Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges

Abstract

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.

Fig. 1. Structures and possible metabolic pathways for methylseleninic acid (MSeA), Se-methylselenocysteine (MSeC), selenoamino acids and inorganic selenite in a chemoprevention context

For selenoamino acids, tissue cysteine β-lyases release hydrogen selenide and methylselenol from selenocysteine and methylselenocysteine, respectively. SeMet leads to massive tissue accumulation of Se due to its non-specific incorporation into general proteins in place of Met. Selenite can cause DNA damage, likely through reactive oxygen species. Methylselenol pool may be selectively enriched by precursor compounds or functional foods such as Se-garlic, bypassing the hydrogen selenide pool. Depending on the entry point to a likely MSeA-MSeH redox cycle, the cellular effect and molecular targets of a next-gen methyl Se will be the integrative balance of MSeA, MSeH and their redox intermediary metabolites. Reported cellular effects and molecular targets of MSeA-MSeH are summarized.

Fig. 2. Schematic relationship of different pools of Se in blood circulation as a function of Se intake level in the nutritional range and in chemoprevention range

Mean or medium baseline plasma Se at enrollment for NPCT vs. SELECT was marked in reference to plasma Se threshold value to support full selenoprotein activity.