika A; Thamake, Sanjay I; Chaudhary, Pankaj; Mott, Brittney; Raut, Sangram; Vishwanatha, Jamboor K; Jones, Harlan P

    2016-01-01

    Aim Low immunogenicity remains a major obstacle in realizing the full potential of cancer vaccines. In this study, we evaluated CpG-coated tumor antigen (Tag)-encapsulating ‘bacteriomimetic’ nanoparticles (CpG-nanoparticle [NP]-Tag NPs) as an approach to enhance anti-tumor immunity. Materials & methods CpG-NP-Tag NPs were synthesized, characterized for their physicochemical properties and tested in vivo. Results We found CpG predosing followed by intraperitoneal (IP) immunization with CpG-NP-Tag NPs significantly attenuated tumor growth in female BALB/c mice compared with respective controls. Histopathological and Immunofluorescence data revealed CpG-NP-Tag tumors had lower proliferation, higher apoptotic activity, greater CD4+ and CD8+ T cell infiltration as well as higher IFN-γ levels as compared with control groups. Conclusion Our findings suggest CpG-NP-Tag NPs can enhance anti-tumor effect of nanoparticulate tumor vaccination system. PMID:25867857

  2. Insulin-like growth factors inhibit dendritic cell-mediated anti-tumor immunity through regulating ERK1/2 phosphorylation and p38 dephosphorylation.

    PubMed

    Huang, Ching-Ting; Chang, Ming-Cheng; Chen, Yu-Li; Chen, Tsung-Ching; Chen, Chi-An; Cheng, Wen-Fang

    2015-04-01

    Insulin-like growth factors (IGFs) can promote tumorigenesis via inhibiting the apoptosis of cancer cells. The relationship between IGFs and dendritic cell (DC)-mediated immunity were investigated. Advanced-stage ovarian carcinoma patients were first evaluated to show higher IGF-1 and IGF-2 concentrations in their ascites than early-stage patients. IGFs could suppress DCs' maturation, antigen presenting abilities, and the ability to activate antigen-specific CD8(+) T cell. IGF-treated DCs also secreted higher concentrations of IL-10 and TNF-α. IGF-treated DCs showed decreased ERK1/2 phosphorylation and reduced p38 dephosphorylation. The percentages of matured DCs in the ascites were significantly lower in the IGF-1 or IGF-2 highly-expressing WF-3 tumor-bearing mice. The IGF1R inhibitor - NVP-AEW541, could block the effects of IGFs to rescue DCs' maturation and to restore DC-mediated antigen-specific immunity through enhancing ERK1/2 phosphorylation and p38 dephosphorylation. IGFs can inhibit DC-mediated anti-tumor immunity through suppressing maturation and function and the IGF1R inhibitor could restore the DC-mediated anti-tumor immunity. Blockade of IGFs could be a potential strategy for cancer immunotherapy.

  3. Induction of anti-tumor immunity elicited by tumor cells expressing a murine LFA-3 analog via a recombinant vaccinia virus.

    PubMed

    Lorenz, M G; Kantor, J A; Schlom, J; Hodge, J W

    1999-03-01

    T cell activation requires binding of the T cell receptor to the major histocompatibility molecule-peptide complex in the presence of adhesion and/or costimulatory molecules such as B7-1 (CD80), B7-2 (CD86), ICAM-1 (CD54), and LFA-3 [corrected]. The major ligand of CD2 is CD48, the murine analog of human leukocyte function-associated antigen 3 (LFA-3). To determine the effect of LFA-3 expression on the immunogenicity of tumor cells, we constructed a recombinant vaccinia virus containing the murine LFA-3 gene (designated rV-LFA-3). rV-LFA-3 was shown to be functional in vitro in terms of expression of LFA-3, T cell proliferation, adhesion, and cytotoxicity. Subcutaneous inoculation of rV-LFA-3-infected murine colon adenocarcinoma tumor cells (MC38) into immunocompetent syngeneic C57BL/6 mice resulted in complete lack of tumor growth. Inoculation of MC38 cells infected with equal doses of control wild-type vaccinia virus resulted in tumor growth in all animals. In addition, partial immunological protection was demonstrated against subsequent challenge with uninfected parental tumor cells up to 56 days after vaccination with rV-LFA-3-infected cells. Anti-tumor memory was also demonstrated by using gamma-irradiated MC38 cells and cells from another carcinoma model (CT26). These studies demonstrate that expression of LFA-3 via a poxvirus vector can be used to induce anti-tumor immunity.

  4. Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses.

    PubMed

    Chen, Yuehong; Sun, Jianhong; Yang, Yuan; Huang, Yupeng; Liu, Gang

    2016-01-01

    The objective of the study is to systematically review the malignancy risk of anti-tumor necrosis factor alpha (anti-TNFα) agents. Databases of PubMed Medline, OVID EMBASE, and Cochrane Library were searched to identify published systematic reviews and meta-analyses of randomized control trials, observational studies, and case series that evaluated malignancy risk of anti-TNFα blockers. Search time duration was restricted from January 1st, 2000 to July 16th, 2015. Overview Quality Assessment Questionnaires were used to assess the quality of included reviews. Two methodology trained reviewers separately and repeatedly screened searched studies according to study selection criteria, collected data, and assessed quality. Totally, 42 reviews proved eligible with only one Cochrane review. Anti-TNFα antagonists were extensively used to treat various diseases; nevertheless, malignancy risks were most commonly described in patients with rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In RA patients, no increased risks of breast cancer, lymphoma, and non-melanoma skin cancer were found, but if the use of anti-TNFα agents was associated with elevated risk of overall malignancy was still uncertainty. In IBD patients, the use of anti-TNFα inhibitors was not connected with enhanced risk of overall cancer. No increased cancer risk was found in other disease conditions. Twenty-nine reviews were rated as good quality, 12 as moderate, and one as poor. There are no sufficient evidences to draw the conclusion that anti-TNFα blockers have relationship with increased malignancy risk.

  5. Discovery of 5-substituted pyrrolo[2,3-d]pyrimidine antifolates as dual acting inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis: implications of inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase to AMPK activation and anti-tumor activity

    PubMed Central

    Raghavan, Sudhir; Ravindra, Manasa Punaha; Hales, Eric; Orr, Steven; Cherian, Christina; Hou, Zhanjun

    2014-01-01

    We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5–10) with 1 to 6 bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 with a 4-carbon bridge was the most active analog and potently inhibited proliferation of folate receptor (FR) α-expressing Chinese hamster ovary and KB human tumor cells. Growth inhibition was reversed completely or in part by excess folic acid, indicating that FRα is involved in cellular uptake, and resulted in S-phase accumulation and apoptosis. Anti-proliferative effects of compound 8 toward KB cells were protected by excess adenosine but not thymidine, establishing de novo purine nucleotide biosynthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both AICA ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase). Inhibition of GARFTase and AICARFTase by compound 8 was confirmed by cellular metabolic assays and resulted in ATP pool depletion. To our knowledge, this is the first example of an antifolate that acts as a dual inhibitor of GARFTase and AICARFTase as its principal mechanism of action. PMID:24256410

  6. Dickkopf-3 Contributes to the Regulation of Anti-Tumor Immune Responses by Mesenchymal Stem Cells

    PubMed Central

    Lu, Kun-Hui; Tounsi, Amel; Shridhar, Naveen; Küblbeck, Günter; Klevenz, Alexandra; Prokosch, Sandra; Bald, Tobias; Tüting, Thomas; Arnold, Bernd

    2015-01-01

    Mesenchymal stem cells (MSCs) are known to limit immune responses in vivo by multiple soluble factors. Dickkopf-3 (DKK3), a secreted glycoprotein, has recently been identified as a novel immune modulator. Since DKK3 has been reported to be produced by MSCs, we investigated whether DKK3 contributes to the immune suppression of anti-tumor responses by MSCs. Whereas wild-type MSCs inhibited immune responses against two different transplantation tumors, DKK3-deficient MSCs did not affect the rejection process. Increased CD8+ T cell and reduced M2-type macrophages infiltration was observed in tumors inoculated together with DKK3-deficient MSCs. Thus, DKK3 could alter the composition of the tumor stroma, thereby supporting the MSCs-mediated suppression of immune responses against these tumor transplants. PMID:26734010

  7. Targeting amino acid metabolism in cancer growth and anti-tumor immune response

    PubMed Central

    Ananieva, Elitsa

    2015-01-01

    Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment, however, tumor cells form metabolic relationships with immune cells, and they often compete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response. PMID:26629311

  8. Dosing of zoledronic acid with its anti-tumor effects in breast cancer

    PubMed Central

    Zhao, Xinmin; Hu, Xichun

    2015-01-01

    Bisphosphonates have played an important role in the treatment of breast cancer, mainly in patients with bone metastasis, by reducing the risk of fracture, spinal cord compression, and hypercalcemia. Zoledronic acid, the most frequently used intravenous agent, has been traditionally administered on a monthly dosing schedule. Preclinical studies have demonstrated that zoledronic acid can inhibit angiogenesis, invasion, and adhesion of tumor cells. Several clinical studies of different timings and schedules of zoledronic acid therapy have demonstrated its anti-tumor effects, as well as its protective effect on bone health, in postmenopausal women during adjuvant breast cancer therapy. In general, early initiation of zoledronic acid, concomitantly with adjuvant therapy, has been found to be most beneficial. However, questions remain over the most effective schedule of treatment and relative potency of zoledronic acid. Therefore, we review the existing clinical studies to examine the influence of dosing of zoledronic acid therapy on clinical outcomes in patients with breast cancer. PMID:26587376

  9. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease.

  10. Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer

    PubMed Central

    Paik, Woo Hyun; Ryu, Ji Kon; Jeong, Kyoung-Sin; Park, Jin Myung; Song, Byeong Jun; Lee, Sang Hyub; Kim, Yong-Tae; Yoon, Yong Bum

    2014-01-01

    AIM: To evaluate the anti-tumor effect of clobenpropit, which is a specific H3 antagonist and H4 agonist, in combination with gemcitabine in a pancreatic cancer cell line. METHODS: Three kinds of human pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and AsPC-1) were used in this study. Expression of H3 and H4 receptors in pancreatic cancer cells was identified with Western blotting. Effects of clobenpropit on cell proliferation, migration and apoptosis were evaluated. Alteration of epithelial and mesenchymal markers after administration of clobenpropit was analyzed. An in vivo study with a Panc-1 xenograft mouse model was also performed. RESULTS: H4 receptors were present as 2 subunits in human pancreatic cancer cells, while there was no expression of H3 receptor. Clobenpropit inhibited cell migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine. Clobenpropit up-regulated E-cadherin, but down-regulated vimentin and matrix metalloproteinase 9 in real-time polymerase chain reaction. Also, clobenpropit inhibited tumor growth (gemcitabine 294 ± 46 mg vs combination 154 ± 54 mg, P = 0.02) and enhanced apoptosis in combination with gemcitabine (control 2.5%, gemcitabine 25.8%, clobenpropit 9.7% and combination 40.9%, P = 0.001) by up-regulation of E-cadherin and down-regulation of Zeb1 in Panc-1 xenograft mouse. CONCLUSION: Clobenpropit enhanced the anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of the epithelial-mesenchymal transition process. PMID:25024609

  11. Anti-tumor effects of AMT in the renal cell carcinoma model.

    PubMed

    Caballero, Marcello; Scheele, Jürgen; Zirrgiebel, Ute; Esser, Norbert; Schächtele, Christoph; Soltau, Jens; Rentschler, Jochen; Diergarten, Klaus; Drevs, Joachim

    2010-01-01

    Auron-Misheil-Therapy (AMT) is a defined but unique combination of approved pharmaceuticals. It consists of insulin, chlorpheniramine and an aqueous camomile extract, and it has been successfully applied clinically in late-stage cancer patients. The purpose of this study was to elucidate the anti-tumor efficacy of AMT in a validated murine renal cell carcinoma animal model (RENCA). There were two independent studies; each animal group consisted of 16 mice. During a 6-week pretreatment period, vehicle (group A) and AMT (1.6 mg/kg/d) (group B) were administered once daily in a 5 days/week schedule either intramuscularly or subcutaneously. Tumor challenge at day 0 was followed by a 3-week treatment period (either vehicle or AMT once daily intramuscularly for 21 days consecutively). In study 2 the AMT dosage was increased up to 4-fold by doubling individual doses and switching to a twice daily schedule. The injections were all intramuscular. With the exception of group D, a six-week pretreatment period preceded the tumor challenge at day 0. Tumor challenge was followed by a 3-week treatment period (vehicle, AMT at either 3.2 mg/kg/d) (group A) or 6.4 mg/kg/d (group B), or AMT0, an AMT preparation which does not stimulate IL-6 secretion (6.4 mg/kg/d, group C) continuously for 21 days. AMT administration for group D (6.4 mg/kg/d) was limited to the treatment period from day 1 to 21. All mice were sacrificed 21 days after tumour transplantation. AMT administration was safe and well tolerated, and significantly reduced primary tumor volume in pretreated animals. The effective route of application was intramuscular, with dose escalation resulting in an improved anti-tumor effect. This is the first demonstration of a significant anti-tumorigenic effect of AMT in a validated tumor model.

  12. Enhanced anti-tumor effect of a gene gun-delivered DNA vaccine encoding the human papillomavirus type 16 oncoproteins genetically fused to the herpes simplex virus glycoprotein D.

    PubMed

    Diniz, M O; Ferreira, L C S

    2011-05-01

    Anti-cancer DNA vaccines have attracted growing interest as a simple and non-invasive method for both the treatment and prevention of tumors induced by human papillomaviruses. Nonetheless, the low immunogenicity of parenterally administered vaccines, particularly regarding the activation of cytotoxic CD8+ T cell responses, suggests that further improvements in both vaccine composition and administration routes are still required. In the present study, we report the immune responses and anti-tumor effects of a DNA vaccine (pgD-E7E6E5) expressing three proteins (E7, E6, and E5) of the human papillomavirus type 16 genetically fused to the glycoprotein D of the human herpes simplex virus type 1, which was administered to mice by the intradermal (id) route using a gene gun. A single id dose of pgD-E7E6E5 (2 µg/dose) induced a strong activation of E7-specific interferon-γ (INF-γ)-producing CD8+ T cells and full prophylactic anti-tumor effects in the vaccinated mice. Three vaccine doses inhibited tumor growth in 70% of the mice with established tumors. In addition, a single vaccine dose consisting of the co-administration of pgD-E7E6E5 and the vector encoding interleukin-12 or granulocyte-macrophage colony-stimulating factor further enhanced the therapeutic anti-tumor effects and conferred protection to 60 and 50% of the vaccinated mice, respectively. In conclusion, id administration of pgD-E7E6E5 significantly enhanced the immunogenicity and anti-tumor effects of the DNA vaccine, representing a promising administration route for future clinical trials.

  13. In vivo anti-tumor efficacy of afucosylated anti-CS1 monoclonal antibody produced in glycoengineered Pichia pastoris.

