Rutin Protects against Pirarubicin-Induced Cardiotoxicity through TGF-β1-p38 MAPK Signaling Pathway

Yadi Wang,Bo Sun,Liqun Ren,Qing Tong,Yang Zhang

doi:10.1155/2017/1759385

Abstract

We investigated the potential protective effect of rutinum (RUT) against pirarubicin- (THP-) induced cardiotoxicity. THP was used to induce toxicity in rat H9c2 cardiomyoblasts. Positive control cells were pretreated with a cardioprotective agent dexrazoxane (DZR) prior to treatment with THP. Some of the cells were preincubated with RUT and a p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, both individually and in combination, prior to THP exposure. At a dose range of 30–70 μM, RUT significantly prevented THP-induced reduction in cell viability; the best cardioprotective effect was observed at a dose of 50 μM. Administration of RUT and SB203580, both individually as well as in combination, suppressed the elevation of intracellular ROS, inhibited cell apoptosis, and reversed the THP-induced upregulation of TGF-β1, p-p38 MAPK, cleaved Caspase-9, Caspase-7, and Caspase-3. A synergistic effect was observed on coadministration of RUT and SB203580. RUT protected against THP-induced cardiotoxicity by inhibition of ROS generation and suppression of cell apoptosis. The cardioprotective effect of RUT appears to be associated with the modulation of the TGF-β1-p38 MAPK signaling pathway.

Highlights

Anthracyclines, such as pirarubicin (THP), are widely used chemotherapeutic agents in neoplasms such as leukemia, lymphoma, and breast cancer
We examined the potential effects of RUT in preventing cardiomyoblast injury
The protective effect of RUT appeared to be associated with its ability to scavenge intracellular reactive oxygen species (ROS) and inhibit cell apoptosis by modulating the Transforming growth factor- (TGF-)β1-p38 mitogen-activated protein kinase (MAPK) signaling pathway

Summary

Introduction

Anthracyclines, such as pirarubicin (THP), are widely used chemotherapeutic agents in neoplasms such as leukemia, lymphoma, and breast cancer. The iron chelator dexrazoxane (DZR) is the only known drug that alleviates anthracycline-induced myocardial injury, without compromising the antineoplastic efficacy of anthracyclines [3]. The mechanism of anthracycline-induced myocardial injury is not completely understood. These agents are thought to induce myocardial apoptosis as a result of their interaction with iron, which triggers excessive production of reactive oxygen species (ROS) [5]. Accumulated evidence suggests the involvement of p38 mitogen-activated protein kinase (MAPK) signaling pathway in the regulation of myocardial apoptosis [7,8,9]. Gu et al found that doxorubicin (DOX) induced H9C2 cell apoptosis by inhibiting AMPK activation and promoting proapoptotic protein expression through p38 MAPK/p53 signaling [10]

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