Department of Molecular Biology, Princeton University, Princeton, New Jersey.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey.
Cancer Res. 2022 Oct 4;82(19):3486-3498. doi: 10.1158/0008-5472.CAN-22-0408.
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.
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.
高剂量抗坏血酸（维生素 C）已显示出有希望的抗癌活性。已经提出了两种氧化还原机制：抗坏血酸本身产生过氧化氢或通过脱氢抗坏血酸（由抗坏血酸氧化形成）耗尽谷胱甘肽。在这里，我们表明高剂量抗坏血酸在体外的代谢作用和细胞毒性是由过氧化氢引起的，与脱氢抗坏血酸无关。这些影响通过抗氧化硒酶（包括谷胱甘肽过氧化物酶 1（GPX1））而不是经典的抑制铁死亡的硒酶 GPX4 被硒抑制。硒通过来自戊糖磷酸途径的 NADPH 介导对抗坏血酸的保护作用。在体内，饮食硒缺乏导致抗坏血酸对神经胶质瘤异种移植物的活性显著增强。这些数据确立了硒蛋白作为癌症氧化还原平衡的关键调节剂。癌症对自由基诱导的治疗（包括抗坏血酸）的敏感性可能取决于硒，为提高其抗癌疗效提供了一种饮食方法。
硒限制增强了抗坏血酸的功效，并延长了胶质母细胞瘤小鼠异种移植模型的寿命，这表明靶向硒介导的抗氧化防御值得在与抗坏血酸和其他促氧化剂治疗联合进行临床评估。