    PubMed

    Gomathinayagam, Sujatha; Laface, Drake; Houston-Cummings, Nga Rewa; Mangadu, Ruban; Moore, Renee; Shandil, Ishaan; Sharkey, Nathan; Li, Huijuan; Stadheim, Terrance A; Zha, Dongxing

    2015-08-20

    Monoclonal antibody (mAb) therapy has been successfully used for the treatment of B-cell lymphomas and is currently extended for the treatment of multiple myeloma (MM). New developments in MM therapeutics have achieved significant survival gains in patients but the disease still remains incurable. Elotuzumab (HuLuc63), an anti-CS1 monoclonal IgG1 antibody, is believed to induce anti-tumor activity and MM cytotoxicity through antibody dependent cellular cytotoxicity (ADCC) and inhibition of MM cell adhesion to bone marrow stromal cells (BMSCs). Modulations of the Fc glycan composition at the N297 site by selective mutations or afucosylation have been explored as strategies to develop bio-better therapeutics with enhanced ADCC activity. Afucosylated therapeutic antibodies with enhanced ADCC activity have been reported to possess greater efficacy in tumor growth inhibition at lower doses when compared to fucosylated therapeutic antibodies. The N-linked glycosylation pathway in Pichia pastoris has been engineered to produce human-like N-linked glycosylation with uniform afucosylated complex type glycans. The purpose of this study was to compare afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris with fucosylated anti-CS1 mAb expressed in mammalian HEK293 cells through in vitro ADCC and in vivo tumor inhibition models. Our results indicate that Fc glycosylation is critical for in vivo efficacy and afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris shows a better in vivo efficacy in tumor regression when compared to fucosylated anti-CS1 mAb expressed in HEK293 cells. Glycoengineered Pichia pastoris could provide an alternative platform for generating homogeneous afucosylated recombinant antibodies where Fc mediated immune effector function is important for efficacy. PMID:26015261

  14. Anti-Tumoral Effects of Anti-Progestins in a Patient-Derived Breast Cancer Xenograft Model.

    PubMed

    Esber, Nathalie; Cherbonnier, Clément; Resche-Rigon, Michèle; Hamze, Abdallah; Alami, Mouad; Fagart, Jérôme; Loosfelt, Hugues; Lombès, Marc; Chabbert-Buffet, Nathalie

    2016-04-01

    Breast cancer is a hormone-dependent disease in which estrogen signaling targeting drugs fail in about 10 % due to resistance. Strong evidences highlighted the mitogen role of progesterone, its ligands, and the corresponding progesterone receptor (PR) isoforms in mammary carcinoma. Several PR antagonists have been synthesized; however, some of them are non-selective and led to side or toxic effects. Herein, we evaluated the anti-tumor activity of a commercially available PR modulator, ulipristal acetate (UPA), and a new selective and passive PR antagonist "APR19" in a novel preclinical approach based on patient-derived breast tumor (HBCx-34) xenografted in nude mice. As opposed to P4 that slightly reduces tumor volume, UPA and APR19 treatment for 42 days led to a significant 30 % reduction in tumor weight, accompanied by a significant 40 % retardation in tumor growth upon UPA exposure while a 1.5-fold increase in necrotic areas was observed in APR19-treated tumors. Interestingly, PR expression was upregulated by a 2.5-fold factor in UPA-treated tumors while APR19 significantly reduced expression of both PR and estrogen receptor α, indicating a potential distinct molecular mechanism among PR antagonists. Cell proliferation was clearly reduced in UPA group compared to vehicle conditions, as revealed by the significant reduction in Ki-67, Cyclin D1, and proliferating cell nuclear antigen (PCNA) expression. Likewise, an increase in activated, cleaved poly(ADP-ribose) polymerase (PARP) expression was also demonstrated upon UPA exposure. Collectively, our findings provide direct in vivo evidence for anti-progestin-mediated control of human breast cancer growth, given their anti-proliferative and pro-apoptotic activities, supporting a potential role in breast cancer therapy. PMID:26941094

  15. GADD45ß, an anti-tumor gene, inhibits avian leukosis virus subgroup J replication in chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Avian leukosis virus subgroup J (ALV-J) is a retrovirus that induces neoplasia, hepatomegaly, immunosuppression and poor performance in chickens. The tumorigenic and pathogenic mechanisms of ALV-J remain a hot topic. To explore anti-tumor genes that confer genetic resistance to ALV-J infection in ch...

  16. More than chemotaxis: a new anti-tumor DC vaccine modified by rAAV2-SLC.

    PubMed

    Liang, Chun-min; Ye, Sheng-long; Zhong, Cui-ping; Zheng, Ning; Bian, Wei; Sun, Rui-xia; Chen, Jun; Li, Ri-lun; Zhou, Shuang; Liu, Yin-kun

    2007-07-01

    Secondary lymphoid tissue chemokine (SLC) is strongly expressed in secondary lymphoid organs. Its ability to facilitate chemotaxis of both dendritic cells (DC) and T cells makes it a promising candidate for cancer therapy. In this study, we modified a BMDC vaccine by incorporating the SLC mature peptide gene. The efficacy of this vaccine was evaluated using a mouse hepatocellular carcinoma (HCC) model, with rAAV2 as the gene delivery vector. The rAAV2 encoding SLC (rAAV2-SLC) transfected immature BMDCs at high efficiency and the anti-tumor effects of SLC gene modified BMDCs (rAAV2-SLC/BMDC) were evaluated. In addition, rAAV2-SLC/BMDC vaccine injected directly into tumors attracted more CD4(+) and CD8(+) T lymphocytes into tumors and showed stronger anti-tumor effects than footpad delivery. Moreover, we found that the phenotypic expression of MHC II, the secretion of IL-12 and IFN-gamma, and T cell stimulation were increased in vitro following treatment with rAAV2-SLC/BMDC vaccine and these responses were inhibited by PTX. In vivo, PTX also inhibited the anti-tumor effects of the vaccine. The results suggest that the expression of SLC by rAAV2-SLC/BMDC plays more than a chemotactic role in anti-tumor responses, thus these studies further demonstrate that SLC has potential to be valuable in cancer therapy.

  17. Anti-tumor immunity elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1.

    PubMed

    Hasegawa, K; Tagawa, M; Takagi, K; Tsukamoto, H; Tomioka, Y; Suzuki, T; Nishioka, Y; Ohrui, T; Numasaki, M

    2016-08-01

    Interleukin (IL)-28A/interferon (IFN)-λ2 and IL-29/IFN-λ1 have been demonstrated to elicit direct and indirect anti-tumor actions. In this study, we constructed an adenovirus vector expressing either IL-28A/IFN-λ2 (AdIL-28A) or IL-29/IFN-λ1 (AdIL-29) to evaluate the therapeutic properties of intratumoral injection of recombinant adenovirus to apply for the clinical implementation of cancer gene therapy. Despite the lack of an anti-proliferative effect on MCA205 and B16-F10 cells, a retarded growth of established subcutaneous tumors was observed following multiple injections of either AdIL-28A or AdIL-29 when compared with AdNull. In vivo cell depletion experiments displayed that both NK cells and CD8(+) T cells have a major role in AdIL-28A-mediated tumor growth suppression. A significant increase in the number of infiltrating CD8(+) T cells into the tumors treated with either AdIL-28A or AdIL-29 was observed. Moreover, specific anti-tumor cytotoxic T lymphocyte reactivity was detected in spleen cells from animals treated with either AdIL-28A or AdIL-29. In IFN-γ-deficient mice, anti-tumor activities of AdIL-28A were completely impaired, indicating that IFN-γ is critically involved in the tumor growth inhibition triggered by AdIL-28A. IL-12 provided a synergistic anti-tumor effect when combined with AdIL-28A. These results indicate that AdIL-28A and AdIL-29 could be successfully utilized as an alternative cancer immunogene therapy. PMID:27561689

  18. Membrane-bound p35 Subunit of IL-12 on Tumor Cells is Functionally Equivalent to Membrane-bound Heterodimeric Single Chain IL-12 for Induction of Anti-tumor Immunity

    PubMed Central

    Kim, Hyun-Jin; Park, Sang Min

    2016-01-01

    In this study, we compared two different tumor cell vaccines for their induction of anti-tumor immunity; one was a tumor cell clone expressing a membrane-bound form of IL-12 p35 subunit (mbIL-12 p35 tumor clone), and the other was a tumor clone expressing heterodimeric IL-12 as a single chain (mb-scIL-12 tumor clone). The stimulatory effect of mb-scIL-12 on the proliferation of ConA-activated splenocytes was higher than that of mbIL-12 p35 in vitro. However, the stimulatory effect of mbIL-12 p35 was equivalent to that of recombinant soluble IL-12 (3 ng/ml). Interestingly, both tumor clones (mbIL-12 p35 and mb-scIL-12) showed similar tumorigenicity and induction of systemic anti-tumor immunity in vivo, suggesting that tumor cell expression of the membrane-bound p35 subunit is sufficient to induce anti-tumor immunity in our tumor vaccine model. PMID:27799876

  19. Development and Characterization of a Humanized Anti-HER2 Antibody HuA21 with Potent Anti-Tumor Properties in Breast Cancer Cells.

    PubMed

    Li, Ruilin; Hu, Siyi; Chang, Yan; Zhang, Zhihui; Zha, Zhao; Huang, Hui; Shen, Guodong; Liu, Jing; Song, Lihua; Wei, Wei

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor activity of the novel engineered monoclonal antibody humanized chA21 (HuA21) that targets HER2 on the basis of chA21, and we describe the underlying mechanisms. Our results reveal that HuA21 markedly inhibits the proliferation and migration of HER2-overexpressing breast cancer cells and causes enhanced antibody-dependent cell-mediated cytotoxicity potency against HER2-overexpressing tumor cells. In particular, HuA21, but not trastuzumab (Tra), markedly suppresses growth and enhances the internalization of the antibody in Tra-resistant BT-474 breast cancer cells. These characteristics are highly associated with the intrinsic ability of HuA21 to down-regulate HER2 activation and inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways. Furthermore, the combination of HuA21 with Tra synergistically enhances the anti-tumor effects in vitro and in vivo and inhibits HER2 activation and the ERK1/2 and Akt signaling pathways. Altogether, our results suggest that HuA21 may represent a unique anti-HER2 antibody with potential as a therapeutic candidate alone or in combination with other anti-HER2 reagents in cancer therapy. PMID:27092488

  20. Combination of PDT and a DNA demethylating agent produces anti-tumor immune response in a mouse tumor model

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Hamblin, Michael R.

    2009-06-01

    Epigenetic mechanisms, which involve DNA methylation and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. However, these changes must be actively maintained after each cell division rendering them a promising target for pharmacologic inhibition. DNA methyltransferase inhibitors like 5-aza-deoxycytidine (5-aza-dC) induce and/or up-regulate the expression of MAGE-type antigens in human and mice cancer cells. Photodynamic therapy (PDT) has been shown to be an effective locally ablative anti-cancer treatment that has the additional advantage of stimulating tumor-directed immune response. We studied the effects of a new therapy that combined the demethylating agent 5-aza-dC with PDT in the breast cancer model 4T1 syngenic to immunocompetent BALB/c mice. PDT was used as a locally ablating tumor treatment that is capable of eliciting strong and tumor directed immune response while 5-aza-dC pretreatment was used promote de novo induction of the expression of P1A.protein. This is the mouse homolog of human MAGE family antigens and is reported to function as a tumor rejection antigen in certain mouse tumors. This strategy led to an increase in PDT-mediated immune response and better treatment outcome. These results strongly suggest that the MAGE family antigens are important target for PDT mediated immune response but that their expression can be silenced by epigenetic mechanisms. Therefore the possibility that PDT can be combined with epigenetic strategies to elicit anti-tumor immunity in MAGE-positive tumor models is highly clinically significant and should be studied in detail.

  1. Intestinal microsporidiosis: a hidden risk in rheumatic disease patients undergoing anti-tumor necrosis factor therapy combined with disease-modifying anti-rheumatic drugs?

    PubMed Central

    Aikawa, Nadia Emi; de Oliveira Twardowsky, Aline; de Carvalho, Jozélio Freire; Silva, Clovis A; Silva, Ivan Leonardo Avelino França e; de Medeiros Ribeiro, Ana Cristina; Saad, Carla Gonçalves Schain; Moraes, Julio César Bertacini; de Toledo, Roberto Acayaba; Bonfá, Eloísa

    2011-01-01

    OBJECTIVE: Immunosuppressed patients are at risk of microsporidiosis, and this parasitosis has an increased rate of dissemination in this population. Our objective was to evaluate the presence of microsporidiosis and other intestinal parasites in rheumatic disease patients undergoing anti-tumor necrosis factor/disease-modifying anti-rheumatic drug treatment. METHODS: Ninety-eight patients (47 with rheumatoid arthritis, 31 with ankylosing spondylitis and 11 with psoriatic arthritis) and 92 healthy control patients were enrolled in the study. Three stool samples and cultures were collected from each subject. RESULTS: The frequency of microsporidia was significantly higher in rheumatic disease patients than in control subjects (36 vs. 4%, respectively; p<0.0001), as well as in those with rheumatic diseases (32 vs. 4%, respectively; p<0.0001), ankylosing spondylitis (45 vs. 4%, respectively; p<0.0001) and psoriatic arthritis (40 vs. 4%, respectively; p<0.0001), despite a similar social-economic class distribution in both the patient and control groups (p = 0.1153). Of note, concomitant fecal leukocytes were observed in the majority of the microsporidia-positive patients (79.5%). Approximately 80% of the patients had gastrointestinal symptoms, such as diarrhea (26%), abdominal pain (31%) and weight loss (5%), although the frequencies of these symptoms were comparable in patients with and without this infection (p>0.05). Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis disease activity parameters were comparable in both groups (p>0.05). The duration of anti-tumor necrosis factor/disease-modifying anti-rheumatic drugs and glucocorticoid use were also similar in both groups. CONCLUSION: We have documented that microsporidiosis with intestinal mucosa disruption is frequent in patients undergoing concomitant anti-tumor necrosis factor/disease-modifying anti-rheumatic drug therapy. Impaired host defenses due to the combination of the underlying disease

  2. Antiradical activity of gallic acid included in lipid interphases.

    PubMed

    Salcedo, C L; Frías, M A; Cutro, A C; Nazareno, M A; Disalvo, E A

    2014-10-01

    Polyphenols are well known as antioxidant agents and by their effects on the hydration layers of lipid interphases. Among them, gallic acid and its derivatives are able to decrease the dipole potential and to act in water as a strong antioxidant. In this work we have studied both effects on lipid interphases in monolayers and bilayers of dimyristoylphosphatidylcholine. The results show that gallic acid (GA) increases the negative surface charges of large unilamellar vesicles (LUVs) and decreases the dipole potential of the lipid interphase. As a result, positively charged radical species such as ABTS(+) are able to penetrate the membrane forming an association with GA. These results allow discussing the antiradical activity (ARA) of GA at the membrane phase which may be taking place in water spaces between the lipids.

  3. Cooperative therapeutic anti-tumor effect of IL-15 agonist ALT-803 and co-targeting soluble NKG2D ligand sMIC

    PubMed Central

    Basher, Fahmin; Jeng, Emily K.; Wong, Hing; Wu, Jennifer

    2016-01-01

    Shedding of the human NKG2D ligand MIC (MHC class I-chain-related molecule) from tumor cell surfaces correlates with progression of many epithelial cancers. Shedding-derived soluble MIC (sMIC) enables tumor immune escape through multiple immune suppressive mechanisms, such as disturbing natural killer (NK) cell homeostatic maintenance, impairing NKG2D expression on NK cells and effector T cells, and facilitating the expansion of arginase I+ myeloid suppressor cells. Our recent study has demonstrated that sMIC is an effective cancer therapeutic target. Whether targeting tumor-derived sMIC would enhance current active immunotherapy is not known. Here, we determined the in vivo therapeutic effect of an antibody co-targeting sMIC with the immunostimulatory IL-15 superagonist complex, ALT-803, using genetically engineered transplantable syngeneic sMIC+ tumor models. We demonstrate that combined therapy of a nonblocking antibody neutralizing sMIC and ALT-803 improved the survival of animals bearing sMIC+ tumors in comparison to monotherapy. We further demonstrate that the enhanced therapeutic effect with combined therapy is through concurrent augmentation of NK and CD8 T cell anti-tumor responses. In particular, expression of activation-induced surface molecules and increased functional potential by cytokine secretion are improved greatly by the administration of combined therapy. Depletion of NK cells abolished the cooperative therapeutic effect. Our findings suggest that administration of the sMIC-neutralizing antibody can enhance the anti-tumor effects of ALT-803. With ALT-803 currently in clinical trials to treat progressive solid tumors, the majority of which are sMIC+, our findings provide a rationale for co-targeting sMIC to enhance the therapeutic efficacy of ALT-803 or other IL-15 agonists. PMID:26625316

  4. Type I Interferons Exert Anti-tumor Effect via Reversing Immunosuppression Mediated by Mesenchymal Stromal Cells

    PubMed Central

    Shou, Peishun; Chen, Qing; Jiang, Jingting; Xu, Chunliang; Zhang, Jimin; Zheng, Chunxing; Jiang, Menghui; Velletri, Tania; Cao, Wei; Huang, Yin; Yang, Qian; Han, Xiaoyan; Zhang, Liying; Wei, Lixin; Rabson, Arnold B.; Chin, Y. Eugene; Wang, Ying; Shi, Yufang

    2016-01-01

    Mesenchymal stromal cells (MSCs) are strongly immunosuppressive via producing nitric oxide (NO) and known to migrate into tumor sites to promote tumor growth, but the underlying mechanisms remain largely elusive. Here, we found that IFNα-secreting MSCs showed more dramatic inhibition effect on tumor progression than that of IFNα alone. Interestingly, IFNα-primed MSCs could also effectively suppress tumor growth. Mechanistically, we demonstrated that both IFNα and IFNβ (type I IFNs) reversed the immunosuppressive effect of MSCs on splenocyte proliferation. This effect of type I IFNs was exerted through inhibiting iNOS (inducible nitric oxide synthase) expression in IFNγ and TNFα-stimulated MSCs. Notably, only NO production was inhibited by IFNα; production of other cytokines or chemokines tested was not suppressed. Furthermore, IFNα promoted the switch from Stat1 homodimers to Stat1-Stat2 heterodimers. Studies using the luciferase reporter system and chromatin immunoprecipitation assay revealed that IFNα suppressed iNOS transcription through inhibiting the binding of Stat1 to iNOS promoter. Therefore, the synergistic anti-tumor effects of type I IFNs and MSCs were achieved by inhibiting NO production. This study provides essential information for understanding the mechanisms of MSC-mediated immunosuppression and for the development of better clinical strategies using IFNs and MSCs for cancer immunotherapy. PMID:27109100

