Doxorubicin-mediated cardiac dysfunction: Revisiting molecular interactions, pharmacological compounds and (nano)theranostic platforms

Although chemotherapy drugs are extensively utilized in cancer therapy, their administration for treatment of patients has faced problems that regardless of chemoresistance, increasing evidence has shown concentration-related toxicity of drugs. Doxorubicin (DOX) is a drug used in treatment of solid and hematological tumors, and its function is based on topoisomerase suppression to impair cancer progression. However, DOX can also affect the other organs of body and after chemotherapy, life quality of cancer patients decreases due to the side effects. Heart is one of the vital organs of body that is significantly affected by DOX during cancer chemotherapy, and this can lead to cardiac dysfunction and predispose to development of cardiovascular diseases and atherosclerosis, among others. The exposure to DOX can stimulate apoptosis and sometimes, pro-survival autophagy stimulation can ameliorate this condition. Moreover, DOX-mediated ferroptosis impairs proper function of heart and by increasing oxidative stress and inflammation, DOX causes cardiac dysfunction. The function of DOX in mediating cardiac toxicity is mediated by several pathways that some of them demonstrate protective function including Nrf2. Therefore, if expression level of such protective mechanisms increases, they can alleviate DOX-mediated cardiac toxicity. For this purpose, pharmacological compounds and therapeutic drugs in preventing DOX-mediated cardiotoxicity have been utilized and they can reduce side effects of DOX to prevent development of cardiovascular diseases in patients underwent chemotherapy. Furthermore, (nano)platforms are used comprehensively in treatment of cardiovascular diseases and using them for DOX delivery can reduce side effects by decreasing concentration of drug. Moreover, when DOX is loaded on nanoparticles, it is delivered into cells in a targeted way and its accumulation in healthy organs is prevented to diminish its adverse impacts. Hence, current paper provides a comprehensive discussion of DOX-mediated toxicity and subsequent alleviation by drugs and nanotherapeutics in treatment of cardiovascular diseases.