Abstract
Simple SummarySelenite, 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.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.
Highlights
The combination of intermittent fasting (IF)/fasting-mimicking diet (FMD) and chemotherapy has been drawn an increasing attention
To investigate influences of glucose on the anticancer activity of selenite, HCT116 human colon cancer cells were cultured in the medium with different levels of glucose and exposed to various concentrations of selenite (0, 1, 2.5 and 5 μM) for 24 h and the changes of cell viability were measured by crystal violet staining
We examined effect of GLUT1 inhibitor BAY-876 on selenite-induced cytotoxicity of HCT116 cells and results demonstrated that an enhanced cytotoxicity was achieved by all the combinations of selenite and BAY-876, further supporting the sensitization effect of glucose deprivation on selenite-induced cytotoxic effect against HCT116 colon cancer cells (Figure 1C)
Summary
The combination of intermittent fasting (IF)/fasting-mimicking diet (FMD) and chemotherapy has been drawn an increasing attention. Overexpression of SLC7A11 leads to increase of cystine uptake, accompanied by augmentation of glutamate export and NADPH consumption (due to NADPH-dependent reduction of cystine to cysteine), which forces cancer cells to be highly dependent on pentose phosphate pathway (PPP) [9]. Such metabolic feature confers the cancer cells with elevated expression of SLC7A11 more sensitive to glucose deprivation owing to cystine accumulation-mediated NADPH depletion and impairment of cellular redox homeostasis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