  5. Biorelevant reactions of the potential anti-tumor agent vanadocene dichloride.

    PubMed

    Sanna, Daniele; Serra, Maria; Ugone, Valeria; Manca, Laura; Pirastru, Monica; Buglyó, Péter; Bíró, Linda; Micera, Giovanni; Garribba, Eugenio

    2016-05-01

    The interaction of the potential anti-tumor agent vanadocene dichloride ([Cp2VCl2] or VDC) with some relevant bioligands of the cytosol such as proteins (Hb), amino acids (glycine and histidine), NADH derivatives (NADH, NADPH, NAD(+) and NADP(+)), reductants (GSH and ascorbic acid), phosphates (HPO4(2-), P2O7(4-), cAMP, AMP, ADP and ATP) and carboxylate derivatives (lactate) and its uptake by red blood cells were studied. The results indicated that [Cp2VCl2] transforms at physiological pH into [Cp2V(OH)2] and that only HPO4(2-), P2O7(4-), lactate, ATP and ADP form mixed species with the [Cp2V](2+) moiety replacing the two hydroxide ions. EPR and electronic absorption spectroscopy, agarose gel electrophoresis and spin trapping measurements allow excluding any direct interaction and/or intercalation with DNA and the formation of reactive oxygen species (ROS) in Fenton-like reactions. Uptake experiments by erythrocytes suggested that VDC crosses the membrane and enters inside the cells, whereas 'bare' V(IV) transforms into V(IV)O species with loss of the two cyclopentadienyl rings. This transformation in the cellular environment could be related to the mechanism of action of VDC. PMID:27121101

  6. Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population

    PubMed Central

    Madkour, Nermeen; Kazerooni, Rashid

    2014-01-01

    Introduction. Anti-tumor necrosis factor (TNF) agents are effective for several immunologic conditions (rheumatoid arthritis (RA), Crohn’s disease (CD), and psoriasis). The purpose of this study was to evaluate the efficacy and safety of anti-TNF agents via chart review. Methods. Single-site, retrospective cohort study that evaluated the efficacy and safety of anti-TNF agents in veterans initiated between 2010 and 2011. Primary aim evaluated response at 12 months post-index date. Secondary aims evaluated initial response prior to 12 months post-index date and infection events. Results. A majority of patients were prescribed anti-TNF agents for CD (27%) and RA (24%). Patients were initiated on etanercept (41%), adalimumab (40%), and infliximab (18%) between 2010 and 2011. No differences in patient demographics were reported. Response rates were high overall. Sixty-five percent of etanercept patients, 82% of adalimumab patients, and 59% of infliximab patients were either partial or full responders, respectively. Approximately 16%, 11%, and 12% of etanercept, adalimumab, and infliximab were non-responders, respectively. Infections between the groups were non-significant. Etanercept and adalimumab patients had higher but non-significant odds of being a responder relative to infliximab. Conclusions. Most patients initiated with anti-TNF agent were responders at 12 months follow-up for all indications in a veteran population. PMID:24883246

  7. The Safety and Anti-Tumor Effects of Ozonated Water in Vivo

    PubMed Central

    Kuroda, Kohei; Azuma, Kazuo; Mori, Takuro; Kawamoto, Kinya; Murahata, Yusuke; Tsuka, Takeshi; Osaki, Tomohiro; Ito, Norihiko; Imagawa, Tomohiro; Itoh, Fumio; Okamoto, Yoshiharu

    2015-01-01

    Ozonated water is easier to handle than ozone gas. However, there have been no previous reports on the biological effects of ozonated water. We conducted a study on the safety of ozonated water and its anti-tumor effects using a tumor-bearing mouse model and normal controls. Local administration of ozonated water (208 mM) was not associated with any detrimental effects in normal tissues. On the other hand, local administration of ozonated water (20.8, 41.6, 104, or 208 mM) directly into the tumor tissue induced necrosis and inhibited proliferation of tumor cells. There was no significant difference in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL)-positive cells following administration of ozonated water. The size of the necrotic areas was dependent on the concentration of ozonated water. These results indicate that ozonated water does not affect normal tissue and damages only the tumor tissue by selectively inducing necrosis. There is a possibility that it exerts through the production of reaction oxygen species (ROS). In addition, the induction of necrosis rather than apoptosis is very useful in tumor immunity. Based on these results, we believe that administration of ozonated water is a safe and potentially simple adjunct or alternative to existing antineoplastic treatments. PMID:26506343

  8. Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn's disease.

    PubMed

    Ma, Christopher; Walters, Brennan; Fedorak, Richard N

    2013-06-01

    Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn's disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal-CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy.

  9. Oleuropein, a non-toxic olive iridoid, is an anti-tumor agent and cytoskeleton disruptor

    SciTech Connect

    Hamdi, Hamdi K. . E-mail: hkhamdi@gmail.com; Castellon, Raquel

    2005-09-02

    Oleuropein, a non-toxic secoiridoid derived from the olive tree, is a powerful antioxidant and anti-angiogenic agent. Here, we show it to be a potent anti-cancer compound, directly disrupting actin filaments in cells and in a cell-free assay. Oleuropein inhibited the proliferation and migration of advanced-grade tumor cell lines in a dose-responsive manner. In a novel tube-disruption assay, Oleuropein irreversibly rounded cancer cells, preventing their replication, motility, and invasiveness; these effects were reversible in normal cells. When administered orally to mice that developed spontaneous tumors, Oleuropein completely regressed tumors in 9-12 days. When tumors were resected prior to complete regression, they lacked cohesiveness and had a crumbly consistency. No viable cells could be recovered from these tumors. These observations elevate Oleuropein from a non-toxic antioxidant into a potent anti-tumor agent with direct effects against tumor cells. Our data may also explain the cancer-protective effects of the olive-rich Mediterranean diet.

  10. Peripheral blood-derived, γ9δ2 t cell-enriched cell lines from glioblastoma multiforme patients exert anti-tumoral effects in vitro.

    PubMed

    Marcu-Malina, V; Garelick, D; Peshes-Yeloz, N; Wohl, A; Zach, L; Nagar, M; Amariglio, N; Besser, M J; Cohen, Z R; Bank, I

    2016-01-01

    The goal of this work was to assess the potential of T cells expressing Vγ9Vδ2+ T cell receptors (TCR, γ9δ2T cells) present in peripheral blood (PB) m ononuclear cells (MC, PBMC) of glioblastoma multiforme (GBM) patients to act as anti-tumoral agents. We found that γ9δ2T cell levels were decreased in patients' PB relative to a cohort of healthy donors (HD) (respectively 0.52±0.55%, n=16, vs 1.12±0.6%, n=14, p=0.008) but did not significantly correlate with postoperative survival (R=0.6, p=0.063). Importantly, however, the γ9δ2T cells could be expanded in vitro to consist 51±23% of the cultured lymphocytes (98% CD3+). This was achieved after 14 days of culture in medium containing the amino-bisphosphonate (ABP) Zoledronate (Zol) and interleukin (IL)-2, resulting in γ9δ2T cell-enriched lines (gdTCEL) similar to those of HD derived gdTCEL (54±19%). Moreover, gdTCEL from patients and HD mediated cytotoxicity to GBM-derived cell lines (GBMDCL), which was abrogated by immune-magnetic removal of the γ9δ2T cells. Furthermore, low level interferon (IFN) γ secretion was induced by gdTCEL briefly co-cultured with GBMDCL or autologous - tumor-derived cells, which was greatly amplified in the presence of Zol. Importantly, IFNγ secretion was inhibited by mevastatin but enhanced by cross-linking of butyrophilin 3A1 (CD277) on a CD277+ GBMDCL (U251MG) or by pretreatment of GBMDCL with temozolomide (TMZ). Taken together, these data suggest that γ9δ2T cells in PB of GBM patients can give rise to gdTCEL that mediate anti-tumoral activities. PMID:27049073

  11. Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity

    PubMed Central

    Germain, Claire; Gnjatic, Sacha; Dieu-Nosjean, Marie-Caroline

    2015-01-01

    It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools. PMID:25755654

  12. Annexin-V promotes anti-tumor immunity and inhibits neuroblastoma growth in vivo.

    PubMed

    Yan, Xiaocai; Doffek, Kara; Yin, Chaobo; Krein, Michael; Phillips, Michael; Sugg, Sonia L; Johnson, Bryon; Shilyansky, Joel

    2012-11-01

    The goal of the current study is to determine the effects of blocking phosphatidylserine (PS) on the growth of neuroblastoma in mice. PS, an anionic phospholipid restricted to the cytoplasmic surface of plasma membranes in most cells, is externalized to the surface of apoptotic cells. PS has been shown to induce immune tolerance to self-antigens. PS can also be found on the surface of live cells and in particular tumor cells. Annexin-V (AnV) is a protein that specifically binds and blocks PS. To determine the effects of blocking PS with AnV on tumor growth and immunogenicity, mice were inoculated with AGN2a, a poorly immunogenic murine neuroblastoma that expresses high level of PS on the cell surface. Survival and anti-tumor T cell response were determined. AGN2a were engineered to secrete AnV. Secreted protein effectively blocked tumor PS. 40 % of mice inoculated with AnV-expressing AGN2a cells survived free of tumor, whereas none of the mice inoculated with control cells survived (p = 0.0062). The benefits of AnV were lost when mice were depleted of T cells. The findings suggest that AnV could protect mice from tumor challenge through an immune mediated mechanism. Mice were then immunized with irradiated AnV-secreting or control cells, and challenged with wild-type AGN2a cells. AnV-secreting cell vaccine protected 80 % of mice from AGN2a challenge, while control cell vaccine prevented tumor growth in only 30 % of animals (p = 0.012). ELISPOT analysis demonstrated that AnV-secreting cell vaccine induced a greater frequency of interferon-gamma producing splenic T cells. T cells isolated from mice immunized with AnV-secreting but not control vaccine lysed AGN2a. In summary, AnV blocked PS, enhanced T cell mediated tumor immunity, and inhibited tumor growth.

  13. Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis

    PubMed Central

    Klement, Rainer J.; Champ, Colin E.; Otto, Christoph; Kämmerer, Ulrike

    2016-01-01

    Background Currently ketogenic diets (KDs) are hyped as an anti-tumor intervention aimed at exploiting the metabolic abnormalities of cancer cells. However, while data in humans is sparse, translation of murine tumor models to the clinic is further hampered by small sample sizes, heterogeneous settings and mixed results concerning tumor growth retardation. The aim was therefore to synthesize the evidence for a growth inhibiting effect of KDs when used as a monotherapy in mice. Methods We conducted a Bayesian random effects meta-analysis on all studies assessing the survival (defined as the time to reach a pre-defined endpoint such as tumor volume) of mice on an unrestricted KD compared to a high carbohydrate standard diet (SD). For 12 studies meeting the inclusion criteria either a mean survival time ratio (MR) or hazard ratio (HR) between the KD and SD groups could be obtained. The posterior estimates for the MR and HR averaged over four priors on the between-study heterogeneity τ2 were MR = 0.85 (95% highest posterior density interval (HPDI) = [0.73, 0.97]) and HR = 0.55 (95% HPDI = [0.26, 0.87]), indicating a significant overall benefit of the KD in terms of prolonged mean survival times and reduced hazard rate. All studies that used a brain tumor model also chose a late starting point for the KD (at least one day after tumor initiation) which accounted for 26% of the heterogeneity. In this subgroup the KD was less effective (MR = 0.89, 95% HPDI = [0.76, 1.04]). Conclusions There was an overall tumor growth delaying effect of unrestricted KDs in mice. Future experiments should aim at differentiating the effects of KD timing versus tumor location, since external evidence is currently consistent with an influence of both of these factors. PMID:27159218

  14. Identification of immune factors regulating anti-tumor immunity using polymeric vaccines with multiple adjuvants

    PubMed Central

    Ali, Omar A.; Verbeke, Catia; Johnson, Chris; Sands, Warren; Lewin, Sarah A.; White, Des; Doherty, Edward; Dranoff, Glenn; Mooney, David J.

    2014-01-01

    The innate cellular and molecular components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. In this study we utilized polymeric cancer vaccines incorporating different classes of adjuvants to induce tumor protection, in order to identify dendritic cell subsets and cytokines critical to this efficacy. Three-dimensional, porous polymer matrices loaded with tumor lysates and presenting distinct combinations of GM-CSF and various TLR agonists effected 70–90% prophylactic tumor protection in B16-F10 melanoma models. In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I:C) or CpG-ODN induced the complete regression of solid tumors (≤40mm2) resulting in 33% long-term survival. Regression analysis revealed that the numbers of vaccine-resident CD8(+) DCs and plasmacytoid DCs, along with local IL-12, and G-CSF concentrations correlated strongly to vaccine efficacy regardless of adjuvant type. Further, vaccine studies in Batf3−/− mice revealed that CD8(+) DCs are required to effect tumor protection, as vaccines in these mice were deficient in cytotoxic T cell priming, and IL-12 induction in comparison to wild-type. These studies broadly demonstrate that three-dimensional polymeric vaccines provide a potent platform for prophylactic and therapeutic protection, and can be used as a tool to identify critical components of a desired immune response. Specifically, these results suggest that CD8(+) DCs, plasmacytoid DCs, IL-12, and G-CSF play important roles in priming effective anti-tumor responses with these vaccines. PMID:24480625

  15. Gold nanoparticles enhance anti-tumor effect of radiotherapy to hypoxic tumor

    PubMed Central

    Kim, Mi Sun; Lee, Eun-Jung; Kim, Jae-Won; Chung, Ui Seok; Koh, Won-Gun; Keum, Ki Chang; Koom, Woong Sub

    2016-01-01

    Purpose Hypoxia can impair the therapeutic efficacy of radiotherapy (RT). Therefore, a new strategy is necessary for enhancing the response to RT. In this study, we investigated whether the combination of nanoparticles and RT is effective in eliminating the radioresistance of hypoxic tumors. Materials and Methods Gold nanoparticles (GNPs) consisting of a silica core with a gold shell were used. CT26 colon cancer mouse model was developed to study whether the combination of RT and GNPs reduced hypoxia-induced radioresistance. Hypoxia inducible factor-1α (HIF-1α) was used as a hypoxia marker. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were conducted to evaluate cell death. Results Hypoxic tumor cells had an impaired response to RT. GNPs combined with RT enhanced anti-tumor effect in hypoxic tumor compared with RT alone. The combination of GNPs and RT decreased tumor cell viability compare to RT alone in vitro. Under hypoxia, tumors treated with GNPs + RT showed a higher response than that shown by tumors treated with RT alone. When a reactive oxygen species (ROS) scavenger was added, the enhanced antitumor effect of GNPs + RT was diminished. Conclusion In the present study, hypoxic tumors treated with GNPs + RT showed favorable responses, which might be attributable to the ROS production induced by GNPs + RT. Taken together, GNPs combined with RT seems to be potential modality for enhancing the response to RT in hypoxic tumors. PMID:27730800

  16. A Potent Gelatinase Inhibitor with Anti-Tumor-Invasive Activity and its Metabolic Disposition

    PubMed Central

    Lee, Mijoon; Celenza, Giuseppe; Boggess, Bill; Blase, Jennifer; Shi, Qicun; Toth, Marta; Bernardo, M. Margarida; Wolter, William R.; Suckow, Mark A.; Hesek, Dusan; Noll, Bruce C.; Fridman, Rafael; Mobashery, Shahriar; Chang, Mayland

    2009-01-01

    Metastatic tumors lead to more than 90% fatality. Despite the importance of invasiveness of tumors to poor disease outcome, no anti-invasive compounds have been commercialized. We describe herein the synthesis and evaluation of 4-(4-(thiiranylmethylsulfonyl)phenoxy)-phenyl methane-sulfonate (compound 2) as a potent and selective inhibitor of gelatinases (matrix metalloproteinases-2 and -9), two enzymes implicated in invasiveness of tumors. It was demonstrated that compound 2 significantly attenuated the invasiveness of human fibrosarcoma cells (HT1080). The metabolism of compound 2 involved hydroxylation at the a-methylene, which generates sulfinic acid, thiirane ring-opening, followed by methylation and oxidation, and cysteine conjugation of both the thiirane and phenyl rings. PMID:19207421

  17. Ley specific antibody with potent anti-tumor activity is internalized and degraded in lysosomes.

    PubMed Central

    Garrigues, J.; Garrigues, U.; Hellström, I.; Hellström, K. E.

