|Chiang, Emily -|
|Shen, Shuren -|
|Kengeri, Seema -|
|Xu, Huiping -|
|Morris, J -|
|Bostwick, David -|
|Waters, David -|
Submitted to: Dose Response
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 12, 2010
Publication Date: February 25, 2010
Repository URL: http://www.dose-response.org
Citation: Chiang, E.C., Shen, S., Kengeri, S.S., Xu, H., Combs, G.F., Morris, J.S., Bostwick, D.G., Waters, D.J. 2010. Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship Between Selenium Status, DNA Damage, and Apoptosis. Dose Response. 8:285-300. Interpretive Summary: We studied the responses of dogs to supplemental selenium. The dog is the only species known to develop spontaneous prostate cancer, risk to which in humans we previously found to be reduced by selenium supplementation. This study revealed an intriguing 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. We also found 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 may reduce cancer risk. This U-shaped relationship provides suggests that, depending on their baseline selenium status, individuals can be either responsive or refractory to selenium supplementation. This may clarify the interpretation of apparently inconsistent findings from human cancer prevention trials using selenium supplements.
Technical 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-supresssing death switch used by prostatic epithelial cells. These provacative 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 selenium-refractory, 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. Morever, 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 selinium levels less than 0.8 ppm in toenails can achieve cancer risk reduction through daily supplementation.