Amir Hossein Ajzashokouhi - School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Hasan Badie Bostan - Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
A Wallace Hayes - University of South Florida, Tampa, FL USA, and Michigan State University, East Lansing, MI, USA
Gholamreza Karimi - School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran- Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran

Introduction: doxorubicin (DOX) is an antineoplastic medication obtained from Streptomyces peucetius. It is used in treating different kinds of cancers such as leukemia, lymphoma, lung, and breast. The main side effect of DOX is cardiotoxicity. Metformin (MET) is an antihyperglycemic drug used for type 2 diabetes treatment. It is proposed that MET has a protective effect against DOX cardiotoxicity.Methods: We reviewed the following databases PubMed, Scopus, ScienceDirect, and Web of Science using the following search terms (keywords) doxorubicin, cardiotoxicity, metformin, adriamycin and heart failure over the years 1980 to February 2019. Only articles in English were reviewed and used in this peer-review.Results: our review demonstrated that MET has several possible mechanisms of action which can prevent or at least reduce DOX-cardiotoxicity including a decrease of free radical generation and oxidative stress, 5 adenosine monophosphate-activated protein kinase (AMPK) activation and ferritin heavy chain (FHC) expression in cardiomyocytes cells. The combination of MET and DOX has been shown to enhance the anti-cancer activity of DOX by a number of authors.Conclusion: oxidative stress is one of the most important mechanisms of DOX-induced heart damage. This drug also has been shown to change aerobic metabolism to anaerobic metabolism. MET can increase the cellular energy level by activation of AMPK, thus increasing the rate of cell survival. Iron hemostasis plays an important role in oxidative stress-induced by DOX in the heart. Increasing the cytosolic and mitochondrial free iron pools induced by DOX can be prevented or at least reduced by MET through FHC expression. DOX has been shown to liberate calcium from the sarcoplasmic reticulum and MET can reduce the [Ca2+]i and thereby, attenuated the DOX-cardiotoxicity. DOX can induce autophagy dysregulation which has been reported to be alleviated by the use of MET.

Doxorubicin, Metformin, Cardiotoxicity, Heart failure, Protective, Adriamycin