Cardiotoxicity is a well-known adverse effect of doxorubicin (Dox) administration, but the underlying molecular mechanism of this effect is not fully understood. Over the past two decades, considerable efforts have focused on the potential molecular targets of cardiotoxicity in the hope that novel targeted therapies will be generated to attenuate Dox-induced cardiotoxicity. Here, we provide a comprehensive overview of genetically modified animals that show enhanced or reduced susceptibility to the cardiotoxic effects of Dox. We focused on the process by which the molecules involved in DNA damage, oxidative stress, apoptosis, autophagy and necrosis are affected in the presence of Dox. We also present a protein-protein interaction network and explain the contribution of the components to the process of Dox-induced cardiotoxicity. More importantly, data from the literature have indicated that PI3Kγ and Rac1 are potential targets with therapeutic advantages in cancer therapy; molecules that target these proteins can simultaneously attenuate Dox-induced cardiotoxicity and enhance its anticancer activity. This review highlights the potential molecular targets that are critical regulators involved in Dox-mediated cardiotoxicity, thus providing further insight into the development of potential treatment strategies to prevent the cardiotoxic effects and enhance the anticancer efficiency of Dox in cancer patients.

中文翻译：

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基于遗传研究的抗阿霉素诱导的心脏毒性干预的潜在目标：文献的系统综述。

心脏毒性是阿霉素（Dox）给药的众所周知的不良反应，但这种作用的潜在分子机制尚未完全明了。在过去的二十年中，大量的努力集中在潜在的心脏毒性分子靶标上，希望能够产生新颖的靶向疗法来减轻Dox诱导的心脏毒性。在这里，我们提供了对转基因动物的全面概述，这些动物对Dox的心脏毒性作用表现出增强或降低的敏感性。我们关注于在Dox存在下影响DNA损伤，氧化应激，细胞凋亡，自噬和坏死的分子受到影响的过程。我们还提出了蛋白质-蛋白质相互作用网络，并解释了成分对Dox诱导的心脏毒性过程的贡献。更重要的是，来自文献的数据表明，PI3Kγ和Rac1是潜在的靶标，在癌症治疗中具有治疗优势。靶向这些蛋白质的分子可以同时减弱Dox引起的心脏毒性并增强其抗癌活性。这篇综述重点介绍了潜在的分子靶标，这些靶标是参与Dox介导的心脏毒性的关键调控因子，从而为开发潜在的治疗策略提供了进一步的见解，以预防癌症患者的心脏毒性作用并增强Dox的抗癌效率。