Editors' ChoiceCancer

Starving cancer cells to death

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Sci. Signal.  07 Aug 2018:
Vol. 11, Issue 542, eaau9719
DOI: 10.1126/scisignal.aau9719

Cisplatin-resistant cancer cells are particularly susceptible to starvation-induced death.

Intermittent fasting has been touted as a strategy for promoting weight loss and insulin sensitivity, reducing blood pressure and systemic inflammation, and generally improving metabolism and physiology. It has also been reported to have benefits for cancer patients because fasting and caloric restriction may sensitize cancer cells to chemotherapeutic agents. Obrist et al. found that A549 human non–small cell lung cancer cells that were resistant to the chemotherapeutic drug cisplatin were more susceptible than nonresistant cells to death induced by microtubule-targeting chemotherapeutic drugs, nutrient restriction, and drugs that mimic caloric restriction by reducing acetyl coenzyme A activity. Starvation for two 24-hour periods per week reduced tumor growth and increased survival in mice bearing xenografts of cisplatin-resistant A549 cells compared with mice bearing xenografts of nonresistant A549 cells. The addition of glutamine suppressed cell death in nutrient-deprived, cisplatin-resistant cells, and withdrawal of glutamine restored cisplatin sensitivity to resistant cells. Metabolomics and metabolism-altering experiments indicated that cisplatin-resistant cells were particularly dependent on glutamine not for generating energy through Krebs cycle but rather for nucleoside biosynthesis. Indeed, supplementing cisplatin-resistant cells with nucleosides rescued starvation-induced death, and cisplatin-resistant cells and xenografts were more sensitive to drugs that interfere with nucleoside and nucleotide biosynthesis than were nonresistant cells and xenografts. These findings suggest that periodic fasting may improve patient outcome in the context of cisplatin-resistant cancers by depriving the cells of the nutrients they require to repair DNA damaged by the drug (see Guidi and Longo).

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