Wenzel Uwe, Nickel Alexander, Kuntz Sabine, Daniel Hannelore
Molecular Nutrition Unit, Department of Food and Nutrition, Technical University of Munich, Hochfeldweg 2, D-85350 Freising, Germany.
Carcinogenesis. 2004 May;25(5):703-12. doi: 10.1093/carcin/bgh079. Epub 2004 Jan 30.
Although a high alimentary intake of antioxidant vitamins such as ascorbic acid may play an important role in cancer prevention, a high level of antioxidants may have quite different effects at different stages of the transformation process. In cancer development, the resistance of cells to apoptosis is one of the most crucial steps. We have tested the effects of ascorbic acid on apoptosis in HT-29 human colon carcinoma cells when induced by two potent apoptosis inducers, the classical antitumor drug camptothecin or the flavonoid flavone. Apoptosis was assessed based on caspase-3-like activity, plasma membrane disintegration and finally nuclear fragmentation and chromatin condensation. Ascorbic acid dose-dependently inhibited the apoptotic response of cells to camptothecin and flavone. RT-PCR analysis and western blot analysis revealed that ascorbic acid specifically blocked the decrease of bcl-X(L) by camptothecin or flavone. An increased generation of mitochondrial O(2)(-.) precedes the down-regulation of bcl-X(L) by camptothecin and flavone and ascorbic acid at a concentration of 1 mM prevented the generation of this reactive oxygen species. In conclusion, ascorbic acid functions as a potent antioxidant in mitochondria of human colon cancer cells and thereby blocks drug-mediated apoptosis induction allowing cancer cells to become insensitive to chemotherapeutics.
尽管高摄入抗坏血酸等抗氧化维生素可能在癌症预防中发挥重要作用，但高水平的抗氧化剂在转化过程的不同阶段可能具有截然不同的效果。在癌症发展过程中，细胞对凋亡的抗性是最关键的步骤之一。我们测试了抗坏血酸对HT-29人结肠癌细胞凋亡的影响，该凋亡由两种强效凋亡诱导剂诱导，即经典抗肿瘤药物喜树碱或类黄酮黄酮。基于半胱天冬酶-3样活性、质膜解体以及最终的核碎裂和染色质凝聚来评估凋亡。抗坏血酸剂量依赖性地抑制细胞对喜树碱和黄酮的凋亡反应。逆转录-聚合酶链反应（RT-PCR）分析和蛋白质印迹分析表明，抗坏血酸特异性地阻断了喜树碱或黄酮导致的bcl-X(L)减少。喜树碱和黄酮以及1 mM浓度的抗坏血酸下调bcl-X(L)之前，线粒体超氧阴离子（O(2)(-.)）的生成增加，而抗坏血酸可阻止这种活性氧的生成。总之，抗坏血酸在人结肠癌细胞的线粒体中作为一种强效抗氧化剂发挥作用，从而阻断药物介导的凋亡诱导，使癌细胞对化疗药物不敏感。
