Schisandrin B Antagonizes Cardiotoxicity Induced by Pirarubicin by Inhibiting Mitochondrial Permeability Transition Pore (mPTP) Opening and Decreasing Cardiomyocyte Apoptosis.

Hongwei Shi,Fengqing Zhu,Hong Yang,Quan He,Yunjie Wei,Li Wen,Heng Tang,Qingfu Zeng,Rui Feng,Peng Pu,Wen Ai

doi:10.3389/fphar.2021.733805

Abstract

Objective: Pirarubicin (THP), one of the anthracycline anticancer drugs, is widely used in the treatment of various cancers, but its cardiotoxicity cannot be ignored. Schisandrin B (SchB) has the ability to upregulate cellular antioxidant defense mechanism and promote mitochondrial function and antioxidant status. However, it has not been reported whether it can resist THP-induced cardiotoxicity. The aim of this study was to investigate the effect of SchB on THP cardiotoxicity and its mechanism. Methods: The rat model of cardiotoxicity induced by THP was established, and SchB treatment was performed at the same time. The changes of ECG, cardiac coefficient, and echocardiogram were observed. The changes of myocardial tissue morphology were observed by H&E staining. Apoptosis was detected by TUNEL. The levels of LDH, BNP, CK-MB, cTnT, SOD, and MDA in serum were measured to observe the heart damage and oxidative stress state of rats. The expression of cleaved-caspase 9, pro/cleaved-caspase 3, Bcl-2/Bax, and cytosol and mitochondrial Cyt C and Bax was evaluated by western blot. H9c2 cardiomyocytes were cocultured with THP, SchB, and mPTP inhibitor CsA to detect the production of ROS and verify the above signaling pathways. The opening of mPTP and mitochondrial swelling were detected by mPTP kit and purified mitochondrial swelling kit. Results: After 8 weeks, a series of cardiotoxicity manifestations were observed in THP rats. These adverse effects can be effectively alleviated by SchB treatment. Further studies showed that SchB had strong antioxidant and antiapoptotic abilities in THP cardiotoxicity. Conclusion: SchB has an obvious protective effect on THP-induced cardiotoxicity. The mechanism may be closely related to the protection of mitochondrial function, inhibition of mPTP opening, and alleviation of oxidative stress and apoptosis of cardiomyocytes.

Highlights

Pirarubicin (THP) is an anthracycline anticancer drug that has been widely used clinically
It is generally believed that the mechanism of cardiotoxicity in anthracycline anticancer drugs involves oxidative stress, which increases cardiomyocyte apoptosis caused by reactive oxygen species (ROS) and calcium overload (Yao et al, 2015; Donato et al, 2017)
The Mitochondrial permeability transition pore (mPTP) is composed of nonspecific voltage-dependent anion channel (VDAC) located in the outer membrane, adenine nucleotide translocase (ANT) located in the inner membrane, and Cyp D receptor located in the mitochondrial matrix (Fayaz et al, 2015)

Summary

Introduction

Pirarubicin (THP) is an anthracycline anticancer drug that has been widely used clinically. It has a broad antitumor spectrum and high clinical efficacy (Greish et al, 2005). It is dosedependent and exhibits cumulative cardiotoxicity (Von Hoff et al, 1979; Octavia et al, 2012). The clinical symptoms, such as arrhythmia and cardiac dysfunction, appear during the early treatment stages (Carvalho et al, 2014). Improving or alleviating oxidative stress injury and cardiomyocyte apoptosis might help to prevent and treat THP cardiotoxicity

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Conclusion