Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship between Selenium Status, DNA Damage, and Apoptosis

Abstract

ᮀ Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to show that the selenium dose that minimizes prostatic DNA damage also maximizes apoptosis-a cancer-suppressing death switch used by prostatic epithelial cells. These provocative findings suggest a new line of thinking about how selenium can reduce cancer risk. Mid-range selenium status (.67-.92 ppm in toenails) favors a process we call "homeostatic housecleaning"-an upregulated apoptosis that preferentially purges damaged prostatic cells. Also, the U-shaped relationship provides valuable insight into stratifying individuals as selenium-responsive or seleniumrefractory, based upon the likelihood of reducing their cancer risk by additional selenium. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a robust experimental approach bridging the gap between laboratory and human studies that can help to define the optimal doses of cancer preventives for large-scale human trials. Moreover, our observations bring much needed clarity to the null results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and set a new research priority: testing whether men with low, suboptimal selenium levels less than 0.8 ppm in toenails can achieve cancer risk reduction through daily supplementation.

Selenium and Human Health: Witnessing a Copernican Revolution?

“…The ability to produce ROS explains dose dependent toxic effects of Se, observed in vitro and in vivo [108] and is considered to underlie its genotoxic [113,114] and proapoptotic activity [115][116][117]. However, some of these dose dependent effects, specifically DNA damage and apoptosis, were observed in vivo after treatment with SeMet, which is a Se compound regarded as nontoxic due to the inability to generate ROS [118][119][120]. Notably, the same compound was used in SELECT, and since SELECT has clearly indicated toxicity of supranutritional level of SeMet in humans, it is probable that detrimental effects of this particular organic Se compound observed in that trial were not related to the ability to produce ROS.…”

Relationship between serum Se concentration in dogs and incidence of some disease conditions

“…The same authors showed much lower selenium concentrations in cancer patients compared to the control group. The antioxidant properties of selenium and glutathione peroxidase and their role in DNA protection are used in anti-cancer therapy [6][7][8].…”

Understanding Heterogeneity in Supplementation Effects of Selenium in Men: A Study of Stratification Variables and Human Genetics in a Prospective Sample from New Zealand

“…Se levels required to maintain DNA integrity have been previously evaluated in dog prostate cancer models [54,55]. These studies have shown that the DNA damage variation (evaluated by the single cell gel electrophoresis or Comet assay) produced a 'U' shaped curve, indicating increased DNA damage at both the extreme ends of the Se spectrum.…”