The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of nonsmall cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify 2 major lessons from the outcomes of these trials: 1) the antioxidant hypothesis was tested in wrong subjects or patient populations, and 2) the selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to revitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials.

Prostate cancer is the most frequently diagnosed malignancy and the second most frequent cause of male cancer death in the United States and other Western countries¹ but is far less frequent in Asian countries.² Prostate cancer risk has been inversely associated with intake of soy and soy foods in observational studies,^3,4 which may explain this geographic variation because soy consumption is low in the United States and high in Asian countries.^5,6 Although it has been repeatedly proposed that soy may prevent prostate cancer development,^5,7,8 this hypothesis has not been tested in randomized studies with cancer as the end point. A substantive fraction (48%-55%) of men diagnosed as having prostate cancer use dietary supplements including soy products, although the exact proportion is not known.^9-11 However, no evidence exists that soy supplementation has any prostate cancer–related benefits for these men. Soy contains several constituents, including isoflavones, which possess anticancer activities in laboratory studies.^12,13 Several animal studies also provide support for the hypothesis that soy consumption may protect against prostate cancer.¹⁴

Cancer patients often use dietary supplements while on therapy, but little is known about interactions of supplements with cancer chemotherapy. Black raspberries (BRB) have anti-cancer effects, but have not been evaluated for interference with chemotherapy for castrate-resistant prostate cancer (CRPC). Here we studied whether BRB and some of their constituents interact with docetaxel and cabazitaxel on CRPC cells in culture and implanted into nude mice. Ellagic acid increased, but BRB extract inhibited, microtubule assembly. Ellagic acid decreased tubulin polymerization by cabazitaxel and bound to tubulin. Ellagic acid, its metabolite urolithin A, BRB extract, and the anthocyanin metabolite protocatechuic acid (PCA) did not alter cytotoxicity of taxanes. Ellagic acid inhibited drug efflux in CRPC cells, but BRB extract and PCA did not. None of these compounds altered CYP3A4 activity. Although dietary ellagic acid did not alter the tumor growth inhibition by docetaxel of xenografted 22Rv1 cells, ellagic acid has the potential to interfere with taxane chemotherapy by reducing tubulin polymerization while inhibiting P-glycoprotein drug efflux. These data are cause for concern of consuming ellagic acid during treatment for CRPC and indicate need for further research, but BRB consumption appears safe.

Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

Testosterone is increasingly prescribed to middle aged and older men, but the safety of this treatment has been called into question, and the possible risk of prostate cancer is unknown. We treated Wistar Cpb: WU rats chronically via slow-release Silastic implants with doses of testosterone that increased circulating levels in a dose-related fashion with or without a preceding single injection of the carcinogen N-nitroso-N-methylurea (MNU). Without MNU, testosterone induced prostate carcinomas in 10%-18% of rats, and after MNU injection, testosterone treatment caused prostate cancer in 50%-71% of rats with a very steep dose response, producing a 50% prostatic tumor incidence even at a testosterone dose that did not elevate circulating testosterone levels. Prostate cancers did not occur in rats given MNU or no treatment, whereas testosterone alone induced a low incidence of prostate cancer and increased the number rats bearing tumors at other sites, particularly malignant tumors. Thus, testosterone was shown to be a weak complete carcinogen and a strong tumor promoter for the rat prostate in this study. These findings have potential significant public health implications for the use of testosterone therapy in men.