Benchekroun N M, Myers C E, Sinha B K
Biochemical & Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Free Radic Biol Med. 1994 Sep;17(3):191-200. doi: 10.1016/0891-5849(94)90074-4.
The benzoquinonoid ansamycin antibiotics, geldanamycin and herbimycin A, are potent cytotoxins against tumor cells in vitro. We have examined the mechanism of their in vitro cytotoxicity against human breast adenocarcinoma (MCF-7) cells and we have found that multidrug-resistant MCF-7/ADRR cells that exhibit the MDR phenotype and the overexpression of P-170-glycoprotein, were cross-resistant to geldanamycin and herbimycin A. Verapamil, which binds competitively with P-170-glycoprotein, enhanced geldanamycin cytotoxicity 12-fold only in resistant cells, suggesting that geldanamycin may interact with the drug efflux protein. Geldanamycin and herbimycin A, like adriamycin, were reductively activated by the NADPH-cytochrome P450-reductase and formed reactive .OH. The formation of .OH was significantly lower in resistant cells. In contrast to adriamycin, the formation of .OH was unaffected by the addition of DNA, indicating that a DNA-complexed drug was redoxactive and may, therefore, may be more effective in killing tumor cells at the DNA level. These observations indicate that both the decreased free radical formation and interactions with P170 glycoprotein may be important in geldanamycin and herbimycin A resistance in multidrug resistant human breast tumor cells.
苯醌类安莎霉素抗生素格尔德霉素和赫米霉素A在体外是针对肿瘤细胞的强效细胞毒素。我们研究了它们对人乳腺腺癌（MCF-7）细胞的体外细胞毒性机制，发现具有多药耐药性的MCF-7/ADRR细胞表现出多药耐药表型且P-170糖蛋白过表达，对格尔德霉素和赫米霉素A具有交叉耐药性。与P-170糖蛋白竞争性结合的维拉帕米仅在耐药细胞中使格尔德霉素的细胞毒性增强了12倍，这表明格尔德霉素可能与药物外排蛋白相互作用。格尔德霉素和赫米霉素A与阿霉素一样，被NADPH-细胞色素P450还原酶还原激活并形成活性·OH。耐药细胞中·OH的形成明显较低。与阿霉素不同，添加DNA对·OH的形成没有影响，这表明与DNA结合的药物具有氧化还原活性，因此可能在DNA水平上对杀死肿瘤细胞更有效。这些观察结果表明，自由基形成减少以及与P170糖蛋白的相互作用可能在多药耐药的人乳腺肿瘤细胞对格尔德霉素和赫米霉素A的耐药性中起重要作用。
