Potential targets for intervention against doxorubicin-induced cardiotoxicity based on genetic studies: a systematic review of the literature

Abstract

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.

Keywords: Cardioprotection; Cardiotoxicity; Doxorubicin; Gene knockout; Mechanism.