    1993-01-01

    BR96 is a monoclonal antibody (MAb) that recognizes many human carcinomas and can kill antigen-positive tumor cells in vitro. Using both gold and radiolabeled MAb, the distribution and cellular processing of BR96 during cytolysis has been determined. After a brief (< 3 minutes) MAb treatment, cells in suspension are stained by the nuclear viability dye propidium iodide. Whole MAb and F(ab')2 fragments are equally cytotoxic; monovalent F(ab) fragments, however, have no effect on dye uptake unless cross-linked with goat anti-mouse IgG. The level of toxicity is dependent on both MAb dose and on cell surface receptor density. Cell contact may regulate receptor expression. BR96 receptors are more abundant on cells migrating into the open areas of a scratch wounded confluent culture than on the adjacent contact-inhibited cells. BR96 can also inhibit the anchorage-independent growth of tumor cells in soft agar showing that its effects on propidium iodide staining are not due to transient changes in membrane permeability. Immunogold electron microscopy reveals that, after a 1-minute treatment, BR96 induces significant infolding of the plasma membrane and that internalized MAb is localized to these structures. Immediately thereafter, large cell surface and intracellular vesicles form, mitochondria are swollen, and membrane integrity is lost. Therefore, BR96 seems to cause morphological changes characteristic of necrosis rather than apoptosis. When bound to adherent carcinoma cells, BR96 is distributed uniformly on the apical surface of cells labeled at 4 C and is enriched at points of cell substratum contact. Upon warming of the cells to 37 C, BR96 localizes in small perinuclear clusters and the cell margin is now devoid of label. Immunogold electron microscopy reveals that BR96 undergoes receptor mediated internalization and is localized within the same coated pits, endosomes, and lysosomes as the transferrin receptor. Quantitative studies using iodinated BR96 show that after 6 hours of chase, a maximum of 53% of the radiolabel is located within the intracellular pool. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicates that 84% of this fraction is nondegraded. BR96 probably cycles between the medium and intracellular pools because the remainder of the radiolabel is in the medium as intact MAb. By 24 hours of chase, the intracellular fraction drops to 30%, while the remaining 70% is present in the culture medium, mostly as low molecular weight degradation products. Images Figure 1 Figure 2 Figure 4 Figure 5 p614-a Figure 6 Figure 7 Figure 8 Figure 9 PMID:8434651

  18. Enhanced in Vitro Anti-Tumor Activity of 5-Azacytidine by Entrapment into Solid Lipid Nanoparticles

    PubMed Central

    Jahanfar, Farhad; Hasani, Akbar; Shanebandi, Dariush; Rahmati, Mohammad; Hamishehkar, Hamed

    2016-01-01

    Purpose: In this study the effectiveness of encapsulating of 5-azacytidine into the lipid nanoparticles was investigated and in vitro effect of encapsulated 5-azacytidine studied on MCF-7 cell lines Methods: 5-azacytidine -loaded solid lipid nanoparticles were produced by double emulsification (w/o/w) method by using stearic acid as lipid matrix, soy lecithin and poloxamer 407 as surfactant and co-surfactant respectively. Particle size, zeta potential, surface morphology, entrapment efficiency and kinetic of drug release were studied. In vitro effect of 5-azacytidine on MCF-7 cell line studied by MTT assay, DAPI staining, Rhodamine B relative uptake, and also Real time RT-PCR was performed for studying difference effect of free and encapsulated drug on expression of RARß2 gene. Results: The formulation F5 with 55.84±0.46 % of entrapment efficiency shows zero order kinetic of drug release and selected for in vitro studies; the cytotoxicity of free drug and encapsulated drug in 48 h of incubation have significant difference. DAPI staining shows morphology of apoptotic nucleus in both free and encapsulated drug, Rhodamine B labeled SLNs show time dependency and accumulation of SLNs in cytoplasm. Real time qRT-PCR doesn’t show any significant difference (p>0.05) in expression of RARß2 gene in both cells treated with free or encapsulated drug. Conclusion: The results of the present study indicated that the entrapment of 5-azacytidine into SLNs enhanced its cytotoxicity performance and may pave a way for the future design of a desired dosage form for 5-azacytidine. PMID:27766220

  19. Lack of anti-tumor activity by anti-VEGF treatments in hepatic hemangiomas.

    PubMed

    Lee, Minsu; Choi, Jin-Young; Lim, Joon Seok; Park, Mi-Suk; Kim, Myeong-Jin; Kim, Honsoul

    2016-04-01

    Recently, anti-vascular endothelial growth factor (anti-VEGF) agents have been described in the literature as a valid treatment option for symptomatic liver hemangiomas, but only limited evidence supports this notion. The purpose of this study was to elucidate whether or not the administration of anti-VEGF agents can reliably achieve a size reduction in liver hemangiomas. We examined patients with incidental hemangiomas who received anti-angiogenic agents for the treatment of other malignancies. Our study population consisted of 17 colorectal cancer patients and one lung cancer patient carrying 21 hemangiomas who received bevacizumab, and seven renal cell carcinoma patients carrying nine hepatic hemangiomas who received sunitinib. We have measured the liver hemangioma volume on both the pre-treatment and post-treatment computed tomography images and then calculated the volume alteration rates. No statistically significant difference (P = 0.365) in the volume of the liver hemangiomas was observed before (1.1-168.8 cm(3); mean ± SD 19.8 ± 39.7 cm(3)) or after (1.2-163.6 cm(3); 19.3 ± 38.0 cm(3)) bevacizumab treatment. The volume reduction rate ranged from -35.0 to 11.2 % (mean ± SD -1.3 ± 10.8 %). The sunitinib treatment group also showed no statistically significant difference (P = 0.889) in hemangioma volume before (1.2-6.5 cm(3); 3.0 ± 1.8 cm(3)) or after (1.2-6.0 cm(3); 3.0-1.7 cm(3)) treatment. The volume reduction rate ranged from -13.3 to 7.7 % (median: mean ± SD -2.5 ± 6.6 %). We did not observe liver hemangioma shrinkage after bevacizumab or sunitinib treatment. Our data do not support the application of anti-VEGF agents for the treatment of hepatic hemangiomas.

  20. Optimal design of active and semi-active suspensions including time delays and preview

    NASA Astrophysics Data System (ADS)

    Hac', A.; Youn, I.

    1993-10-01

    Several control laws for active and semi-active suspension based on a linear half car model are derived and investigated. The strategies proposed take full advantage of the fact that the road input to the rear wheels is a delayed version of that to the front wheels, which in turn can be obtained either from the measurements of the front wheels and body motions or by direct preview of road irregularities if preview sensors are available. The suspension systems are optimized with respect to ride comfort, road holding and suspension rattle space as expressed by the mean-square-values of body acceleration (including effects of heave and pitch), tire deflections and front and rear suspension travels. The optimal control laws that minimize the given performance index and include passivity constraints in the semi-active case are derived using calculus of variation. The optimal semi-active suspension becomes piecewise linear, varying between passive and fully active systems and combinations of them. The performances of active and semi-active systems with and without preview were evaluated by numerical simulation in the time and frequency domains. The results show that incorporation of time delay between the front and rear axles in controller design improves the dynamic behavior of the rear axle and control of body pitch motion, while additional preview improves front wheel dynamics and body heave.

  1. Specific anti-tumor immune response with photodynamic therapy mediated by benzoporphyrin derivative and chlorin(e6)

    NASA Astrophysics Data System (ADS)

    Castano, Ana P.; Gad, Faten; Zahra, Touqir; Hamblin, Michael R.

    2003-07-01

    The purpose of this study was to investigate the induction of anti-tumor immunity by photodynamic therapy (PDT). We used EMT-6 mammary sarcoma, a moderately immunogenic tumor, with 10(6) cells injected s.c. in thighs of immunocompetent Balb/c mice. Mice were treated 10 days later when tumors were 6-mm diameter. Two PDT regimens were equally effective in curing tumors: 1-mg/kg of liposomal benzoporphyrin derivative (BPD) followed after 15 min by 150 J/cm2 690 nm light or 10-mg/kg chlorin(e6) (ce6) followed after 6 hours by 150 J/cm2 665 nm light. BPD-PDT produced a black eschar 24-48 hours after treatment with no visible tumor, followed by healing of the lesion. By contrast ce6-PDT showed no black eschar, but a slow disappearance of tumor over 5-7 days. When cured mice were rechallenged with 10(6) EMT-6 cells in the opposite thigh, all ce6-PDT cured mice rejected the challenge, but BPD-PDT cured mice grew tumors in a proportion of cases. When mice were cured by amputation of the tumor bearing leg, all mice subsequently grew tumors upon rechallenge. Mice were given two EMT6 tumors (1 in each leg) and the mouse was injected with ce6 or BPD but only one tumor was treated with light. Both tumors (PDT-treated and contralateral) regressed at an equal rate until they became undetectable, but in some mice the untreated tumor recurred. Those mice cured of both tumors rejected a subsequent EMT6 rechallenge. Amputation of the tumor bearing leg did not lead to regression of the contralateral tumor. Mice that rejected an EMT6 rechallenge failed to reject a subsequent cross-challenge with J774 reticulum cell sarcoma (an alternative Balb/c murine tumor). These data show that PDT generates a tumor-specific memory immune response, and in addition an active tumoricidal immune response capable of destroying distant established tumors. We hypothesize that ce6-PDT is more effective than BPD-PDT due to more necrotic rather than apoptotic cell death and/or generation of heat

  2. Photodynamic therapy stimulates anti-tumor immunity in a murine model

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Castano, Ana P.; Wu, Mei X.; Kung, Andrew L.; Hamblin, Michael R.

    2007-02-01

    Cancer is a leading cause of death among modern peoples largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with the minimal toxicity. This is best accomplished by educating the body's immune system to recognize the tumor as foreign so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the immune system to recognize tumor-associated antigens (TAA), and induction of heat-shock proteins. The induction of specific CD8+ T lymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. We here report on PDT of mice bearing tumors that either do or do not express an established TAA. We utilized a BALB/c colon adenocarcinoma cell line termed CT26.CL25 retrovirally transduced to stably express β-galactosidase ( β-gal, a bacterial protein), and its non-β-gal expressing wild-type counterpart termed CT26 WT, as well as the control cell line consisting of CT26 transduced with the empty retroviral vector termed CT26-neo. All cells expressed class I MHC restriction element H-2Ld syngenic to BALB/c mice. Vascular PDT with a regimen of 1mg/kg BPD injected IV, and 120 J/cm2 of 690-nm laser light after 15 minutes successfully cured 100% of CT26.CL25 tumors but 0% of CT26-neo tumors and 0% of CT26 WT tumors. After 90 days tumor free interval the CT26.CL25 cured mice were rechallenged with CT26.CL25 tumor cells and 96% rejected the rechallenge while the CT26.CL25 cured mice did not reject a CT26 WT tumor cell challenge. Experiments with mice bearing two CT26.CL25 tumors (one

  3. Design and Synthesis of Analogues of Marine Natural Product Galaxamide, an N-methylated Cyclic Pentapeptide, as Potential Anti-Tumor Agent in Vitro.

    PubMed

    Lunagariya, Jignesh; Zhong, Shenghui; Chen, Jianwei; Bai, Defa; Bhadja, Poonam; Long, Weili; Liao, Xiaojian; Tang, Xiaoli; Xu, Shihai

    2016-01-01

    Herein, we report design and synthesis of novel 26 galaxamide analogues with N-methylated cyclo-pentapeptide, and their in vitro anti-tumor activity towards the panel of human tumor cell line, such as, A549, A549/DPP, HepG2 and SMMC-7721 using MTT assay. We have also investigated the effect of galaxamide and its representative analogues on growth, cell-cycle phases, and induction of apoptosis in SMMC-7721 cells in vitro. Reckon with the significance of conformational space and N-Me aminoacid (aa) comprising this compound template, we designed the analogues with modification in N-Me-aa position, change in aa configuration from l to d aa and substitute one Leu-aa to d/l Phe-aa residue with respective to the parent structure. The efficient solid phase parallel synthesis approach is employed for the linear pentapeptide residue containing N-Me aa, followed by solution phase macrocyclisation to afford target cyclo pentapeptide compounds. In the present study, all galaxamide analogues exhibited growth inhibition in A549, A549/DPP, SMMC-7721 and HepG2 cell lines. Compounds 6, 18, and 22 exhibited interesting activities towards all cell line tested, while Compounds 1, 4, 15, and 22 showed strong activity towards SMMC-7221 cell line in the range of 1-2 μg/mL IC50. Flow cytometry experiment revealed that galaxamide analogues namely Compounds 6, 18, and 22 induced concentration dependent SMMC-7721 cell apoptosis after 48 h. These compounds induced G0/G1 phase cell-cycle arrest and morphological changes indicating induction of apoptosis. Thus, findings of our study suggest that the galaxamide and its analogues 6, 18 and 22 exerted growth inhibitory effect on SMMC-7721 cells by arresting the cell cycle in the G0/G1 phase and inducing apoptosis. Compound 1 showed promising anti-tumor activity towards SMMC-7721 cancer cell line, which is 9 and 10 fold higher than galaxamide and reference DPP (cisplatin), respectively. PMID:27598177

  4. Design and Synthesis of Analogues of Marine Natural Product Galaxamide, an N-methylated Cyclic Pentapeptide, as Potential Anti-Tumor Agent in Vitro

    PubMed Central

    Lunagariya, Jignesh; Zhong, Shenghui; Chen, Jianwei; Bai, Defa; Bhadja, Poonam; Long, Weili; Liao, Xiaojian; Tang, Xiaoli; Xu, Shihai

    2016-01-01

    Herein, we report design and synthesis of novel 26 galaxamide analogues with N-methylated cyclo-pentapeptide, and their in vitro anti-tumor activity towards the panel of human tumor cell line, such as, A549, A549/DPP, HepG2 and SMMC-7721 using MTT assay. We have also investigated the effect of galaxamide and its representative analogues on growth, cell-cycle phases, and induction of apoptosis in SMMC-7721 cells in vitro. Reckon with the significance of conformational space and N-Me aminoacid (aa) comprising this compound template, we designed the analogues with modification in N-Me-aa position, change in aa configuration from l to d aa and substitute one Leu-aa to d/l Phe-aa residue with respective to the parent structure. The efficient solid phase parallel synthesis approach is employed for the linear pentapeptide residue containing N-Me aa, followed by solution phase macrocyclisation to afford target cyclo pentapeptide compounds. In the present study, all galaxamide analogues exhibited growth inhibition in A549, A549/DPP, SMMC-7721 and HepG2 cell lines. Compounds 6, 18, and 22 exhibited interesting activities towards all cell line tested, while Compounds 1, 4, 15, and 22 showed strong activity towards SMMC-7221 cell line in the range of 1–2 μg/mL IC50. Flow cytometry experiment revealed that galaxamide analogues namely Compounds 6, 18, and 22 induced concentration dependent SMMC-7721 cell apoptosis after 48 h. These compounds induced G0/G1 phase cell-cycle arrest and morphological changes indicating induction of apoptosis. Thus, findings of our study suggest that the galaxamide and its analogues 6, 18 and 22 exerted growth inhibitory effect on SMMC-7721 cells by arresting the cell cycle in the G0/G1 phase and inducing apoptosis. Compound 1 showed promising anti-tumor activity towards SMMC-7721 cancer cell line, which is 9 and 10 fold higher than galaxamide and reference DPP (cisplatin), respectively. PMID:27598177

  5. Expression of a Recombinant Anti-HIV and Anti-Tumor Protein, MAP30, in Nicotiana tobacum Hairy Roots: A pH-Stable and Thermophilic Antimicrobial Protein

    PubMed Central

    Moghadam, Ali; Niazi, Ali; Afsharifar, Alireza; Taghavi, Seyed Mohsen

    2016-01-01

    In contrast to conventional antibiotics, which microorganisms can readily evade, it is nearly impossible for a microbial strain that is sensitive to antimicrobial proteins to convert to a resistant strain. Therefore, antimicrobial proteins and peptides that are promising alternative candidates for the control of bacterial infections are under investigation. The MAP30 protein of Momordica charantia is a valuable type I ribosome-inactivating protein (RIP) with anti-HIV and anti-tumor activities. Whereas the antimicrobial activity of some type I RIPs has been confirmed, less attention has been paid to the antimicrobial activity of MAP30 produced in a stable, easily handled, and extremely cost-effective protein-expression system. rMAP30-KDEL was expressed in Nicotiana tobacum hairy roots, and its effect on different microorganisms was investigated. Analysis of the extracted total proteins of transgenic hairy roots showed that rMAP30-KDEL was expressed effectively and that this protein exhibited significant antibacterial activity in a dose-dependent manner. rMAP30-KDEL also possessed thermal and pH stability. Bioinformatic analysis of MAP30 and other RIPs regarding their conserved motifs, amino-acid contents, charge, aliphatic index, GRAVY value, and secondary structures demonstrated that these factors accounted for their thermophilicity. Therefore, RIPs such as MAP30 and its derived peptides might have promising applications as food preservatives, and their analysis might provide useful insights into designing clinically applicable antibiotic agents. PMID:27459300

  6. Expression of a Recombinant Anti-HIV and Anti-Tumor Protein, MAP30, in Nicotiana tobacum Hairy Roots: A pH-Stable and Thermophilic Antimicrobial Protein.

