Abstract 270: Effect of dietary methylseleninic acid and Se-methylselenocysteine on carcinogen-induced, androgen-promoted prostate carcinogenesis in rats

Abstract

Abstract Selenomethionine (SeMet) did not inhibit development of prostate cancer in the SELECT trial and in preclinical rat models. However, we and others have shown that oral intake of next-generation selenium (Se) forms, especially methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC), inhibits prostate carcinogenesis in the TRAMP mouse model and growth of human prostate cancer cells xenografted in immunodeficient mice. We recently showed that MSeA suppresses progression of high-grade prostatic intraepithelial neoplasia to adenocarcinoma in pten-deficient mice (Cancer Prev Res 2016;9:35-42). To determine whether next-generation Se forms inhibit prostate carcinogenesis in models driven by a different etiology, we tested the in vivo effect of different Se forms fed to rats undergoing chemically induced androgen-promoted prostate carcinogenesis. We previously established that SeMet was not inhibitory in this model (Cancer Prev Res 2010;3:381-92). Wistar-Unilever (WU) rats (10-12 wks) were sequentially treated with androgen receptor blocker flutamide for 21 days (10 mg/kg/day by gavage), followed by testosterone propionate (TP, 10 mg/kg, s.c) on day 22. Three days after TP, the carcinogen methylnitrosourea (MNU, 30 mg/kg/bw) was administered by i.p. injection. One week later, the rats received slow-release Silastic implants containing testosterone. Rats were then randomized to one of three groups fed the AIN-93M diet supplemented with 3 ppm of Se as MSeA or MSeC or control AIN-93M diet. Moribund animals were euthanized and the study was terminated 400 days after MNU injection. Mean survival (days ± SEM) after MNU was 344±11 in controls (n=31), 354±8 in MSeA fed rats (n=30), and 363±10 in rats given MSeC (n=29). These differences were not statistically significant, which was confirmed by survival analysis using the logrank test. Overall tumor incidence in all accessory sex glands combined (dorsolateral and anterior prostate plus seminal vesicle) was 68% in controls, 83% in MSeA rats, and 72% in MSeC rats. The incidence of large tumors of uncertain origin was 42% in controls, 40% in MSeA rats, and 41% in MSeC rats. The incidence of smaller tumors clearly confined to dorsolateral and/or anterior prostate was 19% in controls, 20% in MSeA rats, and 38% in MSeC rats (some rats had more than one tumor). None of these differences was statistically significant and there were no shifts from large to small tumor or small to large tumors. Thus, MSeA and MSeC were not preventive in this rat prostate carcinogenesis model. The contrast with the inhibitory effects of MSeA in the TRAMP and pten-deficient mouse models may be due to differences in administered dose or fundamental rat-mouse differences in Se metabolism that impact chemoprevention by Se compounds. Supported by NIH grant CA172169. Citation Format: Maarten C. Bosland, Michael J. Schlicht, Yibin Deng, Junxuan Lu. Effect of dietary methylseleninic acid and Se-methylselenocysteine on carcinogen-induced, androgen-promoted prostate carcinogenesis in rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 270.