Institute of Biochemistry and Clinical Biochemistry, Catholic University School of Medicine, Rome, Italy.
Adv Exp Med Biol. 2012;942:385-419. doi: 10.1007/978-94-007-2869-1_18.
Anthracyclines remain the cornerstone in the treatment of many malignancies including lymphomas, leukaemias, and sarcomas. Unfortunately, the clinical use of these potent chemotherapeutics is severely limited by the development of a progressive dose-dependent cardiomyopathy that irreversibly evolves toward congestive heart failure. The molecular mechanisms responsible for anthracycline anticancer activity as well as those underlying anthracycline-induced cardiotoxicity are incompletely understood and remain a matter of remarkable controversy. Anthracyclines have long been considered to induce cardiotoxicity by mechanisms different from those mediating their anticancer activity. In particular, anthracycline antitumor efficacy is associated with nuclear DNA intercalation, topoisomerase II inhibition and drug-DNA adducts formation, whereas the cardiotoxicity is prevalently ascribed to oxidative stress and mitochondrial dysfunction. At present, however, the view that distinct mechanisms are implied in anticancer and cardiotoxic responses to anthracycline therapy does not seem fully convincing since beneficial (anticancer) and detrimental (cardiotoxic) effects are to some extent overlapping, share the subcellular organelle targets, the molecular effectors and the pathophysiological processes (i.e. DNA strand breaks, oxidative stress, signalling pathways, mitochondrial dysfunctions, apoptosis etc.).Here, we review the potential role of mitochondria in the molecular mechanisms underlying anthracyclines anticancer activity as well as in the pathogenesis of anthracycline-induced cardiotoxicity.
蒽环类药物仍然是治疗多种恶性肿瘤（包括淋巴瘤、白血病和肉瘤）的基石。不幸的是，由于这些强效化疗药物会导致剂量依赖性进行性心肌病，从而不可逆地发展为充血性心力衰竭，其临床应用受到严重限制。蒽环类药物抗癌活性的分子机制以及导致蒽环类药物心脏毒性的分子机制尚不完全清楚，仍然存在很大争议。长期以来，人们认为蒽环类药物通过不同于其抗癌活性的机制诱导心脏毒性。特别是，蒽环类药物的抗肿瘤功效与核 DNA 嵌入、拓扑异构酶 II 抑制和药物-DNA 加合物的形成有关，而心脏毒性则主要归因于氧化应激和线粒体功能障碍。然而，目前认为在蒽环类药物治疗的抗癌和心脏毒性反应中涉及不同的机制似乎并不完全令人信服，因为有益（抗癌）和有害（心脏毒性）作用在某种程度上是重叠的，它们共享亚细胞细胞器靶点、分子效应物和病理生理过程（即 DNA 链断裂、氧化应激、信号通路、线粒体功能障碍、细胞凋亡等）。在这里，我们综述了线粒体在蒽环类药物抗癌活性的分子机制以及蒽环类药物诱导心脏毒性发病机制中的潜在作用。
