The ongoing Selenium-vitamin E Cancer Trial (SELECT) is testing the efficacy of selenium (Se) in the form of selenomethionine (SeMet) alone or in combination with vitamin E to prevent prostate cancer (PCa) in a cohort of some 32,400 North American men. The results are expected in a decade. If a positive preventive efficacy is confirmed, the public health impact of using this form of Se is self-evident, and this will provide an outstanding impetus for further clinical trials to identify more efficacious Se agents to realize even greater preventive benefits. If negative, the quest for effective Se agents takes on significant urgency. Cell culture studies by us and others suggest that methylselenol and its immediate precursors such as methylseleninic acid (MSeA, we refer them collectively as methyl-Se) are much more efficacious than SeMet with respect to a number of anti-PCa processes such as inhibiting angiogenic switch mechanisms, inducing G1 cell cycle arrest, decreasing AKT activation and inducing caspase-mediated apoptosis. We and others have recently shown that methyl-Se inhibits androgen receptor (AR) expression and signaling, which are crucial for PCa development. Furthermore, we have now in pilot studies found that MSeA and methylselenocysteine (MSeC) given by daily oral dosing exerted dose-dependent inhibition of DU145 human PCa xenograft growth in athymic nude mice and SeMet at the same dosage did not. We hypothesize that methyl-Se prevents PCa in vivo by its broad-spectra anti-cancer actions through inhibiting tumor angiogenesis, cell cycle arrest and/or an induction of caspase-mediated apoptosis as well as by the prostate organ-specific inhibition of AR expression and signaling. To test this hypothesis, we propose 3 specific aims in both androgen-dependent (AD) and androgen-independent (AI) PCa xenograft models and the TRAMP (TRansgenic Adenocarcinoma Mouse Prostate) primary prostate carcinogenesis model. We will establish the in vivo chemopreventive efficacy of MSeA and MSeC vs. SeMet and characterize and validate key mechanistic biomarkers such as VEGF suppression for anti-angiogenesis and AR and PSA suppression for inhibition of androgen signaling. We expect to provide valuable efficacy and biomarker data to guide the design of future clinical translational studies with methyl-Se with greater prostate specific targeting actions. They will also be insightful for predicting and interpreting the outcomes of the SELECT study. Narrative: The results from these studies will provide valuable in vivo efficacy and biomarker data to guide the design of future human clinical trials for methyl selenium for prostate cancer chemoprevention. They will also be instructive for predicting and interpreting the outcomes of the ongoing selenium cancer prevention trials.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ONC-B (03))
Program Officer
Perloff, Marjorie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas Tech University
Other Basic Sciences
Schools of Pharmacy
United States
Zip Code
Wang, Lei; Hu, Hongbo; Wang, Zhe et al. (2014) Methylseleninic acid suppresses pancreatic cancer growth involving multiple pathways. Nutr Cancer 66:295-307
Zhang, Jinhui; Wang, Lei; Zhang, Yong et al. (2011) Lobe-specific proteome changes in the dorsal-lateral and ventral prostate of TRAMP mice versus wild-type mice. Proteomics 11:2542-9
Wang, Lei; Zhang, Jinhui; Zhang, Yong et al. (2011) Lobe-specific lineages of carcinogenesis in the transgenic adenocarcinoma of mouse prostate and their responses to chemopreventive selenium. Prostate 71:1429-40
Zhang, Jinhui; Wang, Lei; Li, Guangxun et al. (2011) Mouse prostate proteomes are differentially altered by supranutritional intake of four selenium compounds. Nutr Cancer 63:778-89
Zhang, Yong; Zhang, Jinhui; Wang, Lei et al. (2010) A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila) 3:885-95
Wang, Zhe; Lee, Hyo-Jeong; Chai, Yubo et al. (2010) Persistent p21Cip1 induction mediates G(1) cell cycle arrest by methylseleninic acid in DU145 prostate cancer cells. Curr Cancer Drug Targets 10:307-18
Zhang, Jinhui; Wang, Lei; Anderson, Lorraine B et al. (2010) Proteomic profiling of potential molecular targets of methyl-selenium compounds in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila) 3:994-1006
Jiang, Weiqin; Jiang, Cheng; Pei, Hongying et al. (2009) In vivo molecular mediators of cancer growth suppression and apoptosis by selenium in mammary and prostate models: lack of involvement of gadd genes. Mol Cancer Ther 8:682-91
Wang, Lei; Bonorden, Melissa J L; Li, Guang-xun et al. (2009) Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila) 2:484-95
Li, Guang-xun; Lee, Hyo-Jeong; Wang, Zhe et al. (2008) Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite. Carcinogenesis 29:1005-12