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Research Description:
Despite significant advances towards early detection and targeted therapies, prostate and breast cancers continue to claim thousands of lives each year. The Singh laboratory is interested in preclinical and clinical development of novel agents derived from dietary sources (e.g., garlic and broccoli) and traditional oriental and Indian medicinal plants potentially useful for prevention of prostate and breast cancer in humans. The research interests of the Singh laboratory are thematically aligned with three main areas: (1) preclinical and clinical development of novel cancer chemopreventive agents, (2) rational design of combination chemoprevention regimens, and (3) elucidation of the mechanism of carcinogenesis by environmentally relevant chemicals. Cellular and transgenic animal models are used to screen potential cancer chemopreventive constituents from dietary sources and traditional oriental and Indian medicinal plants. Cutting edge molecular biological (gene manipulation) and imaging techniques (MRI and bioluminescence imaging in live animals) are used by Singh and colleagues to determine the mechanism of action of promising cancer chemopreventive agents and to monitor their effects on cancer progression. Cancer chemoprevention is a relatively new but rapidly emerging sub-discipline in oncology and refers to the use of natural or synthetic agents to reverse or delay the process of carcinogenesis. Despite considerable advances towards early detection and targeted therapies, prostate and breast cancers continue to be the leading causes of cancer related deaths. The long latency of most epithelial cancers, including prostate and breast cancers, provides a large window of opportunity for intervention to prevent or slow disease progression. Accordingly, identification of agents that are relatively safe but can be used to prevent cancers could have a significant impact on disease-related cost, mortality, and morbidity for a large segment of population.  Epidemiological studies continue to support the premise that dietary intake of certain vegetables (e.g., garlic) may be protective against the risk of different types of cancers. Anticancer effect of garlic is attributed to volatile sulfur compounds (e.g., diallyl trisulfide), which are generated upon processing (e.g., cutting) of these vegetables. Recent work from the Singh laboratory has revealed that garlic constituent diallyl trisulfide (DATS) suppresses growth of prostate cancer cells irrespective of their androgen-responsiveness or p53 status by activating a novel checkpoint kinase 1-dependent prometaphase arrest (schematically illustrated in Figure 1) and complex signaling culminating into apoptotic cell death. The DATS-mediated apoptosis involves reactive oxygen species-dependent activation of c-Jun N-terminal kinase. Oral administration of DATS significantly retards growth of prostate cancer xenografts in athymic mice without causing weight loss or any other side effects. Studies are in progress to determine efficacy of DATS against prostate carcinogenesis and metastasis using transgenic animal models. Positive outcome of these preclinical studies would rationalize clinical investigations to determine prostate cancer prevention by DATS in humans. Similar preclinical efficacy and mechanistic studies are underway in the Singh laboratory on prostate and breast cancer chemoprevention by phytochemicals derived from cruciferous vegetables (e.g., isothiocyanates) and traditional oriental (honokiol) and Indian medicine (guggulsterone and withanolides). Another research interest of the Singh laboratory entails elucidation of the mechanism of chemical carcinogenesis by polycyclic aromatic hydrocarbon (PAH) family of environmental pollutants. Singh and his collaborators have discovered a novel mechanism involving cell cycle regulator Cdc25B in PAH-induced neoplastic transformation. These studies have shown that chronic exposure of mouse embryonic fibroblasts (MEFs) derived from the wild type mice, but not Cdc25B knockout mice, to a prototypical PAH (BPDE) results in neoplastic transformation characterized by colony formation and tumor production in nude mice. Investigations are planned to determine in vivo relevance of these cellular findings.
Education:
M.Sc. (Biochemistry), Banaras Hindu University, India, 1979.
Ph.D. (Biochemistry), Banaras Hindu University, India, 1984.
Postdoctoral Fellow, University of Texas Medical Branch at Galveston, 1984-1988.
Important Publications:
- Singh SV, S Choi, Y Zeng, E Hahm and D Xiao. Guggulsterone-induced apoptosis in human prostate cancer cells is caused by reactive oxygen intermediate-dependent activation of c-Jun NH2-terminal kinase. Cancer Res 67:7439-7449, 2007
- Srivastava SK, P Bansal, T Oguri, JS Lazo and SV Singh. Cdc25B Phosphatase is essential for benzo[a]pyrene-7,8-diol-9,10-epoxide induced neoplastic transformation. Cancer Res 67:9150-9157, 2007
- Xiao D and SV Singh. Phenethyl isothiocyanate inhibits angiogenesis in vitro and ex vivo. Cancer Res 67:2239-2246, 2007
- Xiao D, KL Lew, YA Kim, Y Zeng, ER Hahm, R Dhir and SV Singh. Diallyl trisulfide suppresses growth of PC-3 human prostate cancer xenograft in vivo in association with Bax and Bak induction. Clin Cancer Res 12:6836-6843, 2006
- Herman-Antosiewicz A and SV Singh. Checkpoint kinase 1 regulates diallyl trisulfide-induced mitotic arrest in human prostate cancer cells. J Biol Chem 280: 28519-28528, 2005
- Singh SV, SK Srivastava, S Choi, KL Lew, J Antosiewicz, D Xiao, Y Zeng, SC Watkins, CS Johnson, DL Trump, YJ Lee, H Xiao and A Herman-Antosiewicz. Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species. J Biol Chem 280:19911-19924, 2005
- Xiao D, S Choi, DE Johnson, VG Vogel, CS Johnson, DL Trump, YJ Lee and SV Singh. Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2. Oncogene 23:5594-5606, 2004
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