Abstract

Treatment with Adriamycin (ADR) is one of the major causes of chemotherapy-induced cardiotoxicity and therefore is the principal limiting factor in the effectiveness of chemotherapy for cancer patients. Apigenin (API) has been shown to play a cardioprotective role. The present study examined the effect of API on ADR-induced cardiotoxicity in mice. Sixty male Kunming mice were randomly divided into 4 groups: a control group, ADR model group, low-dose API treatment group (125 mg·kg−1), and high-dose API treatment group (250 mg·kg−1). Blood samples were taken to evaluate a spectrum of myocardial enzymes. Cardiomyocyte apoptosis was measured using a TUNEL assay, and cardiomyocyte autophagy was observed using electron microscopy. Moreover, apoptosis-related proteins, such as Bax and Bcl-2, autophagy-related proteins, including Beclin1 and LC3B, and PI3K/AKT/mTOR pathway-related proteins were examined with western blot. Our results demonstrate that ADR caused an increase in the serum levels of cardiac injury markers and enhanced cardiomyocyte apoptosis and autophagy. API administration prevented the effects associated with ADR-induced cardiotoxicity in mice and inhibited ADR-induced apoptosis and autophagy. API also promoted PI3K/AKT/mTOR pathway activity in ADR-treated mice. In conclusion, API may have a protective effect against ADR-induced cardiotoxicity by inhibiting apoptosis and autophagy via activation of the PI3K/AKT/mTOR pathway.

Highlights

  • Since the introduction of Adriamycin (ADR) in the late 1960s, it has been widely applied to the treatment of various types of malignancies, including breast cancer, multiple myeloma, neuroblastoma, leukaemia, and sarcomas, and it is associated with satisfactory clinical effects [1, 2]

  • Several cellular mechanisms, including myocardial fibrosis, apoptosis, oxidative stress, mitochondrial dysfunction, and autophagy, have been proposed to account for the cardiomyopathy caused by ADR [6, 7]

  • API at 125 and 250 mg/kg markedly inhibited lactate dehydrogenase (LDH) and creatine kinase (CK) release into the serum, which indicates that these doses of API can protect against ADRinduced myocardial injury

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Summary

Introduction

Since the introduction of Adriamycin (ADR) in the late 1960s, it has been widely applied to the treatment of various types of malignancies, including breast cancer, multiple myeloma, neuroblastoma, leukaemia, and sarcomas, and it is associated with satisfactory clinical effects [1, 2]. The use of ADR has been limited due to its severe cardiotoxic side effect, which causes fatal congestive heart failure [3]. ADR-induced cardiotoxicity includes acute and chronic cardiotoxicity. Acute cardiotoxicity occurs during or immediately after ADR treatment and is characterized by aberrant electrophysiology and arrhythmias [4]. Chronic cardiotoxicity may occur weeks or many years after ADR administration and presents as cardiac dysfunction [5]. Several cellular mechanisms, including myocardial fibrosis, apoptosis, oxidative stress, mitochondrial dysfunction, and autophagy, have been proposed to account for the cardiomyopathy caused by ADR [6, 7]. To minimize and manage ADR-associated cardiotoxicity, several effective approaches have been put forward, such as dosage optimization or combination therapy, and many of these strategies still await verification in large scale clinical trials [8]

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