Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction
Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction
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DOI：
10.1167/iovs.07-1233
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发表时间：
2008-04-01
影响因子：
4.4
通讯作者：
Polans, Arthur S.
中科院分区：
文献类型：
--
作者：
van Ginkel, Paul R.;Darjatmoko, Soesiawati R.;Polans, Arthur S.
目的。目的探讨无毒植物制剂白藜芦醇治疗葡萄膜黑色素瘤的疗效。方法：在两种葡萄膜黑色素瘤动物模型上，观察口服白藜芦醇和瘤周注射白藜芦醇对肿瘤生长的影响。白藜芦醇对体外培养的葡萄膜黑色素瘤细胞的作用机制：用JC-1染料检测线粒体膜电位；用Western印迹分析细胞色素c和Smac/DIABLO的细胞再分布；用特定底物的荧光实验检测不同caspase的激活。由于口服白藜芦醇导致白藜芦醇的生物利用度相对较低，因此通过瘤周注射白藜芦醇来检验局部药物浓度升高的效果。这种方法导致肿瘤细胞死亡和肿瘤消退。用多种葡萄膜黑色素瘤细胞株进行的体外实验表明，白藜芦醇会导致细胞活力下降，至少部分原因是通过线粒体途径增加了细胞凋亡率。药物作用的早期事件是白藜芦醇直接靶向线粒体，导致线粒体膜电位降低并最终激活caspase-3。结论白藜芦醇可通过内源性线粒体途径抑制肿瘤生长并诱导细胞凋亡，进一步提高白藜芦醇的生物利用度可提高药物的药效，导致肿瘤消退。药物的无毒性质使白藜芦醇成为治疗葡萄膜黑色素瘤的有吸引力的候选药物。
PURPOSE. To test the efficacy of resveratrol, a nontoxic plant product, in the treatment of uveal melanoma.METHODS. The effect of oral administration and peritumor injection of resveratrol was tested on tumor growth in two animal models of uveal melanoma. The mechanism of resveratrol action on uveal melanoma cells was studied in vitro in a cell-viability assay: with JC-1 dye, to measure mitochondrial membrane potential; by Western blot analysis, to analyze the cellular redistribution of cytochrome c and Smac/diablo; and in a fluorescence assay with specific substrates, to measure activation of different caspases.RESULTS. Resveratrol treatment inhibited tumor growth in animal models of uveal melanoma. Since oral administration resulted in relatively low bioavailability of resveratrol, the effect of increased local levels was tested by peritumor injection of the drug. This method resulted in tumor cell death and tumor regression. In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability, resulting at least in part from an increase in apoptosis through a mitochondrial pathway. An early event in drug action is the direct targeting of mitochondria by resveratrol, which leads to a decrease in mitochondrial membrane potential and the eventual activation of caspase-3.CONCLUSION These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mitochondrial pathway and that by further increasing bioavailability of resveratrol the potency of the drug can be increased, leading to tumor regression. The nontoxic nature of the drug at levels needed for therapy make resveratrol an attractive candidate for the treatment of uveal melanoma.