Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs.
Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs.
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DOI：
10.1158/0008-5472.can-08-1490
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
O'Connor OA
中科院分区：
文献类型：
--
作者：
Heaney ML;Gardner JR;Karasavvas N;Golde DW;Scheinberg DA;Smith EA;O'Connor OA
维生素C是一种抗氧化维生素，已被假设为对抗产生活性氧的抗肿瘤药物的效果。比较了常用的抗肿瘤药物阿霉素、顺铂、长春新碱、甲氨蝶呤和伊马替尼对白血病(K562)和淋巴瘤(RL)细胞株的治疗效果，并比较了脱氢抗坏血酸(维生素C)对细胞存活率、克隆形成、细胞凋亡、P-糖蛋白、活性氧和线粒体膜电位的影响。在所有抗肿瘤药物治疗后，通过台盼蓝排斥和集落形成来衡量，维生素C的预处理引起了剂量依赖性的细胞毒性的减弱。在阿霉素治疗之前给予维生素C会导致RL细胞来源的异种肿瘤小鼠的治疗效果显著降低。维生素C治疗导致用抗肿瘤药物治疗的细胞的凋亡率呈剂量依赖性减少，这不是由于P-糖蛋白或抗肿瘤药物调节的维生素C滞留上调所致。维生素C对细胞内ROS的影响不大，而且比N-乙酰半胱氨酸具有更广泛的细胞保护作用；这表明其作用机制不是由ROS介导的。所有受试的抗肿瘤药物均可引起线粒体膜去极化，而维生素C可抑制线粒体膜去极化。这些发现表明，在机制不同的抗肿瘤药物之前给予维生素C，通过保留线粒体膜电位来拮抗血液癌的治疗效果。这些结果支持这样的假设，即癌症治疗期间补充维生素C可能有害地影响治疗反应。
Vitamin C is an antioxidant vitamin that has been hypothesized to antagonize the effects of reactive oxygen species-generating antineoplastic drugs. The therapeutic efficacy of the widely-used antineoplastic drugs, doxorubicin, cisplatin, vincristine, methotrexate and imatinib were compared in leukemia (K562) and lymphoma (RL) cell lines with and without pre-treatment with dehydroascorbic acid, the commonly transported form of vitamin C. The impact of vitamin C on viability, clonogenicity, apoptosis, P-glycoprotein, reactive oxygen species (ROS) and mitochondrial membrane potential was determined. Pre-treatment with vitamin C caused a dose-dependent attenuation of cytotoxicity as measured by trypan blue exclusion and colony formation after treatment with all anti-neoplastic agents tested. Vitamin C administered prior to doxorubicin treatment led to a substantial reduction of therapeutic efficacy in mice with RL cell-derived xenogeneic tumors. Vitamin C treatment led to a dose-dependent decrease in apoptosis in cells treated with the antineoplastic agents that was not due to up-regulation of P-glycoprotein or vitamin C retention modulated by anti-neoplastics. Vitamin C had only modest effects on intracellular ROS and a more general cytoprotective profile than N-acetylcysteine; suggesting a mechanism of action that is not mediated by ROS. All antineoplastic agents tested caused mitochondrial membrane depolarization that was inhibited by vitamin C. These findings indicate that vitamin C administered prior to mechanistically dissimilar antineoplastic agents antagonizes therapeutic efficacy in a model of human hematopoietic cancers by preserving mitochondrial membrane potential. These results support the hypothesis that vitamin C supplementation during cancer treatment may detrimentally affect therapeutic response.