    PubMed

    Moghadam, Ali; Niazi, Ali; Afsharifar, Alireza; Taghavi, Seyed Mohsen

    2016-01-01

    In contrast to conventional antibiotics, which microorganisms can readily evade, it is nearly impossible for a microbial strain that is sensitive to antimicrobial proteins to convert to a resistant strain. Therefore, antimicrobial proteins and peptides that are promising alternative candidates for the control of bacterial infections are under investigation. The MAP30 protein of Momordica charantia is a valuable type I ribosome-inactivating protein (RIP) with anti-HIV and anti-tumor activities. Whereas the antimicrobial activity of some type I RIPs has been confirmed, less attention has been paid to the antimicrobial activity of MAP30 produced in a stable, easily handled, and extremely cost-effective protein-expression system. rMAP30-KDEL was expressed in Nicotiana tobacum hairy roots, and its effect on different microorganisms was investigated. Analysis of the extracted total proteins of transgenic hairy roots showed that rMAP30-KDEL was expressed effectively and that this protein exhibited significant antibacterial activity in a dose-dependent manner. rMAP30-KDEL also possessed thermal and pH stability. Bioinformatic analysis of MAP30 and other RIPs regarding their conserved motifs, amino-acid contents, charge, aliphatic index, GRAVY value, and secondary structures demonstrated that these factors accounted for their thermophilicity. Therefore, RIPs such as MAP30 and its derived peptides might have promising applications as food preservatives, and their analysis might provide useful insights into designing clinically applicable antibiotic agents. PMID:27459300

  7. Boosting the MHC Class II-Restricted Tumor Antigen Presentation to CD4+ T Helper Cells: A Critical Issue for Triggering Protective Immunity and Re-Orienting the Tumor Microenvironment Toward an Anti-Tumor State.

    PubMed

    Accolla, Roberto S; Lombardo, Letizia; Abdallah, Rawan; Raval, Goutham; Forlani, Greta; Tosi, Giovanna

    2014-01-01

    Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.

  8. Boosting the MHC Class II-Restricted Tumor Antigen Presentation to CD4+ T Helper Cells: A Critical Issue for Triggering Protective Immunity and Re-Orienting the Tumor Microenvironment Toward an Anti-Tumor State

    PubMed Central

    Accolla, Roberto S.; Lombardo, Letizia; Abdallah, Rawan; Raval, Goutham; Forlani, Greta; Tosi, Giovanna

    2014-01-01

    Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes. PMID:24600588

  9. Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer

    PubMed Central

    Herrmann, Amanda C.; Bernatchez, Chantale; Haymaker, Cara; Molldrem, Jeffrey J.; Hong, Waun Ki; Perez-Soler, Roman

    2016-01-01

    Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation. PMID:27467256

  10. Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer.

    PubMed

    Im, Jin S; Herrmann, Amanda C; Bernatchez, Chantale; Haymaker, Cara; Molldrem, Jeffrey J; Hong, Waun Ki; Perez-Soler, Roman

    2016-01-01

    Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation. PMID:27467256

  11. Comparison of the Anti-tumor Effects of Two Platinum Agents (Miriplatin and Fine-Powder Cisplatin)

    SciTech Connect

    Watanabe, Shobu Nitta, Norihisa Ohta, Shinichi Sonoda, Akinaga Otani, Hideji Tomozawa, Yuki Nitta-Seko, Ayumi Tsuchiya, Keiko Tanka, Toyohiko Takahashi, Masashi Murata, Kiyoshi

    2012-04-15

    Purpose: This study was designed to evaluate the anti-tumor effects of miriplatin-lipidol and fine-powder cisplatin-lipiodol suspensions. Methods: Assessment of the cytotoxicity of two drugs was performed: a soluble derivative of miriplatin (DPC) and fine-powder cisplatin. We randomly divided 15 rabbits with transplanted VX2 liver tumors into three equal groups. They were infused via the proper hepatic artery with a miriplatin-lipiodol suspension (ML), a fine-powder cisplatin-lipiodol suspension (CL), or saline (control) and the tumor growth rate was determined on MR images acquired before and 7 days after treatment. The concentration of platinum (PCs) in blood was assayed immediately, and 10, 30, and 60 min, and 24 h and 7 days after drug administration. Its concentration in tumor and surrounding normal liver tissues was determined at 7 days postadministration. Results: At high concentrations, fine-powder cisplatin exhibited stronger cytotoxicity than DPC. At low concentrations, both agents manifested weak cytotoxicity. While there was no difference between the tumor growth rate of the ML and the CL groups, the difference between the controls and ML- and CL-treated rabbits was significant. The blood PCs peaked at 10 min and then gradually decreased over time. On the other hand, no platinum was detected at any point after the administration of ML. There was no difference between the ML and CL groups in the PCs in tumor tissues; however, in normal hepatic tissue, the PCs were higher in ML- than CL-treated rabbits. Conclusions: We confirmed the anti-tumor effect of ML and CL. There was no significant difference between the anti-tumor effect of ML and CL at 7 days postadministration.

  12. Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic, anti-tumor effects

    PubMed Central

    Yoo, Ji Young; Hurwitz, Brian S; Bolyard, Chelsea; Yu, Jun-Ge; Zhang, Jianying; Selvendiran, Karuppaiyah; Rath, Kellie S; He, Shun; Bailey, Zachary; Eaves, David; Cripe, Timothy P; Parris, Deborah S.; Caligiuri, Michael A.; Yu, Jianhua; Old, Matthew; Kaur, Balveen

    2014-01-01

    Background Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic HSV-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for anti-tumor efficacy. Methods The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western-blot assays were used to evaluate induction of ER stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Anti-tumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan-Meier curves and two-sided log rank test. Results Combination treatment with bortezomib and oHSV, 34.5ENVE, displayed strong synergistic interaction in ovarian cancer, head & neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK and IRE1α (western blot analysis) and the UPR (induction of hsp40, 70 and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (p value <0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced anti-tumor efficacy in multiple different tumor models in vivo. Conclusions The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib- induced UPR and warrants future clinical testing in patients. PMID:24815720

  13. Improved Anti-Tumoral Therapeutic Efficacy of 4-Hydroxynonenal Incorporated in Novel Lipid Nanocapsules in 2D and 3D Models.

    PubMed

    Pizzimenti, Stefania; Daga, Martina; Ciamporcero, Eric; Toaldo, Cristina; Pettazzoni, Piergiorgio; Osella-Abate, Simona; Novelli, Mauro; Minelli, Rosalba; Bisazza, Agnese; Gamba, Paola; Testa, Gabriella; Ullio, Chiara; Ferruti, Paolo; Ranucci, Elisabetta; Bernengo, Maria Grazia; Ferretti, Carlo; Dianzani, Chiara; Biasi, Fiorella; Barrera, Giuseppina; Cavalli, Roberta

    2015-12-01

    4-hydroxynonenal (HNE), a lipid peroxidation product, is a promising anti-neoplastic drug due to its remarkable anti-cancer activities. However, this possibility has not been explored, because the delivery of HNE is very challenging as a result of its low solubility and its poor stability. This study intentionally designed a new type of lipid nanocapsules specifically for HNE delivery. They consist of a medium chain triglyceride liquid oil core surrounded by a polymer shell. A β-cyclodextrin-poly(4-acryloylmorpholine) conjugate was selected as the shell component. HNE-loaded nanocapsules were about 350 nm in size with a negative surface charge. They were stable for two years when stored in suspensions at 4 degrees C. In vitro experiments showed that HNE was released from the nanocapsules at a considerable rate. Nanocapsule uptake into cells was evaluated using a fluorescent formulation that revealed rapid internalisation. Cytotoxicity studies demonstrated the safety of the formulation. Enhanced anti-tumoral activity against various cell lines, depending on increased HNE stability, was obtained by using HNE-loaded nanocapsules. In particular, we have demonstrated an increase in anti-proliferative, pro-apoptotic and differentiative activity in several tumour cell lines from different tissues. Moreover, we evaluated the effects of these new nanocapsules on a three-dimensional human reconstructed model of skin melanoma. Interestingly, the encouraging results obtained with topical administration on the epidermal surface could open new perspectives in melanoma treatments. PMID:26510311

  14. The in vitro and in vivo anti-tumor effects of MTX-Fe3O 4-PLLA-PEG-PLLA microspheres prepared by suspension-enhanced dispersion by supercritical CO2.

    PubMed

    Chen, AiZheng; Dang, TingTing; Wang, ShiBin; Tang, Na; Liu, YuanGang; Wu, WenGuo

    2014-07-01

    The in vitro and in vivo anti-tumor efficacy of methotrexate-loaded Fe3O4-poly-L-lactide-poly(ethylene glycol)-poly-L-lactide magnetic composite microspheres (MTX-Fe3O4-PLLA-PEG-PLLA MCMs, MMCMs), which were produced by co-precipitation (C) and microencapsulation (M) in a supercritical process, was evaluated at various levels: cellular, molecular, and integrated. The results at the cellular level indicate that MMCMs (M) show a better anti-proliferation activity than raw MTX and could induce morphological changes of cells undergoing apoptosis. At the molecular level, MMCMs (M) lead to a significantly higher relative mRNA expression of bax/bcl-2 and caspase-3 than MMCMs (C) at 10 μg mL(-1) (P<0.01); and the pro-caspase-3 protein expression measured by Western blot analysis also demonstrates that MMCMs (M) can effectively activate pro-caspase-3. At the integrated level, mice bearing a sarcoma-180 tumor are used; in vivo anti-tumor activity tests reveal that MMCMs (M) with magnetic induction display a much higher tumor suppression rate and lower toxicity than raw MTX. Pharmacokinetic studies show that MMCMs (M) with magnetic induction significantly increase the accumulation of MTX in the tumor tissue compared with the other treatments. These results suggest that the MMCMs (M) prepared by the SpEDS process have great potential to play a positive role in the magnetic targeted therapy field. PMID:24935781

  15. Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack

    PubMed Central

    Cacan, Ercan; Spring, Alexander M.; Kumari, Anita; Greer, Susanna F.; Garnett-Benson, Charlie

    2015-01-01

    Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8+ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity. PMID:26703577

  16. Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects.

    PubMed

    Da, Ya-jing; Yuan, Wei-dong; Xin, Ting; Nie, Yong-yan; Ye, Ying; Yan, Yi-Jia; Liang, Li-sha; Chen, Zhi-long

    2012-12-15

    The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activities were evaluated by Ang II receptor binding assay as well as by in vivo assay. All of the synthesized compounds showed nanomolar affinity for the AT(1) receptor subtype. The vivo biological evaluation showed that compounds 1a, 2 and 4 produced a dose-dependent antihypertensive effect both in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Compound 4 especially showed an efficient and long-lasting effect in reducing blood pressure which can last more than 24 h at dose of 10 mg/kg in SHR, which was much better than control Losartan and Valsartan. Compound 4 can also inhibit the prostate cancer in vitro and in vivo. So compound 4 was selected for in-depth investigation as potent, novel and long-lasting non-tetrazole anti-hypertension and anti-tumor drug candidate. PMID:23122933

  17. Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo

    SciTech Connect

    Kurio, Naito; Shimo, Tsuyoshi; Fukazawa, Takuya; Takaoka, Munenori; Okui, Tatsuo; Hassan, Nur Mohammad Monsur; Honami, Tatsuki; Hatakeyama, Shinji; Ikeda, Masahiko; Naomoto, Yoshio; Sasaki, Akira

    2011-05-01

    Focal adhesion kinase (FAK) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAK overexpression is frequently found in invasive and metastatic cancers of the breast, colon, thyroid, and prostate, but its role in osteolytic metastasis is not well understood. In this study, we have analyzed anti-tumor effects of the novel FAK Tyr{sup 397} inhibitor TAE226 against bone metastasis in breast cancer by using TAE226. Oral administration of TAE226 in mice significantly decreased bone metastasis and osteoclasts involved which were induced by MDA-MB-231 breast cancer cells and increased the survival rate of the mouse models of bone metastasis. TAE226 also suppressed the growth of subcutaneous tumors in vivo and the proliferation and migration of MDA-MB-231 cells in vitro. Significantly, TAE226 inhibited the osteoclast formation in murine pre-osteoclastic RAW264.7 cells, and actin ring and pit formation in mature osteoclasts. Moreover, TAE226 inhibited the receptor activator for nuclear factor {kappa} B Ligand (RANKL) gene expression induced by parathyroid hormone-related protein (PTHrP) in bone stromal ST2 cells and blood free calcium concentration induced by PTHrP administration in vivo. These findings suggest that FAK was critically involved in osteolytic metastasis and activated in tumors, pre-osteoclasts, mature osteoclasts, and bone stromal cells and TAE226 can be effectively used for the treatment of cancer induced bone metastasis and other bone diseases.

  18. Scaling dynamic response and destructive metabolism in an immunosurveillant anti-tumor system modulated by different external periodic interventions.

    PubMed

    Shao, Yuanzhi; Hu, Wenyong; Zhong, Weirong; Li, Li

    2011-01-14

    On the basis of two universal power-law scaling laws, i.e. the scaling dynamic hysteresis in physics and the allometric scaling metabolism in biosystem, we studied the dynamic response and the evolution of an immunosurveillant anti-tumor system subjected to a periodic external intervention, which is equivalent to the scheme of a radiotherapy or chemotherapy, within the framework of the growth dynamics of tumor. Under the modulation of either an abrupt or a gradual change external intervention, the population density of tumors exhibits a dynamic hysteresis to the intervention. The area of dynamic hysteresis loop characterizes a sort of dissipative-therapeutic relationship of the dynamic responding of treated tumors with the dose consumption of accumulated external intervention per cycle of therapy. Scaling the area of dynamic hysteresis loops against the intensity of an external intervention, we deduced a characteristic quantity which was defined as the theoretical therapeutic effectiveness of treated tumor and related with the destructive metabolism of tumor under treatment. The calculated dose-effectiveness profiles, namely the dose cumulant per cycle of intervention versus the therapeutic effectiveness, could be well scaled into a universal quadratic formula regardless of either an abrupt or a gradual change intervention involved. We present a new concept, i.e., the therapy-effect matrix and the dose cumulant matrix, to expound the new finding observed in the growth and regression dynamics of a modulated anti-tumor system.

  19. The anti-tumor effect of resveratrol alone or in combination with immunotherapy in a neuroblastoma model.

    PubMed

    Soto, Brenda L; Hank, Jacquelyn A; Van De Voort, Tyler J; Subramanian, Lalita; Polans, Arthur S; Rakhmilevich, Alexander L; Yang, Richard K; Seo, Songwong; Kim, KyungMann; Reisfeld, Ralph A; Gillies, Stephen D; Sondel, Paul M

    2011-05-01

    We investigated the anti-tumor effect of peritumoral resveratrol in combination with immunotherapy in vivo in neuroblastoma-bearing mice. Subcutaneous NXS2 tumors were induced in A/J mice. On day 10, some mice received 15 mcg of intravenous immunocytokine for 5 days, mice received 20 mg of peritumoral resveratrol twice a week (starting on day 12) for a total of 5 injections, and a separate group received a combination of both regimens. Tumor progression and survival were assessed every 3-4 days. Blood and primary tumor tissue samples were collected on day 20 for Complete Blood Count and CD45 immunohistochemistry and histology, respectively. The primary tumor regressed in all mice receiving peritumoral resveratrol. Most of these mice receiving peritumoral resveratrol alone developed metastatic tumors and recurrence of the primary tumor after cessation of therapy. When resveratrol and immunocytokine regimens were combined, 61% of the mice receiving this combination therapy resolved their primary tumors and survived without developing metastatic tumors, compared to 15 and 13% receiving resveratrol or immunocytokine alone, respectively. None of the therapeutic regimes prevented lymphocyte infiltration or affected the complete blood count. Greater necrosis was observed microscopically in tumors from mice receiving the combination therapy. These results demonstrate that the combination therapy of peritumoral resveratrol plus intravenous immunocytokine provides better anti-tumor effects in this model than either therapy alone.

