Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
Mol Pharm. 2013 Jan 7;10(1):161-74. doi: 10.1021/mp300311b. Epub 2012 Dec 7.
In previous studies, we showed that nitric oxide (NO) donors and synthetic doxorubicins (DOXs) modified with moieties containing NO-releasing groups--such as nitrooxy-DOX (NitDOX) or 3-phenylsulfonylfuroxan-DOX (FurDOX)--overcome drug resistance by decreasing the activity of ATP-binding cassette (ABC) transporters that can extrude the drug. Here, we have investigated the biochemical mechanisms by which NitDOX and FurDOX exert antitumor effects. Both NitDOX and FurDOX were more cytotoxic than DOX against drug-resistant cells. Interestingly, NitDOX exhibited a faster uptake and an extranuclear distribution. NitDOX was preferentially localized in the mitochondria, where it nitrated and inhibited the mitochondria-associated ABC transporters, decreased the flux through the tricarboxylic acid cycle, slowed down the activity of complex I, lowered the synthesis of ATP, induced oxidative and nitrosative stress, and elicited the release of cytochrome c and the activation of caspase-9 and -3 in DOX-resistant cells. We suggest that NitDOX may represent the prototype of a new class of multifunctional anthracyclines, which have cellular targets different from conventional anthracyclines and greater efficacy against drug-resistant tumors.
在之前的研究中，我们表明，通过降低能够将药物排出的三磷酸腺苷结合盒（ABC）转运蛋白的活性，一氧化氮（NO）供体和含有 NO 释放基团的合成阿霉素（DOX）类似物（如硝基氧基-DOX（NitDOX）或 3-苯磺酰基呋喃-DOX（FurDOX））克服了耐药性。在这里，我们研究了 NitDOX 和 FurDOX 发挥抗肿瘤作用的生化机制。与 DOX 相比，NitDOX 和 FurDOX 对耐药细胞的细胞毒性更强。有趣的是，NitDOX 的摄取速度更快，且分布在核外。NitDOX 优先定位于线粒体，在那里它硝化并抑制与线粒体相关的 ABC 转运蛋白，减少三羧酸循环的通量，减缓复合物 I 的活性，降低 ATP 的合成，诱导氧化和硝化应激，并引发细胞色素 c 的释放和 caspase-9 和 -3 在 DOX 耐药细胞中的激活。我们认为，NitDOX 可能代表一类新型多功能阿霉素的原型，其具有不同于传统阿霉素的细胞靶标，并且对耐药肿瘤更有效。
