Emily C. Chiang

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

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 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. 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.

Noninvasive Prediction of Prostatic DNA Damage by Oxidative Stress Challenge of Peripheral Blood Lymphocytes

To move closer to the goal of individualized risk prediction for prostate cancer, we used an in vivo canine model to evaluate whether the susceptibility of peripheral blood lymphocytes (PBLs) to oxidative stress-induced DNA damage could identify those individuals with the highest prostatic DNA damage. This hypothesis was tested in a population of 69 elderly male beagle dogs after they had completed a 7-month randomized feeding trial to achieve the broad range of dietary selenium status observed in U.S. men. The alkaline Comet assay was used to directly compare the extent of DNA damage in PBLs with prostatic DNA damage in each dog. Using stepwise logistic regression, the sensitivity of PBLs to oxidative stress challenge with hydrogen peroxide (H2O2) predicted dogs in the highest tertile of prostatic DNA damage. Dogs with PBLs highly sensitive to H2O2 were 7.6 times [95% confidence interval (95% CI), 1.5-38.3] more likely to have high prostatic DNA damage than those in the H2O2-resistant group. This risk stratification was observed in multivariate analysis that considered other factors that might influence DNA damage, such as age, toenail selenium concentration, and serum testosterone concentration. Our data show that the sensitivity of PBLs to oxidative stress challenge, but not endogenous DNA damage in PBLs, provides a noninvasive surrogate marker for prostatic DNA damage. These findings lend support to the concept that oxidative stress contributes to genotoxic damage, and that oxidative stress challenge may stratify men for prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1906–10)

The Art of Casting Nets: Fishing for the Prize of Personalized Cancer Prevention

Now, more than ever, there is great need for personalized cancer prevention. We define personalized cancer prevention as a strategy that will enable each person to reduce his or her risk for lethal cancer by matching the dose, duration, and timing of an intervention with their own cancer risk profile. Most research studies provide us with data on the average person. But who is the average person anyway? The central tenet of personalized cancer prevention is that average is overrated. In this article, we frame what are the major obstacles to developing personalized cancer-reducing interventions: the lack of validated, non-invasive stratifiers of risk; the U-shaped dose response between cancer-fighting nutrients (e.g., selenium) and DNA damage, meaning that more of a good thing is not necessarily a good thing; the relatively brief duration of interventions evaluated in human prevention trials; the challenge of finding populations in which the impact of early life interventions on the incidence of cancers affecting older adults can be studied; and the interindividual differences in gene expression that may influence a persons response to a particular nutrient. Moreover, we contend that those who study personalized cancer prevention will need a unique constellation of expertise, including an understanding of cancer and aging, a passion for prevention, and proven health communication skills. We propose that becoming cross-trained in cancer and aging and taking more responsibility for communicating health-related research to the public in the proper context are two of the most important ways scientists can move us all closer to the goal of personalized cancer prevention. Every fisherman knows that where he casts his net determines his catch. Now, we ask: When it comes to solving the cancer problem, where should we be casting our nets?

Selenium Form-Dependent Anti-Carcinogenesis: Preferential Eliminationof Oxidant-Damaged Prostate Cancer Cell Populations by MethylseleninicAcid is Not Shared by Selenite

Selenium has received considerable attention as a cancer preventive agent. But the puzzling, disquieting results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) have called into question how much is really understood about the biology behind selenium and cancer risk. This predicament should provide researchers with a renewed stimulus for exploring mechanisms of selenium anti-carcinogenesis. One such line of inquiry is homeostatic housecleaning — that selenium can preferentially eliminate DNA-damaged cell populations through apoptosis, consistent with the decreased DNA damage and increased apoptosis observed in the prostate of selenium-replete dogs after receiving additional dietary selenium supplementation. Because growing experimental evidence suggests the anti-carcinogenic effects of selenium on prostatic cells are form-dependent and apoptosis is a DNA damage response, the aim of this research was to determine whether selenite, a form of selenium that induces DNA damage, possesses potent homeostatic housecleaning activity. To test this hypothesis, we exposed human and canine prostate cancer cells to non-cytotoxic concentrations of hydrogen peroxide (H2O2) to create cell populations with higher levels of oxidant-induced DNA damage, and then evaluated the extent to which oxidant damage sensitizes prostate cancer cell populations to selenite-triggered apoptosis compared to apoptosis triggered by methylseleninic acid (MSA), a non-DNA damaging methylselenol precursor we previously showed to have strong homeostatic housecleaning activity. In this brief communication, we report that non-cytotoxic oxidant-induced damage does not sensitize prostate cancer cell populations to selenite-triggered apoptosis. Intensity of apoptosis triggered by MSA in H2O2-damaged prostate cancer cells was 3 times higher than undamaged cell populations not exposed to H2O2 (P ≤ 0.01). In contrast, neither human nor canine prostate cancer cells with oxidant-induced damage had a significant increase in intensity of selenite-triggered apoptosis compared to undamaged cells. The divergent results between MSA and selenite in our experiments contribute to a growing catalogue of observations that suggest there are important form-dependent differences in the extent to which selenium can impact the emergence of prostate cancer. By carefully documenting the form-dependent biological effects of selenium and other nutrients, we commit ourselves to more precisely qualifying the implications of laboratory results and to more carefully designing and interpreting the results of large-scale human trials.