  20. Anti-Tumor Effect of Steamed Codonopsis lanceolata in H22 Tumor-Bearing Mice and Its Possible Mechanism

    PubMed Central

    Li, Wei; Xu, Qi; He, Yu-Fang; Liu, Ying; Yang, Shu-Bao; Wang, Zi; Zhang, Jing; Zhao, Li-Chun

    2015-01-01

    Although previous studies confirmed that steaming and the fermentation process could significantly improve the cognitive-enhancement and neuroprotective effects of Codonopsis lanceolata, the anti-tumor efficacy of steamed C. lanceolata (SCL) and what mechanisms are involved remain largely unknown. The present study was designed to evaluate the anti-tumor effect in vivo of SCL in H22 tumor-bearing mice. The results clearly indicated that SCL could not only inhibit the tumor growth, but also prolong the survival time of H22 tumor-bearing mice. Besides, the serum levels of cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-2 (IL-2), were enhanced by SCL administration. The observations of Hoechst 33258 staining demonstrated that SCL was able to induce tumor cell apoptosis. Finally, immunohistochemical analysis revealed that SCL treatment significantly increased Bax expression and decreased Bcl-2 and vascular endothelial growth factor (VEGF) expression of H22 tumor tissues in a dose-dependent manner. Moreover, LC/MS analysis of SCL indicated that it mainly contained lobetyolin and six saponins. Taken all together, the findings in the present study clearly demonstrated that SCL inhibited the H22 tumor growth in vivo at least partly via improving the immune functions, inducing apoptosis and inhibiting angiogenesis. PMID:26426041

  1. Downregulation of amplified in breast cancer 1 contributes to the anti-tumor effects of sorafenib on human hepatocellular carcinoma

    PubMed Central

    Dan, Yuzhen; Tong, Zhangwei; Chen, Wenbo; Qin, Liping; Liu, Kun; Li, Wengang; Mo, Pingli; Yu, Chundong

    2016-01-01

    Multi-kinase inhibitor sorafenib represents a major breakthrough in the therapy of advanced hepatocellular carcinoma (HCC). Amplified in breast cancer 1 (AIB1) is frequently overexpressed in human HCC tissues and promotes HCC progression. In this study, we investigated the effects of sorafenib on AIB1 expression and the role of AIB1 in anti-tumor effects of sorafenib. We found that sorafenib downregulated AIB1 protein expression by inhibiting AIB1 mRNA translation through simultaneously blocking eIF4E and mTOR/p70S6K/RP-S6 signaling. Knockdown of AIB1 significantly promoted sorafenib-induced cell death, whereas overexpression of AIB1 substantially diminished sorafenib-induced cell death. Downregulation of AIB1 contributed to sorafenib-induced cell death at least in part through upregulating the levels of reactive oxygen species in HCC cells. In addition, resistance to sorafenib-induced downregulation of AIB1 protein contributes to the acquired resistance of HCC cells to sorafenib-induced cell death. Collectively, our study implicates that AIB1 is a molecular target of sorafenib and downregulation of AIB1 contributes to the anti-tumor effects of sorafenib. PMID:27105488

  2. In vitro Anti-Tumor Effects of Statins on Head and Neck Squamous Cell Carcinoma: A Systematic Review

    PubMed Central

    Pavan, Ludmila Madeira Cardoso; Rêgo, Daniela Fortunato; Elias, Silvia Taveira; De Luca Canto, Graziela; Guerra, Eliete Neves Silva

    2015-01-01

    Background Statins are commonly used against arteriosclerotic disease, but recent retrospective analyses have suggested that statins also prevent cancer. The aim of this systematic review is to verify the vitro anti-tumor effects of statins on head and neck squamous cell carcinoma. Methods Studies were gathered by searching Cochrane, MEDLINE, EMBASE, LILACS, and PubMed, up until May 9, 2015, with no time or language restrictions. Only in vitro studies that discuss the effect of statins on head and neck carcinoma were selected. Results Of 153 identified papers, 14 studies met the inclusion criteria. These studies demonstrated that statins had a significant effect on head and neck squamous cell carcinoma cell lines and influenced cell viability, cell cycle, cell death, and protein expression levels involved in pathways of carcinogenesis, which corroborates with the potential in vitro anti-tumor effects. It provides highlights about the biological mechanisms of statins used alone or associated with traditional therapy for cancer. Conclusions Though there are few studies on the topic, currently available evidence suggests that statins shows that preclinical experiments supports the potentiality of statin as an adjuvant agent in chemotherapy and/or radiotherapy approaches routinely used in the management of HNSCC and should undergo further clinical assessment. PMID:26098683

  3. A TLR9 agonist enhances the anti-tumor immunity of peptide and lipopeptide vaccines via different mechanisms.

    PubMed

    Song, Ying-Chyi; Liu, Shih-Jen

    2015-01-01

    The toll-like receptor 9 (TLR9) agonists CpG oligodeoxynucleotides (CpG ODNs) have been recognized as promising adjuvants for vaccines against infectious diseases and cancer. However, the role of TLR9 signaling in the regulation of antigen uptake and presentation is not well understood. Therefore, to investigate the effects of TLR9 signaling, this study used synthetic peptides (IDG) and lipopeptides (lipoIDG), which are internalized by dendritic cells (DCs) via endocytosis-dependent and endocytosis-independent pathways, respectively. Our data demonstrated that the internalization of lipoIDG and IDG by bone marrow-derived dendritic cells (BMDCs) was not enhanced in the presence of CpG ODNs; however, CpG ODNs prolonged the co-localization of IDG with CpG ODNs in early endosomes. Surprisingly, CpG ODNs enhanced CD8(+) T cell responses, and the anti-tumor effects of IDG immunization were stronger than those of lipoIDG immunization. LipoIDG admixed with CpG ODNs induced low levels of CD8(+) T cells and partially inhibit tumor growth. Our findings suggest that CpG ODNs increase the retention of antigens in early endosomes, which is important for eliciting anti-tumor immunity. These results will facilitate the application of CpG adjuvants in the design of different vaccines.

  4. CD4+CD25+FOXP3+ Regulatory T Cells Suppress Anti-Tumor Immune Responses in Patients with Colorectal Cancer

    PubMed Central

    Plant, Andrea; Wright, Kate L.; El-Shanawany, Tariq M.; Harrop, Richard; Torkington, Jared; Rees, Brian I.; Williams, Geraint T.

    2006-01-01

    Background A wealth of evidence obtained using mouse models indicates that CD4+CD25+FOXP3+ regulatory T cells (Treg) maintain peripheral tolerance to self-antigens and also inhibit anti-tumor immune responses. To date there is limited information about CD4+ T cell responses in patients with colorectal cancer (CRC). We set out to measure T cell responses to a tumor-associated antigen and examine whether Treg impinge on those anti-tumor immune responses in CRC patients. Methodology and Principal Findings Treg were identified and characterized as CD4+CD25+FOXP3+ using flow cytometry. An increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4+ T cell responses, as observed by IFNγ release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group. Conclusions/Significance Collectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen-specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy. PMID:17205133

  5. Characterization of a Newly Isolated Marine Fungus Aspergillus dimorphicus for Optimized Production of the Anti-Tumor Agent Wentilactones

    PubMed Central

    Xu, Rui; Xu, Gang-Ming; Li, Xiao-Ming; Li, Chun-Shun; Wang, Bin-Gui

    2015-01-01

    The potential anti-tumor agent wentilactones were produced by a newly isolated marine fungus Aspergillus dimorphicus. This fungus was derived from deep-sea sediment and identified by polyphasic approach, combining phenotypic, molecular, and extrolite profiles. However, wentilactone production was detected only under static cultures with very low yields. In order to improve wentilactone production, culture conditions were optimized using the response surface methodology. Under the optimal static fermentation conditions, the experimental values were closely consistent with the prediction model. The yields of wentilactone A and B were increased about 11-fold to 13.4 and 6.5 mg/L, respectively. The result was further verified by fermentation scale-up for wentilactone production. Moreover, some small-molecule elicitors were found to have capacity of stimulating wentilactone production. To our knowledge, this is first report of optimized production of tetranorlabdane diterpenoids by a deep-sea derived marine fungus. The present study might be valuable for efficient production of wentilactones and fundamental investigation of the anti-tumor mechanism of norditerpenoids. PMID:26610530

  6. Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

    NASA Astrophysics Data System (ADS)

    Acquaviva, Joseph T.; Hasanjee, Aamr M.; Bahavar, Cody F.; Zhou, Fefian; Liu, Hong; Howard, Eric W.; Bullen, Liz C.; Silvy, Ricardo P.; Chen, Wei R.

    2015-03-01

    Laser immunotherapy (LIT) is being developed as a treatment modality for metastatic cancer which can destroy primary tumors and induce effective systemic anti-tumor responses by using a targeted treatment approach in conjunction with the use of a novel immunoadjuvant, glycated chitosan (GC). In this study, Non-invasive Laser Immunotherapy (NLIT) was used as the primary treatment mode. We incorporated single-walled carbon nanotubes (SWNTs) into the treatment regimen to boost the tumor-killing effect of LIT. SWNTs and GC were conjugated to create a completely novel, immunologically modified carbon nanotube (SWNT-GC). To determine the efficacy of different laser irradiation durations, 5 minutes or 10 minutes, a series of experiments were performed. Rats were inoculated with DMBA-4 cancer cells, a highly aggressive metastatic cancer cell line. Half of the treatment group of rats receiving laser irradiation for 10 minutes survived without primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 minutes had no survivors. Thus, Laser+SWNT-GC treatment with 10 minutes of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

  7. ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy

    PubMed Central

    Li, Chunyang; Li, Weiyun; Xiao, Jun; Jiao, Shaozhuo; Teng, Fei; Xue, Shengjie; Zhang, Chi; Sheng, Chun; Leng, Qibin; Rudd, Christopher E; Wei, Bin; Wang, Hongyan

    2015-01-01

    PD-1 negatively regulates CD8+ cytotoxic T lymphocytes (CTL) cytotoxicity and anti-tumor immunity. However, it is not fully understood how PD-1 expression on CD8+ CTL is regulated during anti-tumor immunotherapy. In this study, we have identified that the ADAP-SKAP55 signaling module reduced CD8+ CTL cytotoxicity and enhanced PD-1 expression in a Fyn-, Ca2+-, and NFATc1-dependent manner. In DC vaccine-based tumor prevention and therapeutic models, knockout of SKAP55 or ADAP showed a heightened protection from tumor formation or metastases in mice and reduced PD-1 expression in CD8+ effector cells. Interestingly, CTLA-4 levels and the percentages of tumor infiltrating CD4+Foxp3+ Tregs remained unchanged. Furthermore, adoptive transfer of SKAP55-deficient or ADAP-deficient CD8+ CTLs significantly blocked tumor growth and increased anti-tumor immunity. Pretreatment of wild-type CD8+ CTLs with the NFATc1 inhibitor CsA could also downregulate PD-1 expression and enhance anti-tumor therapeutic efficacy. Together, we propose that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway might increase efficacy of anti-tumor immunotherapy. PMID:25851535

  8. Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn's disease treated with anti-tumor necrosis factor antibodies.

    PubMed

    Eder, Piotr; Michalak, Michal; Katulska, Katarzyna; Lykowska-Szuber, Liliana; Krela-Kazmierczak, Iwona; Stawczyk-Eder, Kamila; Klimczak, Katarzyna; Szymczak, Aleksandra; Linke, Krzysztof

    2015-01-01

    The aim of the study was to assess the role of magnetic resonance enterography (MRE) in predicting one-year efficacy of anti-tumor necrosis factor antibodies--infliximab (IFX), adalimumab (ADA) in Crohn's disease (CD) patients primarily responding to therapy. We performed retrospective analysis among 61 CD patients who had undergone a successful IFX/ADA induction therapy and were treated with maintenance doses. All patients underwent MRE at week 0. We assessed which MRE features were predictive for steroid-free remission at week 52, and which were associated with a secondary loss of response. 44 patients were in steroid-free remission at week 52, 17--were secondary non-responders. The ROC curve showed that bowel thickening with contrast enhancement analyzed together at week 0 were associated with steroid-free remission at week 52 (p = 0.01; AUC 0.67). Bowel stenosis with or without prestenotic dilatation [OR 5.8 (95% CI 1.4-25) and 2.4 (95% CI 1.2 - 5) respectively; p = 0.01] and the presence of intra-abdominal fistulas [OR 1.4 (95% CI 1.1-2); p=0.004] were related to secondary non-response. A high baseline inflammatory activity detected by MRE predicts one-year response in CD after IFX/ADA. In case of bowel stenosis, intra-abdominal fistulas, other therapeutic options should be considered.

  9. Prodigiosin rescues deficient p53 signaling and anti-tumor effects via up-regulating p73 and disrupting its interaction with mutant p53

    PubMed Central

    Hong, Bo; Prabhu, Varun V.; Zhang, Shengliang; van den Heuvel, A. Pieter J.; Dicker, David T.; Kopelovich, Levy; El-Deiry, Wafik S.

    2015-01-01

    p53 reactivation offers a broad-based strategy for cancer therapy. In this study we report the identification of prodigiosin that can reactivate p53 family-dependent transcriptional activity in p53 deficient human colon cancer cells. Prodigiosin and its structural analogue (compound R) induced the expression of p53 target genes accompanied by cell cycle arrest and apoptosis in p53 deficient cancer cells. Prodigiosin restored p53 signaling in cancer cells harboring hotspot p53 mutations, with little to no detectable cytotoxicity in normal human fibroblasts and with no genotoxicity. Prodigiosin induced the expression of p73 and disrupted its interaction with mutant p53, thereby rescuing p53 pathway deficiency and promoting anti-tumor effects. The disruption of mutant p53/p73 interaction was specific to prodigiosin and not related to mTOR inhibition. Our findings suggest that mutant p53 needs to be targeted in the context of p73 stimulation to allow efficient restoration of the p53 pathway. In exhibiting this capability, prodigiosin and its analogue provide lead compounds to rescue deficiencies in the p53 pathway in cancer cells by up-regulating p73 and targeting mutant p53/p73 interaction there. PMID:24247721

  10. Multivalent presentation of MPL by porous silicon microparticles favors T helper 1 polarization enhancing the anti-tumor efficacy of doxorubicin nanoliposomes.

    PubMed

    Meraz, Ismail M; Hearnden, Claire H; Liu, Xuewu; Yang, Marie; Williams, Laura; Savage, David J; Gu, Jianhua; Rhudy, Jessica R; Yokoi, Kenji; Lavelle, Ed C; Serda, Rita E

    2014-01-01

    Porous silicon (pSi) microparticles, in diverse sizes and shapes, can be functionalized to present pathogen-associated molecular patterns that activate dendritic cells. Intraperitoneal injection of MPL-adsorbed pSi microparticles, in contrast to free MPL, resulted in the induction of local inflammation, reflected in the recruitment of neutrophils, eosinophils and proinflammatory monocytes, and the depletion of resident macrophages and mast cells at the injection site. Injection of microparticle-bound MPL resulted in enhanced secretion of the T helper 1 associated cytokines IFN-γ and TNF-α by peritoneal exudate and lymph node cells in response to secondary stimuli while decreasing the anti-inflammatory cytokine IL-10. MPL-pSi microparticles independently exhibited anti-tumor effects and enhanced tumor suppression by low dose doxorubicin nanoliposomes. Intravascular injection of the MPL-bound microparticles increased serum IL-1β levels, which was blocked by the IL-1 receptor antagonist Anakinra. The microparticles also potentiated tumor infiltration by dendritic cells, cytotoxic T lymphocytes, and F4/80+ macrophages, however, a specific reduction was observed in CD204+ macrophages.

  11. Turmeric enhancing anti-tumor effect of Rhizoma paridis saponins by influencing their metabolic profiling in tumors of H22 hepatocarcinoma mice.

