Glucose Limitation Sensitizes Cancer Cells to Selenite-Induced Cytotoxicity via SLC7A11-Mediated Redox Collapse

SIMPLE SUMMARY: Selenite, a representative inorganic form of selenium, is preferentially accumulated in tumors. The therapeutic potential of sodium selenite in tumors has received significant attention. However, the effect of sodium selenite in the treatment of established tumors is hampered by its systemic toxicities. In this study, we found selenite exerted a stronger lethality to the cancer cells under the condition of glucose limitation in vitro and an enhanced inhibitory effect on tumor growth when combined with intermittent fasting in vivo. In addition, this treatment showed no obvious toxicity to normal cells and mice. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer. ABSTRACT: Combination of intermittent fasting and chemotherapy has been drawn an increasing attention because of the encouraging efficacy. In this study, we evaluated the anti-cancer effect of combination of glucose limitation and selenite (Se), a representative inorganic form of selenium, that is preferentially accumulated in tumors. Results showed that cytotoxic effect of selenite on cancer cells, but not on normal cells, was significantly enhanced in response to the combination of selenite and glucose limitation. Furthermore, in vivo therapeutic efficacy of combining selenite with fasting was dramatically improved in xenograft models of lung and colon cancer. Mechanistically, we found that SLC7A11 expression in cancer cells was up-regulated by selenite both in vitro and in vivo. The elevated SLC7A11 led to cystine accumulation, NADPH depletion and the conversion of cystine to cysteine inhibition, which in turn boosted selenite-mediated reactive oxygen species (ROS), followed by enhancement of selenite-mediated cytotoxic effect. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.