Cryptotanshinone Ameliorates Doxorubicin-Induced Cardiotoxicity by Targeting Akt-GSK-3β-mPTP Pathway In Vitro.

Xiaoping Wang,Qianbin Sun,Jing Cao,Linghui Lu,Chun Li,Qianqian Jiang,Peng Wei,Yawen Zhang,Yong Wang,Yanyan Jiang,Qiyan Wang

doi:10.3390/molecules26051460

Abstract

Cardiotoxicity is one of the main side effects of doxorubicin (Dox) treatment. Dox could induce oxidative stress, leading to an opening of the mitochondrial permeability transition pore (mPTP) and apoptosis in cardiomyocytes. Previous studies have shown that Cryptotanshinone (Cts) has potential cardioprotective effects, but its role in Dox-induced cardiotoxicity (DIC) remains unknown. A Dox-stimulated H9C2 cell model was established. The effects of Cts on cell viability, reactive oxygen species (ROS), superoxide ion accumulation, apoptosis and mitochondrial membrane potential (MMP) were evaluated. Expressions of proteins in Akt-GSK-3β pathway were detected by Western blot. An Akt inhibitor was applied to investigate the effects of Cts on the Akt-GSK-3β pathway. The effects of Cts on the binding of p-GSK-3β to ANT and the formation of the ANT-CypD complex were explored by immunoprecipitation assay. The results showed that Cts could increase cell viability, reduce ROS levels, inhibit apoptosis and protect mitochondrial membrane integrity. Cts increased phosphorylated levels of Akt and GSK-3β. After cells were co-treated with an Akt inhibitor, the effects of Cts were abolished. An immunoprecipitation assay showed that Cts significantly increased GSK-3β-ANT interaction and attenuated Dox-induced formation of the ANT-CypD complex, thereby inhibiting opening of the mPTP. In conclusion, Cts could ameliorate oxidative stress and apoptosis via the Akt-GSK-3β-mPTP pathway.

Highlights

Doxorubicin (Dox) is an effective first-line chemotherapeutic agent that is widely used in the treatment of various kinds of cancers
The induction of double-strand DNA breaks arising from the treatment of H9C2 cells with Dox was assessed by a neutral comet assay
Results showed that Dox produced significant DNA breaks in a dose-dependent manner, as measured by percent tail DNA after treatment

Summary

Introduction

Doxorubicin (Dox) is an effective first-line chemotherapeutic agent that is widely used in the treatment of various kinds of cancers. Accumulation of Dox can cause side effects, cardiotoxicity being the most serious one [1]. There are few effective drugs that can be used to prevent Dox-induced cardiotoxicity (DIC) and the underlying mechanism of DIC remains poorly understood. Mitochondrial dysfunction is one of the major pathogenic changes caused by DIC. Administration of Dox could induce oxidative stress, and subsequently lead to the opening of the mitochondrial permeability transition pore (mPTP) in cardiomyocytes [2,3,4]. Modulating mPTP opening-induced apoptosis is a potential way to ameliorate cardiotoxicity caused by Dox

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