    PubMed

    Man, Shuli; Chai, Hongyan; Qiu, Peiyu; Liu, Zhen; Fan, Wei; Wang, Jiaming; Gao, Wenyuan

    2015-12-01

    Rhizoma Paridis saponins combined with turmeric (RT) showed well anti-hepatocarcinoma activities in our previous research. The aim of this study was to investigate the progression of the biochemical response to RT and capture metabolic variations during intragastric administration of their compatibility. In the experiment, histopathological examination and (1)H NMR method were developed and validated for the metabolic profiling of RT intervention in H22 tumor growth. Data were analyzed with principal components analysis (PCA) and partial least-squares discrimination analysis (PLS-DA). As a result, Rhizoma paridis saponins (RPS) or RT induced inflammatory cell infiltration in tumors. RT also mediated the tumor microenvironment to promote anti-tumor immunity of mice. RT significantly inhibited tumor growth rate through suppressing levels of amino acids containing alanine, asparagine, glutamine, putrescine, and sarcosine, lipid compounds, and carbohydrates like myo-inositol and arabinose in the tumor tissues. In conclusion, these results uncovered unexpectedly poor nutritional conditions in the RT-treated tumor tissues whose effect was stronger than RPS's. Therefore, RT could be a novel anticancer agent that targets on cancer metabolism through starving tumors reducing viability of cancer cells.

  12. Dysregulated Expression of Glycolipids in Tumor Cells: From Negative Modulator of Anti-tumor Immunity to Promising Targets for Developing Therapeutic Agents

    PubMed Central

    Daniotti, Jose Luis; Lardone, Ricardo D.; Vilcaes, Aldo A.

    2016-01-01

    Glycolipids are complex molecules consisting of a ceramide lipid moiety linked to a glycan chain of variable length and structure. Among these are found the gangliosides, which are sialylated glycolipids ubiquitously distributed on the outer layer of vertebrate plasma membranes. Changes in the expression of certain species of gangliosides have been described to occur during cell proliferation, differentiation, and ontogenesis. However, the aberrant and elevated expression of gangliosides has been also observed in different types of cancer cells, thereby promoting tumor survival. Moreover, gangliosides are actively released from the membrane of tumor cells, having a strong impact on impairing anti-tumor immunity. Beyond the undesirable effects of gangliosides in cancer cells, a substantial number of cancer immunotherapies have been developed in recent years that have used gangliosides as the main target. This has resulted in successful immune cell- or antibody-responses against glycolipids, with promising results having been obtained in clinical trials. In this review, we provide a general overview on the metabolism of glycolipids, both in normal and tumor cells, as well as examining glycolipid-mediated immune modulation and the main successes achieved in immunotherapies using gangliosides as molecular targets. PMID:26779443

  13. Use of anti-tumor necrosis factor biologics in the treatment of rheumatoid arthritis does not change human T-lymphotropic virus type 1 markers: a case series.

    PubMed

    Umekita, Kunihiko; Umeki, Kazumi; Miyauchi, Shunichi; Ueno, Shiro; Kubo, Kazuyoshi; Kusumoto, Norio; Takajo, Ichiro; Nagatomo, Yasuhiro; Okayama, Akihiko

    2015-09-01

    Anti-tumor necrosis factor (anti-TNF) biologics are effective in the treatment of rheumatoid arthritis (RA); however, it is still not clear whether this treatment promotes the development of malignancies such as lymphoma. Human T-lymphotropic virus type 1 (HTLV-1), which is a causative agent of adult T-cell lymphoma (ATL), is prevalent in Japan. Many HTLV-1-positive patients with RA are assumed to exist; however, there have thus far been no reports on the effect of anti-TNF biologics on HTLV-1-positive patients. We analyzed the response to treatment with anti-TNF biologics and change of HTLV-1 markers in two cases of RA. The two cases showed no response based on the European League Against of Rheumatism response criteria 60-96 weeks after administration of anti-TNF biologics (infliximab and etanercept). No signs of ATL were observed and HTLV-1 markers, such as proviral load and clonality of HTLV-1-infected cells, showed no significant change in either of two cases. Therefore, treatment with anti-TNF biologics did not induce activation of HTLV-1, although the effect on RA was not as effective as in HTLV-1-negative patients in this limited study. Further long-term study with a greater number of patients is necessary to clarify the safety and efficacy of anti-TNF biologics in HTLV-1-positive patients with RA.

  14. Aerosol delivery of beclin1 enhanced the anti-tumor effect of radiation in the lungs of K-rasLA1 mice.

    PubMed

    Shin, Ji-Young; Lim, Hwang-Tae; Minai-Tehrani, Arash; Noh, Mi-Suk; Kim, Ji-Eun; Kim, Ji-Hye; Jiang, Hu-Lin; Arote, Rohidas; Kim, Doo-Yeol; Chae, Chanhee; Lee, Kee-Ho; Kim, Mi-Sook; Cho, Myung-Haing

    2012-07-01

    Radiotherapy alone has several limitations for treating lung cancer. Inhalation, a non-invasive approach for direct delivery of therapeutic agents to the lung, may help to enhance the therapeutic efficacy of radiation. Up-regulating beclin1, known as a tumor suppressor gene that plays a major role in autophagy, may sensitize tumors and lead to tumor regression in lungs of K-ras(LA1) lung cancer model mice. To minimize the side-effects of radiotherapy, fractionated exposures (five times, 24-h interval) with low dose (2 Gy) of radiation to the restricted area (thorax, 2 cm) were conducted. After sensitizing the lungs with radiation, beclin1, complexed with a nano-sized biodegradable poly(ester amine), was prepared and delivered into the murine lung via aerosol three times/week for four weeks. In a histopathological analysis, animals treated with beclin1 and radiation showed highly significant tumor regression and low progression to adenocarcinoma. An increase in the number of autophagic vacuoles and secondary lysosomes was detected. Dissociation of beclin1-bcl2 stimulated autophagy activation and showed a synergistic anti-tumor effect by inhibiting the Akt-mTOR pathway, cell proliferation and angiogenesis. The combination of radiation with non-invasive aerosol delivery of beclin1 may provide a prospect for developing novel therapy regimens applicable in clinics. PMID:22843615

  15. Synergistic anti-tumor actions of luteolin and silibinin prevented cell migration and invasion and induced apoptosis in glioblastoma SNB19 cells and glioblastoma stem cells.

    PubMed

    Chakrabarti, Mrinmay; Ray, Swapan K

    2015-12-10

    Glioblastoma is the most lethal brain tumor. Failure of conventional chemotherapies prompted the search for natural compounds for treatment of glioblastoma. Plant-derived flavonoids could be alternative medicine for inhibiting not only glioblastoma cells but also glioblastoma stem cells (GSC). Two plant-derived flavonoids are luteolin (LUT) and silibinin (SIL). We investigated anti-tumor mechanisms of LUT and SIL in different human glioblastoma cells and GSC and found significant synergistic inhibition of human glioblastoma LN18 and SNB19 cells and GSC following treatment with combination of 20µM LUT and 50µM SIL. Combination of 20µM LUT and 50µM SIL was more effective than a conventional chemotherapeutic agent (BCNU or TMZ). We continued our studies with SNB19 cells and GSC and found dramatic inhibition of cell migration from spheroids and also cell invasion through matrigel following treatment with combination of LUT and SIL. This combination was highly effective to block angiogenesis and survival pathways leading to induction of apoptosis. Inhibition of PKCα, XIAP, and iNOS ultimately caused induction of extrinsic and intrinsic pathways of apoptosis. Collectively, synergistic efficacy of LUT and SIL could be a promising therapy to inhibit cell migration and invasion and induce apoptosis in different glioblastoma cells including GSC.

  16. Modulation of the Anti-Tumor Efficacy of Photodynamic Therapy by Nitric Oxide

    PubMed Central

    Girotti, Albert W.

    2016-01-01

    Nitric oxide (NO) produced by nitric oxide synthase (NOS) enzymes is a free radical molecule involved in a wide variety of normophysiologic and pathophysiologic processes. Included in the latter category are cancer promotion, progression, and resistance to therapeutic intervention. Animal tumor photodynamic therapy (PDT) studies several years ago revealed that endogenous NO can reduce PDT efficacy and that NOS inhibitors can alleviate this. Until relatively recently, little else was known about this anti-PDT effect of NO, including: (a) the underlying mechanisms; (b) type(s) of NOS involved; and (c) whether active NO was generated in vascular cells, tumor cells, or both. In addressing these questions for various cancer cell lines exposed to PDT-like conditions, the author’s group has made several novel findings, including: (i) exogenous NO can scavenge lipid-derived free radicals arising from photostress, thereby protecting cells from membrane-damaging chain peroxidation; (ii) cancer cells can upregulate inducible NOS (iNOS) after a PDT-like challenge and the resulting NO can signal for resistance to photokilling; (iii) photostress-surviving cells with elevated iNOS/NO proliferate and migrate/invade more aggressively; and (iv) NO produced by photostress-targeted cells can induce greater aggressiveness in non-targeted bystander cells. In this article, the author briefly discusses these various means by which NO can interfere with PDT and how this may be mitigated by use of NOS inhibitors as PDT adjuvants. PMID:27775600

  17. Structure and Functional Characterization of Human Aspartate Transcarbamoylase, the Target of the Anti-tumoral Drug PALA.

    PubMed

    Ruiz-Ramos, Alba; Velázquez-Campoy, Adrián; Grande-García, Araceli; Moreno-Morcillo, María; Ramón-Maiques, Santiago

    2016-07-01

    CAD, the multienzymatic protein that initiates and controls de novo synthesis of pyrimidines in animals, associates through its aspartate transcarbamoylase (ATCase) domain into particles of 1.5 MDa. Despite numerous structures of prokaryotic ATCases, we lack structural information on the ATCase domain of CAD. Here, we report the structure and functional characterization of human ATCase, confirming the overall similarity with bacterial homologs. Unexpectedly, human ATCase exhibits cooperativity effects that reduce the affinity for the anti-tumoral drug PALA. Combining structural, mutagenic, and biochemical analysis, we identified key elements for the necessary regulation and transmission of conformational changes leading to cooperativity between subunits. Mutation of one of these elements, R2024, was recently found to cause the first non-lethal CAD deficit. We reproduced this mutation in human ATCase and measured its effect, demonstrating that this arginine is part of a molecular switch that regulates the equilibrium between low- and high-affinity states for the ligands.

  18. Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses.

    PubMed

    Joshi, Nikhil S; Akama-Garren, Elliot H; Lu, Yisi; Lee, Da-Yae; Chang, Gregory P; Li, Amy; DuPage, Michel; Tammela, Tuomas; Kerper, Natanya R; Farago, Anna F; Robbins, Rebecca; Crowley, Denise M; Bronson, Roderick T; Jacks, Tyler

    2015-09-15

    Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs have been described in human lung cancers, but their function remains to be determined. TLSs in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen-presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLSs upon Treg cell depletion, leading to tumor destruction. Thus, we propose that Treg cells in TA-TLSs can inhibit endogenous immune responses against tumors, and targeting these cells might provide therapeutic benefit for cancer patients.

  19. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses

    PubMed Central

    Joshi, Nikhil S.; Akama-Garren, Elliot H.; Lu, Yisi; Lee, Da-Yae; Chang, Gregory P.; Li, Amy; DuPage, Michel; Tammela, Tuomas; Kerper, Natanya R.; Farago, Anna F.; Robbins, Rebecca; Crowley, Denise M.; Bronson, Roderick T.; Jacks, Tyler

    2016-01-01

    SUMMARY Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically-engineered mouse lung adenocarcinoma model and found Treg cells suppress anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLS). TA-TLS have been described in human lung cancers, but their function remains to be determined. TLS in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLS upon Treg cell depletion, leading to tumor destruction. Thus, we propose Treg cells in TA-TLS can inhibit endogenous immune responses against tumors, and targeting these cells may provide therapeutic benefit for cancer patients. PMID:26341400

  20. The properties of the anti-tumor model with coupling non-Gaussian noise and Gaussian colored noise

    NASA Astrophysics Data System (ADS)

    Guo, Qin; Sun, Zhongkui; Xu, Wei

    2016-05-01

    The anti-tumor model with correlation between multiplicative non-Gaussian noise and additive Gaussian-colored noise has been investigated in this paper. The behaviors of the stationary probability distribution demonstrate that the multiplicative non-Gaussian noise plays a dual role in the development of tumor and an appropriate additive Gaussian colored noise can lead to a minimum of the mean value of tumor cell population. The mean first passage time is calculated to quantify the effects of noises on the transition time of tumors between the stable states. An increase in both the non-Gaussian noise intensity and the departure from the Gaussian noise can accelerate the transition from the disease state to the healthy state. On the contrary, an increase in cross-correlated degree will slow down the transition. Moreover, the correlation time can enhance the stability of the disease state.

  1. Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/iNOS and NF-κB/p300 Signaling Pathways

    PubMed Central

    Yu, Zhenlong; Xiao, Yao; Wang, Jingshu; Qiu, Huijuan; Yu, Wendan; Tang, Ranran; Yuan, Yuhui; Guo, Wei; Deng, Wuguo

    2014-01-01

    Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy. PMID:25000190

  2. Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways.

    PubMed

    Yi, Canhui; Zhang, Yong; Yu, Zhenlong; Xiao, Yao; Wang, Jingshu; Qiu, Huijuan; Yu, Wendan; Tang, Ranran; Yuan, Yuhui; Guo, Wei; Deng, Wuguo

    2014-01-01

    Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy.

  3. Properties of a non-bioactive fluorescent derivative of differentiation-inducing factor-3, an anti-tumor agent found in Dictyostelium discoideum.

    PubMed

    Kubohara, Yuzuru; Kikuchi, Haruhisa; Matsuo, Yusuke; Oshima, Yoshiteru; Homma, Yoshimi

    2014-01-01

    Differentiation-inducing factor-3 (DIF-3), found in the cellular slime mold Dictyostelium discoideum, and its derivatives, such as butoxy-DIF-3 (Bu-DIF-3), are potent anti-tumor agents. To investigate the activity of DIF-like molecules in tumor cells, we recently synthesized a green fluorescent DIF-3 derivative, BODIPY-DIF-3G, and analyzed its bioactivity and cellular localization. In this study, we synthesized a red (orange) fluorescent DIF-3 derivative, BODIPY-DIF-3R, and compared the cellular localization and bioactivities of the two BODIPY-DIF-3s in HeLa human cervical cancer cells. Both fluorescent compounds penetrated the extracellular membrane within 0.5 h and localized mainly to the mitochondria. In formalin-fixed cells, the two BODIPY-DIF-3s also localized to the mitochondria, indicating that the BODIPY-DIF-3s were incorporated into mitochondria independently of the mitochondrial membrane potential. After treatment for 3 days, BODIPY-DIF-3G, but not BODIPY-DIF-3R, induced mitochondrial swelling and suppressed cell proliferation. Interestingly, the swollen mitochondria were stainable with BODIPY-DIF-3G but not with BODIPY-DIF-3R. When added to isolated mitochondria in vitro, BODIPY-DIF-3G increased dose-dependently the rate of O2 consumption, but BODIPY-DIF-3R did not. These results suggest that the bioactive BODIPY-DIF-3G suppresses cell proliferation, at least in part, by altering mitochondrial activity, whereas the non-bioactive BODIPY-DIF-3R localizes to the mitochondria but does not affect mitochondrial activity or cell proliferation. PMID:24682009

  4. Phloretin increases the anti-tumor efficacy of intratumorally delivered heat-shock protein 70 kDa (HSP70) in a murine model of melanoma.

