A Review on Cardio Deleterious Effect of Doxorubicin Therapy with Possible Strategies that may Counteract Cardiotoxicity

Abstract

Doxorubicin is an anthracyclines that was first isolated from Streptomyces peucetius strain and revealed activity to counter tumor of murine with trade name Adriamycin. Doxorubicin revealed important efficacious therapeutic role in different cancer types, however it have a deleterious toxicity on the heart. This cardiotoxicity could attributed to free radical generation, disturbance of myocyte oxidative stress, lipid peroxidation, programmed cell death and disoriented autophagy. Its usefulness has been restricted due to acute (dose- dependent) and chronic (cumulative) cardiotoxicity with prolonged QT wave interval in ECG. Accumulation of doxorubicin within mitochondria lead to disruption of the electron transport chain and an elevation of ROS hydrogen peroxide H2O2 and superoxide O2• ˗ production, in addition to enhancing OH• formation by forming a complex with Fe3+ that enter a redox cycle and initiating lipid peroxidation and DNA destruction. Doxorubicin can form ternary complex via binding with topoisomerase 2 isozymes and DNA that prevents replication of DNA and arrest cell cycle causing its apoptosis. Myocytes mediated mitophagy of damaged mitochondria may interrupted by doxorubicin inducing accumulation of injured mitochondria and eventually autophagy. An extra mechanism of doxorubicin-induced cardiotoxicity have been reported thereby affecting cardiac progenitor cells growth and functional characteristics. The main cells have been suggested to mediate cardiotoxic effects of doxorubicin are cardiac fibroblasts which stimulate apoptosis of cardiomyocytes. Antioxidants can neutralize the clinical appearance of cardiotoxicities of anthracyclines doxorubicin for example dietary supplements like vitamin E, vitamin C, vitamin A, omega-3 fatty acids, coenzyme Q and flavonoids recognized to prevent oxidative injury.