Editors' ChoiceCancer

Vitamin C puts the pedal to the metal

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Science Translational Medicine  12 Apr 2017:
Vol. 9, Issue 385, eaan2778
DOI: 10.1126/scitranslmed.aan2778

Abstract

Increased iron in cancer cells drives selective sensitization of tumors to ascorbate treatment to prolong survival.

It has been over 40 years since the initial discovery that vitamin C, also known as ascorbate, is selectively toxic to cancer cells versus normal cells. This uncharacteristic role of ascorbate is counter to the protective function it normally serves as an antioxidant, as well as its homeostatic role in the prevention of scurvy. Although studies over the past four decades have yielded both promising and disappointing outcomes, there have been enough positive and intriguing results at the bench and in clinical trials, as well as a consistent lack of systemic toxicity to normal tissues, to keep ascorbate in the game for cancer researchers. However, still shrouded in mystery has been how, across numerous tumor types, ascorbate could mechanistically serve an anticancer role.

Schoenfeld et al. set out to address this using cell lines from two highly malignant tumors, advanced non–small cell lung cancer (NSCLC) and glioblastoma (GBM). First, they demonstrated ascorbate’s selective targeting of NSCLC and GBM cells as compared with their normal counterparts, as well as an increase in ascorbate’s ability to kill the cancer cells when it was combined with the standard of care radio- and chemotherapy used for these cancers. They then began to peel back the intracellular dynamics driving the selective toxicity to the cancer cells. Through a multitude of biochemical and genetic studies, the authors showed that alterations in oxidative metabolism inherent to the cancer cells resulted in an increase in intracellular labile iron, which was essential for ascorbate toxicity. Furthermore, ascorbate could increase the iron in the cancer cells, creating a positive feedback loop that amplified its toxicity. Lacking that extra pool of iron, normal cells were protected from the negative effects of ascorbate treatment. Last, in a small cohort of NSCLC and GBM patients, the authors demonstrated extended overall and progression-free survival with combined treatment of intravenous ascorbate and standard of care.

These studies help elucidate the mechanistic underpinning of a long-appreciated role for ascorbate in cancer therapy. Expansion of these clinical studies could further support including ascorbate treatment for the good of tumor eradication.

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