Abstract 3693: Methaneseleninic acid and γ-tocopherol combination inhibits prostate tumor growth in a xenograft model .

Prostate Cancer (PCa) is the second leading cause of cancer-related deaths in American males. Several in vitro and in vivo studies have suggested that vitamin E as well as selenium possesses potential in the management of PCa. However, results from the large-scale Selenium and Vitamin E Cancer Prevention Trial (SELECT) found that vitamin E (α-tocopheryl acetate; 400 mg) and/or selenium (L-selenomethionine; 200 μg) were ineffective in preventing PCa. Based on these seemingly contradictory outcomes, we believe that the dose and formulation of both these agents were sub-optimal in the SELECT trial, and may be critical in providing appropriate biological response in PCa. Thus, additional studies are needed to define the most appropriate formulations of vitamin E and selenium as well as the optimal dosages of these two agents. Following a careful analysis of literature, we evaluated the effect of methylseleninic acid (MSA in sterile water; oral gavage) and/or γ-tocopherol (γT in tocopherol-stripped corn oil; oral gavage), at a dose much lower than used in SELECT, against prostate tumors in an immunecompromised mouse model. Sixty Nu/J mice were implanted with 22Rν1 cells, tumors were allowed to grow to an average volume of 36 mm3, followed by treatment in 6 groups (10 animals each): 1) Control (vehicle alone); 2) MSA (41 μg/kg); 3) γT (20.8 mg/kg); 4) γT (41.7 mg/kg); 5) MSA (41 μg/kg) + γT (20.8 mg/kg); and 6) MSA (41 μg/kg) + γT (41.7 mg/kg). The mice were treated for 2 weeks (5 days per week) and followed for tumor growth. At the end of experiment, the mice were sacrificed and further studies were done. Our data demonstrated that the combination of γT (20.8 mg/kg) and MSA (41 μg/kg) resulted in a significant decrease in i) serum prostate specific antigen levels, ii) tumor volume and tumor wet weight, and iii) Ki-67 proliferation index. We found that this combination also resulted in i) an up-regulation of pro-apoptotic Bax coupled with a down-regulation of the pro-survival protein Bcl2, thereby resulting in an increased Bax/Bcl2 ratio, and ii) an increase in pro-apoptotic protein Bad. Further, γT and MSA combination modulated levels of apolipoprotein E, selenoprotein P and Nrf2 in a fashion that favors anti-proliferative responses in PCa. Interestingly, we found that the combination using a lower dose of γT was much more effective than the higher dose, in most of the parameters evaluated. In the most effective treatment group, the approximate daily human equivalent dose for γT was 72 mg/day (corresponding to 20.8 mg/kg in mouse) and for MSA is 142 μg/day (corresponding to 41 μg/kg in mouse), which is significantly lower than the doses used in SELECT. Overall, our study suggests that γT and MSA, at the lower dose regimen, could be useful in PCa management. However, further studies with additional formulations and doses in more relevant animal model(s) are needed to confirm our findings. Citation Format: Chandra K. Singh, Mary A. Ndiaye, Imtiaz A. Siddiqui, Minakshi Nihal, Thomas Havighurst, Weixiong Zhong, Hasan Mukhtar, Nihal Ahmad. Methaneseleninic acid and γ-tocopherol combination inhibits prostate tumor growth in a xenograft model . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3693. doi:10.1158/1538-7445.AM2013-3693