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Against effect of melatonin and its combination with therapeutic exercise on Doxorubicin induced Cardiotoxicity

Tserentogtokh Lkhagvasuren1, Seunghoon Lee2, Jeong-Hwa Hong1, and Yonggeun Hong2,3. 1Department of Smart Foods & Drugs, Inje University, 2Department of Rehabilitation Science, Inje University, 3Cardiovascular & Metabolic Disease Center, Inje University, Gimhae, Gyeongnam 621-749, Korea

Abstract

Doxorubicin (DOX) has been known as strong therapeutic effective in cancers. DOX induced oxidative stress may cause necrosis apoptosis and left ventricular dysfunction and cardiac toxicity. We have known that melatonin protects against DOX induced cardiac damage. Also therapeutic exercise potential improve the ejection, left ventricle filling, due to reduction of myocardial oxidative stress by exercise. Thus, the purpose of this study was to determine synergistic effect of melatonin and exercise in DOX induced cardiac disease animal model. Cardiac toxicity was induced by i.p. injection of DOX. At 2-week after induction, the rats were randomly divided into 4 groups as follow; vehicle, melatonin, exercise, and melatonin with exercise. It was decreased left ventricle mass and increased ratio of heart/tibia in melatonin and exercise group compared to vehicle group. Single treated with melatonin or exercise group shown protective effect against DOX induced cardiac damage whereas DOX induced cardiac inflammation was significantly higher in vehicle group. Taken together, melatonin and exercise have synergistic protective effect on DOX induced cardiac damage suggesting that melatonin and DOX co-treatment is beneficial to reduce side effect of DOX in heart

Keywords; Melatonin, doxorubicin, therapeuticexercise, ….

Introduction

Doxorubicin (DOX) or Adriamycin is a cancer drug, one of the most widely used successful chemotherapeutic agent for cancers, including breast, prostate and hepatocellular carcinoma. However its clinical use is limited that dose dependent side effects of DOX were studied in human organs (brain, kidney, gastrointestinal disturbance and cumulative toxicity e.g.) [1].

Roles of DOX are down-regulation macromolecular biosynthesis and up-regulation apoptosis by generated reactive oxygen species (ROS) in cancer [pic][2]. Therefore ROS generation and cumulative toxicity leads to critical pathological changes. Specially, DOXinduced cardiac toxicity playing a pivotal role to cardiac dysfunction, cardiomyopathy and eventually heart failure and death[pic][3].

Many studies demonstrated that DOX plays critical source to cardiac toxicity, as it may be explained by chemical structure of DOX. Mitochondrial enzymes (e.g. DADH dehydrogenase) activate DOX to redox-cycling that ROS, reactive nitrogen species (RNS) during drug metabolism [pic][2, 3].Although the chemotherapeutic effect of doxorubicin has focused primary on its ability to induce apoptosis, otherwise showed that in hepatoma cell low dose DOX induced cell death trough mitotic catastrophe, whereas high dose DOX induces apoptosis [pic][4]. Then DOX-induced cardiac toxicity is associated cardiomyocyte apoptosis, necrosis, autophagy, senescence and thus pathological changes lead to cardiomyopathy and cardiomyocyte death [pic][2].

In recent years, pineal hormone melatonin’s usage was increased in clinical medicine. A number of studies has shown that melatonin is significantly better than classic antioxidant (e.g. vitamin E) in resisting free radical based molecular destruction[pic][5]. Specially, melatonin has been administrated in both physiological and pharmacological amounts to humans and animals, and there is widespread agreement that it is a nontoxic molecule [pic][6]. Melatonin’s direct scavengingon ROS (hydrogen peroxide, hydroxyl radical e.g.), RNS (nitric oxide, peroxynitrite anion e.g.) was studied, it also down-regulates pro-oxidative enzymes and up-regulates antioxidative enzymes[pic][7].

Exercisetraining has been shown to confer...
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