Prostate Cancer (PCa), next only to lung cancer, is the second leading cause of cancer-related deaths in American males. At present, there are inadequate treatment options for the management of PCa. The public health impact from PCa has spawned tremendous interest in Chemoprevention trials. Preclinical, epidemiological, and phase III randomized, placebo-controlled clinical trials suggest that selenium and vitamin E could be effective in PCa prevention. Based on these studies, 'Selenium and Vitamin E Chemoprevention Trial (SELECT)'has been initiated. It is a randomized, prospective, double-blind study (7- 12 years) designed to determine whether selenium and vitamin E alone and in combination could reduce the risk of PCa among healthy men. This is an outstanding effort of its kind. However, several investigators are critical about the rationale whereas several others have arguments. Two popular questions in this direction are: (1) whether there are sufficient data on these supplements to justify this trial;and (2) whether more biomarkers (which could suggest the possible molecular mechanisms involved) should be included in SELECT trial. The present proposal, on a pre-clinical SELECT Trial in a well-established mouse model of prostate carcinogenesis, should provide answers to these questions. The hypothesis of this proposal is that a combination of vitamin E and selenium will provide synergistic chemopreventive effect against PCa via inhibiting oxidative stress and enhancing apoptotic and/or senescence response. Employing transgenic adenocarcinoma mouse prostate (TRAMP) mice, we propose to conduct a pre-clinical Chemoprevention/ intervention trial that mimics SELECT trial (in human) to determine whether selenium and vitamin E alone and in combination can inhibit PCa development and its metastasis. We will also study the involvement of oxidative stress, apoptosis and cellular senescence during PCa development and its inhibition by vitamin E and/or selenium. Finally, we will study the involvement of NF-kappaB pathway during the modulation in oxidative stress and apoptotic/senescence response of selenium and/or vitamin E treatments in TRAMP model. We believe that a successful completion of our study will provide important information regarding the possible outcome of SELECT trial in humans and may even provide novel information on which suggestions could be made for the modifications for the ongoing or future trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114060-05
Application #
7751312
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Parnes, Howard L
Project Start
2006-02-07
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$250,774
Indirect Cost
Name
University of Wisconsin Madison
Department
Dermatology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Singh, Chandra K; Ndiaye, Mary A; Siddiqui, Imtiaz A et al. (2014) Methaneseleninic acid and ?-Tocopherol combination inhibits prostate tumor growth in Vivo in a xenograft mouse model. Oncotarget 5:3651-61
Ndiaye, Mary; Philippe, Carol; Mukhtar, Hasan et al. (2011) The grape antioxidant resveratrol for skin disorders: promise, prospects, and challenges. Arch Biochem Biophys 508:164-70
Jung-Hynes, Brittney; Schmit, Travis L; Reagan-Shaw, Shannon R et al. (2011) Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model. J Pineal Res 50:140-9
Ledesma, Mark C; Jung-Hynes, Brittney; Schmit, Travis L et al. (2011) Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17:134-43
Johnson, Jeremy J; Nihal, Minakshi; Siddiqui, Imtiaz A et al. (2011) Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res 55:1169-76
Reagan-Shaw, Shannon; Nihal, Minakshi; Ahsan, Haseeb et al. (2008) Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio. Prostate 68:1624-34
Ahsan, Haseeb; Reagan-Shaw, Shannon; Eggert, David M et al. (2007) Protective effect of sanguinarine on ultraviolet B-mediated damages in SKH-1 hairless mouse skin: implications for prevention of skin cancer. Photochem Photobiol 83:986-93
Schmit, Travis L; Ahmad, Nihal (2007) Regulation of mitosis via mitotic kinases: new opportunities for cancer management. Mol Cancer Ther 6:1920-31