Selenium Modulates Cancer Cell Response to Pharmacologic Ascorbate.

TitleSelenium Modulates Cancer Cell Response to Pharmacologic Ascorbate.
Publication TypeJournal Article
Year of Publication2022
AuthorsJankowski, CSR, Rabinowitz, JD
JournalCancer Res
Volume82
Issue19
Pagination3486-3498
Date Published2022 Oct 04
ISSN1538-7445
KeywordsAnimals, Antioxidants, Ascorbic Acid, Glioblastoma, Glutathione, Glutathione Peroxidase, Humans, Hydrogen Peroxide, Mice, NADP, Reactive Oxygen Species, Selenium, Selenoproteins
Abstract

<p><b>UNLABELLED: </b>High-dose ascorbate (vitamin C) has shown promising anticancer activity. Two redox mechanisms have been proposed: hydrogen peroxide generation by ascorbate itself or glutathione depletion by dehydroascorbate (formed by ascorbate oxidation). Here we show that the metabolic effects and cytotoxicity of high-dose ascorbate in vitro result from hydrogen peroxide independently of dehydroascorbate. These effects were suppressed by selenium through antioxidant selenoenzymes including glutathione peroxidase 1 (GPX1) but not the classic ferroptosis-inhibiting selenoenzyme GPX4. Selenium-mediated protection from ascorbate was powered by NADPH from the pentose phosphate pathway. In vivo, dietary selenium deficiency resulted in significant enhancement of ascorbate activity against glioblastoma xenografts. These data establish selenoproteins as key mediators of cancer redox homeostasis. Cancer sensitivity to free radical-inducing therapies, including ascorbate, may depend on selenium, providing a dietary approach for improving their anticancer efficacy.</p><p><b>SIGNIFICANCE: </b>Selenium restriction augments ascorbate efficacy and extends lifespan in a mouse xenograft model of glioblastoma, suggesting that targeting selenium-mediated antioxidant defenses merits clinical evaluation in combination with ascorbate and other pro-oxidant therapies.</p>

DOI10.1158/0008-5472.CAN-22-0408
Alternate JournalCancer Res
PubMed ID35916672
PubMed Central IDPMC9532358
Grant ListP30 CA072720 / CA / NCI NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States