Myricitrin Protects against Doxorubicin-Induced Cardiotoxicity by Counteracting Oxidative Stress and Inhibiting Mitochondrial Apoptosis via ERK/P53 Pathway.

Jing Sun,Xiangbao Meng,Xiaolan Cui,Xiaobo Sun,Meng Qin,Guibo Sun

doi:10.1155/2016/6093783

Abstract

Doxorubicin (Dox) is one of the most effective and widely used anthracycline antineoplastic antibiotics. Unfortunately, the use of Dox is limited by its cumulative and dose-dependent cardiac toxicity. Myricitrin, a natural flavonoid which is isolated from the ground bark of Myrica rubra, has recently been found to have a strong antioxidative effect. This study aimed to evaluate the possible protective effect of myricitrin against Dox-induced cardiotoxicity and the underlying mechanisms. An in vivo investigation in SD rats demonstrated that myricitrin significantly reduced the Dox-induced myocardial damage, as indicated by the decreases in the cardiac index, amelioration of heart pathological injuries, and decreases in the serum cardiac enzyme levels. In addition, in vitro studies showed that myricitrin effectively reduced the Dox-induced cell toxicity. Further study showed that myricitrin exerted its function by counteracting oxidative stress and increasing the activities of antioxidant enzymes. Moreover, myricitrin suppressed the myocardial apoptosis induced by Dox, as indicated by decreases in the activation of caspase-3 and the numbers of TUNEL-positive cells, maintenance of the mitochondrial membrane potential, and increase in the Bcl-2/Bax ratio. Further mechanism study revealed that myricitrin-induced suppression of myocardial apoptosis relied on the ERK/p53-mediated mitochondrial apoptosis pathway.

Highlights

Doxorubicin (Dox), an anthracycline chemotherapeutic agent, is widely used in treatment of a broad range of solid tumors and malignant hematologic diseases
None of the rats treated with myricitrin alone at either concentration showed any obvious abnormalities compared with the controls (Figures 2(b), 2(c), and 2(d))
Our laboratory previously reported that myricitrin, which is isolated from the ground bark of Myrica rubra, prevented atherosclerosis by inhibiting oxidative stressinduced endothelial damage [21, 22]

Summary

Introduction

Doxorubicin (Dox), an anthracycline chemotherapeutic agent, is widely used in treatment of a broad range of solid tumors and malignant hematologic diseases. Its clinical use is often limited by its dose-related cardiotoxicity, which may eventually progress to heart failure [1, 2]. Additional evidence has shown that increased oxidative stress and cardiomyocyte apoptosis play important roles in the Dox-induced cardiotoxicity [3, 4]. Large doses and/or long-term use of Dox decreases the levels of the endogenous antioxidant enzymes that are responsible for scavenging the ROS [5, 6]. Under these conditions, ROS are generated, and oxidative stress, which is characterized by an imbalance between prooxidants and antioxidants, is stimulated.

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Conclusion