Methyl-selenium for prostate cancer chemoprevention

Summary

Principal Investigator: Junxuan Lu
Affiliation: University of Minnesota
Country: USA
Abstract: 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.
Funding Period: ----------------2007 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite
    Guang Xun Li
    Hormel Institute, University of Minnesota, 801 16th Avenue Northeast, Austin, MN 55912, USA
    Carcinogenesis 29:1005-12. 2008
  2. doi Methylseleninic acid suppresses pancreatic cancer growth involving multiple pathways
    Lei Wang
    a Hormel Institute, University of Minnesota, Austin, Minnesota, USA
    Nutr Cancer 66:295-307. 2014
  3. pmc Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit
    Lei Wang
    Hormel Institute, University of Minnesota, 801 16th Avenue Northeast, Austin, MN 55912, USA
    Cancer Prev Res (Phila) 2:484-95. 2009
  4. ncbi Persistent p21Cip1 induction mediates G(1) cell cycle arrest by methylseleninic acid in DU145 prostate cancer cells
    Zhe Wang
    The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA
    Curr Cancer Drug Targets 10:307-18. 2010
  5. doi A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model
    Yong Zhang
    Hormel Institute, University of Minnesota, Austin, 55912, USA
    Cancer Prev Res (Phila) 3:885-95. 2010
  6. pmc In vivo molecular mediators of cancer growth suppression and apoptosis by selenium in mammary and prostate models: lack of involvement of gadd genes
    Weiqin Jiang
    Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA
    Mol Cancer Ther 8:682-91. 2009
  7. ncbi Lobe-specific lineages of carcinogenesis in the transgenic adenocarcinoma of mouse prostate and their responses to chemopreventive selenium
    Lei Wang
    Hormel Institute, University of Minnesota, Austin, Minnesota, USA
    Prostate 71:1429-40. 2011
  8. pmc Lobe-specific proteome changes in the dorsal-lateral and ventral prostate of TRAMP mice versus wild-type mice
    Jinhui Zhang
    The Hormel Institute, University of Minnesota, Austin, MN, USA
    Proteomics 11:2542-9. 2011
  9. doi Mouse prostate proteomes are differentially altered by supranutritional intake of four selenium compounds
    Jinhui Zhang
    The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
    Nutr Cancer 63:778-89. 2011
  10. doi Proteomic profiling of potential molecular targets of methyl-selenium compounds in the transgenic adenocarcinoma of mouse prostate model
    Jinhui Zhang
    The Hormel Institute, University of Minnesota, Austin, 55912, USA
    Cancer Prev Res (Phila) 3:994-1006. 2010

Scientific Experts

  • Jinhui Zhang
  • Junxuan Lu
  • Lei Wang
  • Hongbo Hu
  • Yong Zhang
  • Zhe Wang
  • Joshua D Liao
  • Hyo Jeong Lee
  • Guang Xun Li
  • Emily Quealy
  • Margot P Cleary
  • Cheng Jiang
  • Weiqin Jiang
  • Yan Cheng
  • Hua Xiong
  • Joshua Dezhong Liao
  • Yibin Deng
  • Katai Nkhata
  • Robert C Reynolds
  • Bernard D Gary
  • Gary A Piazza
  • Yubo Chai
  • Melissa J L Bonorden
  • Hongying Pei
  • Jennifer C Watts
  • Gerald F Combs

Detail Information

Publications10

  1. pmc Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite
    Guang Xun Li
    Hormel Institute, University of Minnesota, 801 16th Avenue Northeast, Austin, MN 55912, USA
    Carcinogenesis 29:1005-12. 2008
    ..In summary, our data demonstrated superior in vivo growth inhibitory efficacy of MSeA over SeMet and selenite, against two human PCa xenograft models without the genotoxic property of selenite...
  2. doi Methylseleninic acid suppresses pancreatic cancer growth involving multiple pathways
    Lei Wang
    a Hormel Institute, University of Minnesota, Austin, Minnesota, USA
    Nutr Cancer 66:295-307. 2014
    ..These results provide impetus for further research of MSeA in the therapy and/or chemoprevention of pancreatic cancer...
  3. pmc Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit
    Lei Wang
    Hormel Institute, University of Minnesota, 801 16th Avenue Northeast, Austin, MN 55912, USA
    Cancer Prev Res (Phila) 2:484-95. 2009
    ..Therefore, these selenium compounds may effectively inhibit this model of prostate cancer carcinogenesis...
  4. ncbi Persistent p21Cip1 induction mediates G(1) cell cycle arrest by methylseleninic acid in DU145 prostate cancer cells
    Zhe Wang
    The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA
    Curr Cancer Drug Targets 10:307-18. 2010
    ....
  5. doi A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model
    Yong Zhang
    Hormel Institute, University of Minnesota, Austin, 55912, USA
    Cancer Prev Res (Phila) 3:885-95. 2010
    ..Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis...
  6. pmc In vivo molecular mediators of cancer growth suppression and apoptosis by selenium in mammary and prostate models: lack of involvement of gadd genes
    Weiqin Jiang
    Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA
    Mol Cancer Ther 8:682-91. 2009
    ..They cast doubt on the three gadd genes as mediators of Se action in vivo...
  7. ncbi Lobe-specific lineages of carcinogenesis in the transgenic adenocarcinoma of mouse prostate and their responses to chemopreventive selenium
    Lei Wang
    Hormel Institute, University of Minnesota, Austin, Minnesota, USA
    Prostate 71:1429-40. 2011
    ..It is critical to characterize the prostate lobe-specificity of lesion lineages to consolidate the advantages of this model and minimize its limitations for chemoprevention studies...
  8. pmc Lobe-specific proteome changes in the dorsal-lateral and ventral prostate of TRAMP mice versus wild-type mice
    Jinhui Zhang
    The Hormel Institute, University of Minnesota, Austin, MN, USA
    Proteomics 11:2542-9. 2011
    ..In addition to serving as reference for prostate proteomic profiles, our data suggest that different sets of proteins are involved in the carcinogenesis in DLP versus VP in the TRAMP model...
  9. doi Mouse prostate proteomes are differentially altered by supranutritional intake of four selenium compounds
    Jinhui Zhang
    The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
    Nutr Cancer 63:778-89. 2011
    ..We propose that the balance of oncogenic vs. suppressor protein patterns in the prostate may impact the direction of PCa risk modification by a given selenium...
  10. doi Proteomic profiling of potential molecular targets of methyl-selenium compounds in the transgenic adenocarcinoma of mouse prostate model
    Jinhui Zhang
    The Hormel Institute, University of Minnesota, Austin, 55912, USA
    Cancer Prev Res (Phila) 3:994-1006. 2010
    ..Although MSeA and MSeC are presumed precursors of methylselenol and were equally effective against the TRAMP model, their distinct affected protein profiles suggest biological differences in their molecular targets outweigh similarities...