Gammella Elena, Maccarinelli Federica, Buratti Paolo, Recalcati Stefania, Cairo Gaetano
Department of Biomedical Sciences for Health, University of Milano Milano, Italy.
Department of Molecular and Translational Medicine, University of Brescia Brescia, Italy.
Front Pharmacol. 2014 Feb 26;5:25. doi: 10.3389/fphar.2014.00025. eCollection 2014.
The clinical use of the antitumor anthracycline Doxorubicin is limited by the risk of severe cardiotoxicity. The mechanisms underlying anthracycline-dependent cardiotoxicity are multiple and remain uncompletely understood, but many observations indicate that interactions with cellular iron metabolism are important. Convincing evidence showing that iron plays a role in Doxorubicin cardiotoxicity is provided by the protecting efficacy of iron chelation in patients and experimental models, and studies showing that iron overload exacerbates the cardiotoxic effects of the drug, but the underlying molecular mechanisms remain to be completely characterized. Since anthracyclines generate reactive oxygen species, increased iron-catalyzed formation of free radicals appears an obvious explanation for the aggravating role of iron in Doxorubicin cardiotoxicity, but antioxidants did not offer protection in clinical settings. Moreover, how the interaction between reactive oxygen species and iron damages heart cells exposed to Doxorubicin is still unclear. This review discusses the pathogenic role of the disruption of iron homeostasis in Doxorubicin-mediated cardiotoxicity in the context of current and future pharmacologic approaches to cardioprotection.
抗肿瘤蒽环类药物阿霉素的临床应用因严重心脏毒性风险而受到限制。蒽环类药物依赖性心脏毒性的潜在机制是多方面的，目前仍未完全明确，但许多观察结果表明，与细胞铁代谢的相互作用很重要。铁螯合在患者和实验模型中的保护作用，以及铁过载会加剧该药物心脏毒性作用的研究，都提供了令人信服的证据，表明铁在阿霉素心脏毒性中起作用，但潜在的分子机制仍有待完全阐明。由于蒽环类药物会产生活性氧，铁催化自由基生成增加似乎是铁在阿霉素心脏毒性中起加重作用的一个明显解释，但抗氧化剂在临床环境中并未提供保护作用。此外，活性氧与铁之间的相互作用如何损害暴露于阿霉素的心脏细胞仍不清楚。本综述在当前和未来心脏保护药理学方法的背景下，讨论了铁稳态破坏在阿霉素介导的心脏毒性中的致病作用。
