Giansanti Manuela, Karimi Terry, Faraoni Isabella, Graziani Grazia
Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, 00185 Rome, Italy.
Cancers (Basel). 2021 Mar 20;13(6):1428. doi: 10.3390/cancers13061428.
High-dose vitamin C has been proposed as a potential therapeutic approach for patients with advanced tumors who failed previous treatment with chemotherapy. Due to vitamin C complex pharmacokinetics, only intravenous administration allows reaching sufficiently high plasma concentrations required for most of the antitumor effects observed in preclinical studies (>0.250 mM). Moreover, vitamin C entry into cells is tightly regulated by SVCT and GLUT transporters, and is cell type-dependent. Importantly, besides its well-recognized pro-oxidant effects, vitamin C modulates TET enzymes promoting DNA demethylation and acts as cofactor of HIF hydroxylases, whose activity is required for HIF-1α proteasomal degradation. Furthermore, at pharmacological concentrations lower than those required for its pro-oxidant activity (<1 mM), vitamin C in specific genetic contexts may alter the DNA damage response by increasing 5-hydroxymethylcytosine levels. These more recently described vitamin C mechanisms offer new treatment opportunities for tumors with specific molecular defects (e.g., HIF-1α over-expression or TET2, IDH1/2, and WT1 alterations). Moreover, vitamin C action at DNA levels may provide the rationale basis for combination therapies with PARP inhibitors and hypomethylating agents. This review outlines the pharmacokinetic and pharmacodynamic properties of vitamin C to be taken into account in designing clinical studies that evaluate its potential use as anticancer agent.
高剂量维生素C已被提议作为晚期肿瘤患者的一种潜在治疗方法，这些患者先前接受化疗治疗失败。由于维生素C复杂的药代动力学，只有静脉给药才能达到临床前研究中观察到的大多数抗肿瘤作用所需的足够高的血浆浓度（>0.250 mM）。此外，维生素C进入细胞受到钠-维生素C协同转运蛋白（SVCT）和葡萄糖转运蛋白（GLUT）的严格调控，并且具有细胞类型依赖性。重要的是，除了其广为人知的促氧化作用外，维生素C还调节促进DNA去甲基化的TET酶，并作为缺氧诱导因子（HIF）羟化酶的辅助因子，其活性是HIF-1α蛋白酶体降解所必需的。此外，在低于其促氧化活性所需浓度（<1 mM）的药理浓度下，维生素C在特定基因背景下可能通过增加5-羟甲基胞嘧啶水平来改变DNA损伤反应。这些最近描述的维生素C机制为具有特定分子缺陷（例如，HIF-1α过表达或TET2、异柠檬酸脱氢酶1/2（IDH1/2）和威尔姆斯瘤基因1（WT1）改变）的肿瘤提供了新的治疗机会。此外，维生素C在DNA水平上的作用可能为与聚（ADP-核糖）聚合酶（PARP）抑制剂和去甲基化剂联合治疗提供理论基础。本综述概述了在设计评估维生素C作为抗癌剂潜在用途的临床研究时需要考虑的维生素C的药代动力学和药效学特性。
