Molecular Mechanisms of Cardiotoxicity: A Review on Major Side-effect of Doxorubicin

Abstract

Mobaraki, et al.: Molecular Mechanisms of Doxorubicin-induced CardiotoxicityDoxorubicin is among the most widely used drugs for the treatment of both adult and child cancers. Doxorubicin is the major cause of chemotherapy-induced cardiotoxicity that is dose limiting for the treatment of cancer. Many studies have explored pathophysiology and mechanisms of doxorubicininduced cardiotoxicity. Cellular and animal experiments proposed that doxorubicin-induced cardiotoxicity mechanism is multifactorial. Oxidative stress has been considered as the primary cause of cardiotoxicity. Although there is no effective treatment for doxorubicin-induced cardiotoxicity currently but many investigations are underway to discover preventive treatments whereas no specific treatment has been approved. Studies have shown that reactive oxygen species and topoisomerase 2b are molecular targets for cardioprotection. Therapeutic imaging methods and cardio-biomarkers may be helpful in the improvement of rapid detection of cardiac damage. In this review, effects of doxorubicin on DNA damage, free radical generation, mitochondrial damage, cell death and other parameters have been studied.

Untitled

“…Doxorubicin-Induced Cardiotoxicity: Rats were randomly divided into eight groups of ten animals in each. A series of a single intraperitoneal dose of doxorubicin (13,14,15,16,17,18,19 and 20 mg/kg) was injected to each animal after a 16 h fast. All animals were sacrificed by cervical dislocation three days after the administration of doxorubicin.…”

“…The present study was conducted to determine the dose-dependent cardiotoxic changes observed in doxorubicin-induced acute cardiotoxicity because the acute cardiotoxicity has a higher prevalence than the chronic cardiotoxicity 13 . Although, the chronic cardiotoxicity is dose-dependent, and the extent of damage depends on the cumulative dosage, the acute cardiotoxicity can be evident even with the administration of one dose of doxorubicin.…”

“…In this mechanism, doxorubicin intercalates into DNA and disrupt topoisomerase II-α mediated DNA repair by inhibiting its relegation reaction and cause the accumulation of protein-linked double and singlestranded DNA breaks (cleavable complexes) and induction of apoptosis that ultimately lead to cytotoxic DNA damage and cell death 11,12 . Redox injury and interference with protein synthesis play an important role in doxorubicin cardiotoxicity 13 . Conditions that exacerbate free-radical formation may enhance doxorubicin-induced cardiotoxicity.…”

Cardioprotective Effect of Marine Astaxanthin on Doxorubicin-Induced Cardiotoxicity in Normal Rats

“…Although there are several cellular pathways involved in DOX induce cardiotoxicity such as release of vasoactive substances, mitochondrial deteriorations, lipid peroxidation and depletion of the cellular antioxidants such as glutathione. As ROS liberation plays an essential role in the DOX induced cardiotoxicity we and other researchers focused on the potential involvement of ROS in DOX induced cardiotoxicity [2,3,4,6,33] ; Article no. JPRI.48804 effects as cardiotoxicity which may be exaggerated to reach heart failure major and the most serious adverse effect of DOX which limit its clinical usefulness.…”

“…It has been reported that the cardiomyopathy and congestive heart failure after treatment with DOX is dosedependent [4,5]. Doxorubicin induces its cardiotoxicity by many mechanisms such as DNA and RNA damages, induction of oxidative stress through liberation of reactive oxygen specious, lipid peroxidation, increase the endoplasmic reticulum-mediated apoptosis, inhibition of autophagy and interference with of calcium homeostasis [2,6]. In addition, DOX metabolism produces superoxide anion and hydroxyl radical which lead to toxic manifestation in the cellular membrane of the normal cells.…”