Selenium Modulates Cancer Cell Response to Pharmacologic Ascorbate.
Cancer Res
; 82(19): 3486-3498, 2022 Oct 04.
Article
em En
| MEDLINE
| ID: mdl-35916672
ABSTRACT
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. SIGNIFICANCE:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Selênio
/
Glioblastoma
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article