    PubMed

    Abkin, Sergey V; Ostroumova, Olga S; Komarova, Elena Y; Meshalkina, Darya A; Shevtsov, Maxim A; Margulis, Boris A; Guzhova, Irina V

    2016-01-01

    Recombinant HSP70 chaperone exerts a profound anticancer effect when administered intratumorally. This action is based on the ability of HSP70 to penetrate tumor cells and extract its endogenous homolog. To enhance the efficacy of HSP70 cycling, we employed phloretin, a flavonoid that enhances the pore-forming activity of the chaperone on artificial membranes. Phloretin increased the efficacy of HSP70 penetration in B16 mouse melanoma cells and K-562 human erythroblasts; this was accompanied with increased transport of the endogenous HSP70 to the plasma membrane. Importantly, treatment with HSP70 combined with phloretin led to the elevation of cell sensitivity to cytotoxic lymphocytes by 16-18 % compared to treatment with the chaperone alone. The incubation of K-562 cells with biotinylated HSP70 and phloretin increased the amount of the chaperone released from cells, suggesting that chaperone cycling could trigger a specific anti-tumor response. We studied the effect of the combination of HSP70 and phloretin using B16 melanoma and a novel method of HSP70-gel application. We found that the addition of phloretin to the gel reduced tumor weight almost fivefold compared with untreated mice, while the life span of the animals extended from 25 to 39 days. The increased survival was corroborated by the activation of innate and adaptive immunity; interestingly, HSP70 was more active in induction of CD8+ cell-mediated toxicity and γIFN production while phloretin contributed largely to the CD56+ cell response. In conclusion, the combination of HSP70 with phloretin could be a novel treatment for efficient immunotherapy of intractable cancers such as skin melanoma. PMID:26646850

  5. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors

    PubMed Central

    Du, Yi; Yamaguchi, Hirohito; Wei, Yongkun; Hsu, Jennifer L.; Wang, Hung-Ling; Hsu, Yi-Hsin; Lin, Wan-Chi; Yu, Wen-Hsuan; Leonard, Paul G.; Lee, Gilbert R.; Chen, Mei-Kuang; Nakai, Katsuya; Hsu, Ming-Chuan; Chen, Chun-Te; Sun, Ye; Wu, Yun; Chang, Wei-Chao; Huang, Wen-Chien; Liu, Chien-Liang; Chang, Yuan-Ching; Chen, Chung-Hsuan; Park, Morag; Jones, Philip; Hortobagyi, Gabriel N.; Hung, Mien-Chie

    2016-01-01

    Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials1. One PARP inhibitor, olaparib (Lynparza™, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with BRCA mutations. BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition2,3. Here we show that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone. PMID:26779812

  6. Structural characterization and anti-tumor effects of an inulin-type fructan from Atractylodes chinensis.

    PubMed

    Xu, Jing; Chen, Dan; Liu, Chang; Wu, Xiong-Zhi; Dong, Cai-Xia; Zhou, Jing

    2016-01-01

    A fructan (ACPS-1) with a molecular weight of 11.2 kDa was isolated from Atractylodes chinensis rhizome and characterized by chemical derivatization, HPLC, GC-MS, FT-IR, and NMR. Structural analyses revealed that ACPS-1 is predominately composed of fructose and a small amount of glucose and a polymerization degree of about 53. The fructan was deduced to be an inulin-type fructan containing a linear backbone composed of (2→1)-linked β-d-Fruf residues. The in vitro antitumor activity of ACPS-1 was evaluated on four human cancer cell lines, including a cervical cancer cell line (Hela), two liver hepatocellular carcinoma cell lines (HepG2 and 7721), and an ovarian carcinoma cell line (Skov3). Results showed that ACPS-1 could significantly inhibit Hela, HepG2, and 7721 cell proliferation, especially HepG2, for which the fructan showed a proliferative inhibition rate as high as 87.40%. This result suggests that ACPS-1 may have anticancer potentiality against hepatocellular carcinoma and warrants further investigation.

  7. Combination Immune Therapies to Enhance Anti-Tumor Responses by NK Cells

    PubMed Central

    Mentlik James, Ashley; Cohen, Adam D.; Campbell, Kerry S.

    2013-01-01

    Natural killer (NK) cells are critical innate immune lymphocytes capable of destroying virally infected or cancerous cells through targeted cytotoxicity and further assisting in the immune response by releasing inflammatory cytokines. NK cells are thought to contribute to the process of tumor killing by certain therapeutic monoclonal antibodies (mAb) by directing antibody-dependent cellular cytotoxicity (ADCC) through FcγRIIIA (CD16). Numerous therapeutic mAb have been developed that target distinct cancer-specific cell markers and may direct NK cell-mediated ADCC. Recent therapeutic approaches have combined some of these cancer-specific mAb with additional strategies to optimize NK cell cytotoxicity. These include agonistic mAb targeting NK cell activating receptors and mAbs blocking NK cell inhibitory receptors to enhance NK cell functions. Furthermore, several drugs that can potentiate NK cell cytotoxicity through other mechanisms are being used in combination with therapeutic mAb. In this review, we examine the mechanisms employed by several promising agents used in combination therapies that enhance natural or Ab-dependent cytotoxicity of cancer cells by NK cells, with a focus on treatments for leukemia and multiple myeloma. PMID:24391651

  8. Extraction, Isolation, Structural Characterization and Anti-Tumor Properties of an Apigalacturonan-Rich Polysaccharide from the Sea Grass Zostera caespitosa Miki

    PubMed Central

    Lv, Youjing; Shan, Xindi; Zhao, Xia; Cai, Chao; Zhao, Xiaoliang; Lang, Yinzhi; Zhu, He; Yu, Guangli

    2015-01-01

    An apigalacturonan (AGA)-rich polysaccharide, ZCMP, was isolated from the sea grass Zostera caespitosa Miki. The depolymerized fragments derived from ZCMP were obtained by either acidic degradation or pectinase degradation, and their structures were characterized by electrospray ionization collision-induced-dissociation mass spectrometry (ESI-CID-MS2) and nuclear magnetic resonance (NMR) spectroscopy. The average molecular weight of ZCMP was 77.2 kD and it consisted of galacturonic acid (GalA), apiosefuranose (Api), galactose (Gal), rhamnose (Rha), arabinose (Ara), xylose (Xyl), and mannose (Man), at a molar ratio of 51.4꞉15.5꞉6.0꞉11.8꞉4.2꞉4.4꞉4.2. There were two regions of AGA (70%) and rhamnogalacturonan-I (RG-Ι, 30%) in ZCMP. AGA was composed of an α-1,4-d-galactopyranosyluronan backbone mainly substituted at the O-3 position by single Api residues. RG-Ι possessed a backbone of repeating disaccharide units of →4GalAα1,2Rhaα1→, with a few α-l-arabinose and β-d-galactose residues as side chains. The anti-angiogenesis assay showed that ZCMP inhibited the migratory activity of human umbilical vein endothelial cell (HUVECs), with no influence on endothelial cells growth. ZCMP also promoted macrophage phagocytosis. These findings of the present study demonstrated the potential anti-tumor activity of ZCMP through anti-angiogenic and immunoregulatory pathways. PMID:26110894

  9. Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents

    PubMed Central

    Sestak, Vit; Stariat, Jan; Cermanova, Jolana; Potuckova, Eliska; Chladek, Jaroslav; Roh, Jaroslav; Bures, Jan; Jansova, Hana; Prusa, Petr; Sterba, Martin; Micuda, Stanislav; Simunek, Tomas; Kalinowski, Danuta S.; Richardson, Des R.; Kovarikova, Petra

    2015-01-01

    Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment. PMID:26623727

  10. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells

    PubMed Central

    Muniyan, Sakthivel; D’Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G.; Bu, Xiu R.; Batra, Surinder K.; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents. PMID:26121643

  11. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    PubMed

    Ingersoll, Matthew A; Lyons, Anastesia S; Muniyan, Sakthivel; D'Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G; Bu, Xiu R; Batra, Surinder K; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents. PMID:26121643

  12. POLE proofreading mutations elicit an anti-tumor immune response in endometrial cancer

    PubMed Central

    van Gool, Inge C; Eggink, Florine A; Freeman-Mills, Luke; Stelloo, Ellen; Marchi, Emanuele; de Bruyn, Marco; Palles, Claire; Nout, Remi A; de Kroon, Cor D; Osse, Elisabeth M; Klenerman, Paul; Creutzberg, Carien L; Tomlinson, Ian PM; Smit, Vincent THBM; Nijman, Hans W

    2015-01-01

    Purpose Recent studies have shown that 7-12% of endometrial cancers (ECs) are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response and clinical outcome in cancer, we investigated whether POLE-mutant ECs showed evidence of increased immunogenicity. Experimental design We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined EC cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA EC series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant ECs. Results Compared to other ECs, POLE-mutants displayed an enhanced cytotoxic T cell response, evidenced by increased numbers of CD8+ tumor infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T cell gene signature, and strong upregulation of the T cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF and granzyme B. This was accompanied by upregulation of T cell exhaustion markers, consistent with chronic antigen exposure. In-silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neo-epitopes than other ECs, providing a potential explanation for our findings. Conclusions Ultramutated POLE proofreading-mutant ECs are characterized by a robust intratumoral T cell response, which correlates with, and may be caused by an enrichment of antigenic neo-peptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers. PMID:25878334

  13. Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

    PubMed Central

    Zampeli, Evanthia; Gizis, Michalis; Siakavellas, Spyros I; Bamias, Giorgos

    2014-01-01

    Ulcerative colitis (UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor (anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve (primary non-response) or lose response after a period of improvement (secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters that may predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular (immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy. PMID:25133030

  14. How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

    PubMed

    Ward, Mark G; Irving, Peter M; Sparrow, Miles P

    2015-10-28

    In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients.

  15. How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

    PubMed Central

    Ward, Mark G; Irving, Peter M; Sparrow, Miles P

    2015-01-01

    In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients. PMID:26525434

  16. Mitochondria are the target organelle of differentiation-inducing factor-3, an anti-tumor agent isolated from Dictyostelium discoideum [corrected].

    PubMed

    Kubohara, Yuzuru; Kikuchi, Haruhisa; Matsuo, Yusuke; Oshima, Yoshiteru; Homma, Yoshimi

    2013-01-01

    Differentiation-inducing factor-3 (DIF-3), found in the cellular slime mold Dictyostelium discoideum, and its derivatives such as butoxy-DIF-3 (Bu-DIF-3) are potent anti-tumor agents. However, the precise mechanisms underlying the actions of DIF-3 remain to be elucidated. In this study, we synthesized a green fluorescent derivative of DIF-3, BODIPY-DIF-3, and a control fluorescent compound, Bu-BODIPY (butyl-BODIPY), and investigated how DIF-like molecules behave in human cervical cancer HeLa cells by using both fluorescence and electron microscopy. BODIPY-DIF-3 at 5-20 µ M suppressed cell growth in a dose-dependent manner, whereas Bu-BODIPY had minimal effect on cell growth. When cells were incubated with BODIPY-DIF-3 at 20 µM, it penetrated cell membranes within 0.5 h and localized mainly in mitochondria, while Bu-BODIPY did not stain the cells. Exposure of cells for 1-3 days to DIF-3, Bu-DIF-3, BODIPY-DIF-3, or CCCP (a mitochondrial uncoupler) induced substantial mitochondrial swelling, suppressing cell growth. When added to isolated mitochondria, DIF-3, Bu-DIF-3, and BOIDPY-DIF-3, like CCCP, dose-dependently promoted the rate of oxygen consumption, but Bu-BODIPY did not. Our results suggest that these bioactive DIF-like molecules suppress cell growth, at least in part, by disturbing mitochondrial activity. This is the first report showing the cellular localization and behavior of DIF-like molecules in mammalian tumor cells. PMID:23977224

  17. Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis

    PubMed Central

    Dun, Jiening; Chen, Xueyan; Gao, Haixia; Zhang, Yan; Zhang, Huajun

    2015-01-01

    Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment (P < 0.01). The combination of 5-FU and Res significantly increased the percentage of apoptotic cells and the level of activated caspase-3, cleaved PARP and p53 proteins as well as increased the Bax/Bcl-2 ratio. In conclusion, the 5-FU/Res combination enabled a more effective inhibition of cell growth and the induction of apoptosis in cancer cells than 5-FU alone. The results of this study suggest that chemotherapy using natural dietary agents with chemical agents represents a superior cancer treatment option. PMID:25736303

  18. Preparation of the core-shell structure adriamycin lipiodol microemulsions and their synergistic anti-tumor effects with diethyldithiocarbamate in vivo.

    PubMed

    Daocheng, Wu; Mingxi, Wan

    2010-11-01

    We prepared the core-shell structure adriamycin lipiodol microemulsions (ADM-CSLMs) and evaluated their in vivo antitumor effects in combination with Diethyldithiocarbamate (DDC). Two types of ADM-CSLMs, adriamycin liposome-lipiodol microemulsion(ADM-LLM) and adriamycin microsphere lipiodol microemulsion (ADM-MLM), were prepared through the emulsification method. The drug loading and encapsulation efficiency of ADM-CSLMs were measured by the high-performance liquid chromatograph (HPLC). The size and shape of the ADM-CSLMs were determined by an atom force microscopy (AFM), a transmission electron microscopy (TEM), and a particle size analyzer, respectively. The synergistic effects of DDC and ADM-CSLMs for cancer treatment of carcinoma drug-resistance cell was evaluated by the MTT method, the activation of superoxide dismutase (SOD) was detected by chemiluminescence, and the ADM accumulation in cells was measured by flow cytometry. Walker-256 carcinoma was transplanted to the livers of the male SD rats, ADM-CSLMs were administrated to the livers of the rats by intervention hepatic artery embolization through microsurgery. The tumor growth and animal survival were evaluated. The results show that the average diameter of ADM-LLM and ADM-MLM were 4.23 ± 1.2 μm and 4.67 ± 1.4 μm, respectively, and their ADM encapsulation efficiency were 83.7% and 87.2% with respect to loading efficiency of 82 μg/ml and 91 μg/ml. The tumor growth and animal survival in two of the ADM-CSLMs combined with DDC groups were significantly higher than that of ADM only treatment, ADM liposome combined with DDC (P < 0.01), as well as the ADM microsphere combined with DDC (P < 0.01). Therefore, ADM-CSLMs are useful carriers for the treatment of carcinoma and their anti-tumor effect can be enhanced by DDC in a suitable concentration. PMID:20888179

  19. PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma.

    PubMed

    Luo, Tian; Loira-Pastoriza, Cristina; Patil, Harshad P; Ucakar, Bernard; Muccioli, Giulio G; Bosquillon, Cynthia; Vanbever, Rita

    2016-10-10

    Pulmonary delivery offers an attractive route of administration for chemotherapeutic agents, with the advantages of high drug concentrations locally and low side effects systemically. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lungs. Moreover, the local toxicity induced by antineoplastic drugs is considered a major obstacle for the clinical application of inhaled chemotherapy. In this study, we explored the utility of 6kDa and 20kDa polyethylene glycol-paclitaxel (PEG-PTX) conjugates to retain paclitaxel within the lungs, achieve its sustained release locally, and thereby, improve its efficacy and reduce its pulmonary toxicity. The conjugates increased the maximum tolerated dose of paclitaxel by up to 100-fold following intratracheal instillation in healthy mice. PEG-PTX conjugates induced lung inflammation. However, the inflammation was lower than that induced by an equivalent dose of the free drug and it was reversible. Conjugation of paclitaxel to both PEG sizes significantly enhanced its anti-tumor efficacy following intratracheal instillation of a single dose in a Lewis lung carcinoma model in mice. PEG-PTX 20k showed equivalent efficacy as PEG-PTX 6k delivered at a 2.5-fold higher dose, suggesting that the molecular weight of the conjugate plays a role in anti-cancer activity. PEG-PTX 20k conjugate presented a prolonged residency and a sustained paclitaxel release within the lungs. This study showed that PEGylation of paclitaxel offers a potential delivery system for inhalation with improved anti-cancer efficacy, prolonged exposure of lung-resident tumors to the antineoplastic drug and reduced local toxicity. PMID:27515664

  20. [Anti-tumor effect of fluoropyrimidines on human tumor cell lines transplanted in nude mice with CCl4-induced liver dysfunction].

    PubMed

    Nio, Y; Imai, S; Shiraishi, T; Ohgaki, K; Tobe, T

    1989-04-01

    Tegafur (FT) is a masked compound of 5-fluorouracil (5-FU) and supposed to be activated in the liver. The present study was designed to estimate anti-tumor effect of FT on human tumors transplanted in nude mice with liver dysfunction induced by CCl4. Histologically, cirrhotic changes of liver were observed after injection with 1ml/kg 10% CCl4 twice a week for 8 weeks. Mice were transplanted with human gastric (GC-SF) or colonic cancer (CC-ZK) lines, and daily administered intragastrically with 5-FU (15mg/kg), FT (100mg/kg) or UFT (FT 20mg/kg + Uracil 44.8mg/kg) for 4 weeks. The growth of GC-SF was enhanced by liver dysfunction, but that of CC-ZK was not affected. The mean growth inhibition rates (MGIR) of CC-ZK by 5-FU, FT or UFT were 18.3, 33.1 and 54.2%, respectively, in mice without liver dysfunction, and 14.0, 50.0 and 59.5%, respectively, in mice with liver dysfunction. The MGIRs of GC-SF were 39.0, 63.8 and 48.0%, respectively, in mice without liver dysfunction, and 12.6, 53.6 and 50.0%, respectively, in mice with liver dysfunction. In both lines effect of 5-FU was reduced in liver dysfunction, but those of FT and UFT was not. These results suggest that FT and UFT can be used for cancer patients with liver dysfunction.