高剂量维生素C杀死肾癌细胞相关机理研究
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摘要
维生素C在癌症治疗中的作用已经被研究了几十年,临床研究显示静脉注射高浓度的维生素C可以对癌症治疗产生积极作用,且体外实验显示癌细胞比正常细胞更容易被维生素C杀死,然而维生素C的细胞毒性以及这种选择性杀伤作用产生的机理至今不明。我们以肾透明型肾癌细胞(CCRCC)作为肿瘤细胞研究模型,通过研究维生素C对肾癌细胞产生细胞毒性的机理,发现维生素C可以通过依赖低氧诱导因子(HIF)介导细胞死亡,以此为切入点我们进步发现, HIF阳性的肾癌细胞可以通过肿瘤细胞普遍高表达的GLUT1在胞内累积更多的维生素C,并与胞内的铁离子反应产生更多的活性氧基团(ROS),进而诱发严重的DNA损伤。另外,细胞对DNA损伤的修复会造成NAD+和ATP骤降,由于HIF阳性的肾癌细胞通过―Warburg效应‖以低效率的糖酵解途径获取能量,其对NAD+和ATP骤降的缓冲能力较弱,细胞因此走向坏死。我们的研究阐明了维生素C对肾癌细胞产生细胞毒性以及其选择性杀伤作用产生的机理,并且为针对肿瘤某特征多靶点复合式筛选药物提供了个很好的典范。
It has been studied for decades about Vitamin C's role in cancer therapy. Clinical research indicated that intravenous ascorbic acid in high concentrations could have a positive effect on cancer treatment. In vitro experiments showed that cancer cells are more easily killed than normal cells. However, the mechanism of cytotoxicity to cancer cells remains unsolved. Here we used CCRCC cells as cancer cell model to study the mechanism of cytotoxicity of Vitamin C to renal cancer cells. We demonstrated that vitamin C could induce cell death depending on HIF activity. HIF activated renal cancer cells could accumulate more intracellular vitamin C through GLUT1 which is usually overexpressed in cancer cells. Those intracellular vitamin C reacted with ferrous and produced more reactive oxygen species (ROS). ROS triggered DNA damage and induced DNA repair pathway which caused NAD+ and ATP consumption suddenly. HIF activated renal cancer cells use aerobic glycosis (Warburg effect) for producing ATP which is less effective and makes them more sensitive to NAD+ and ATP depletion. Thereafter they entered into necrosis because of the poor ability of recovery from ATP depletion. Our results here provided molecular pathway that vitamin C kill renal cancer cells in detail and also the concept that compounds targeting multiple defects of cancer cells might be more effective.
It has been studied for decades about Vitamin C's role in cancer therapy. Clinical research indicated that intravenous ascorbic acid in high concentrations could have a positive effect on cancer treatment. In vitro experiments showed that cancer cells are more easily killed than normal cells. However, the mechanism of cytotoxicity to cancer cells remains unsolved. Here we used CCRCC cells as cancer cell model to study the mechanism of cytotoxicity of Vitamin C to renal cancer cells. We demonstrated that vitamin C could induce cell death depending on HIF activity. HIF activated renal cancer cells could accumulate more intracellular vitamin C through GLUT1 which is usually overexpressed in cancer cells. Those intracellular vitamin C reacted with ferrous and produced more reactive oxygen species (ROS). ROS triggered DNA damage and induced DNA repair pathway which caused NAD+ and ATP consumption suddenly. HIF activated renal cancer cells use aerobic glycosis (Warburg effect) for producing ATP which is less effective and makes them more sensitive to NAD+ and ATP depletion. Thereafter they entered into necrosis because of the poor ability of recovery from ATP depletion. Our results here provided molecular pathway that vitamin C kill renal cancer cells in detail and also the concept that compounds targeting multiple defects of cancer cells might be more effective.
引文
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