Ginkgolide B Exerts Cardioprotective Properties against Doxorubicin-Induced Cardiotoxicity by Regulating Reactive Oxygen Species, Akt and Calcium Signaling Pathways In Vitro and In Vivo.

Junqing Gao,Jianpu Zheng,Zongjun Liu,Deqiang Zhao,Tao Chen,Tao Lu

doi:10.1371/journal.pone.0168219

Junqing Gao, Jianpu Zheng + Show 4 more

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https://doi.org/10.1371/journal.pone.0168219

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Journal: PloS one	Publication Date: Dec 14, 2016
Citations: 33	License type: CC BY 4.0

Affiliation: Shanghai University of Traditional Chinese Medicine

Abstract

The aim of this study was to evaluate the effect of Ginkgolide B (GB) on doxorubicin (DOX) induced cardiotoxicity in vitro and in vivo. Rat cardiomyocyte cell line H9c2 was pretreated with GB and subsequently subjected to doxorubicin treatment. Cell viability and cell apoptosis were assessed by MTT assay and Hoechst staining, respectively. Reactive oxygen species (ROS), Akt phosphorylation and intracellular calcium were equally determined in order to explore the underlying molecular mechanism. To verify the in vivo therapeutic effect of GB, we established a mouse model of cardiotoxicity and determined left ventricle ejection fraction (LVEF) and left ventricular mass (LVM). The in vitro experimental results indicated that pretreatment with GB significantly decreases the viability and apoptosis of H9c2 cells by decreasing ROS and intracellular calcium levels and activating Akt phosphorylation. In the in vivo study, we recorded an improved LVEF and a decreased LVM in the group of cardiotoxic rats treated with GB. Altogether, our findings anticipate that GB exerts a cardioprotective effect through possible regulation of the ROS, Akt and calcium pathways. The findings suggest that combination of GB with DOX in chemotherapy could help avoid the cardiotoxic side effects of GB.

Highlights

Doxorubicin (DOX), a potent anthracycline antibiotic, is widely recognized as an effective chemotherapeutic agent used in the therapy of different types of cancer in clinical settings [1,2,3,4,5,6,7,8,9]
The results showed that 5 μM DOX could achieve an appropriate degree of cell death after 48 h (Fig 1A) and the viability of cardiomyocytes was not affected up to 50 μM Ginkgolide B (GB) (Fig 1B)
Thereafter, we employed two models to test the protective effect of GB against DOX cardiotoxicity and found that in the model of cardiomyocytes treatment with DOX for 3 h before GB application, GB treatment did not reverse the toxic effect of DOX on cardiomyocytes (Fig 1C)

Summary

Introduction

Doxorubicin (DOX), a potent anthracycline antibiotic, is widely recognized as an effective chemotherapeutic agent used in the therapy of different types of cancer in clinical settings [1,2,3,4,5,6,7,8,9]. Due to the relevance and the efficacy of DOX in cancer chemotherapy, strategies for preventing or attenuating the side effects of DOX administration, including the alternative drugs with antagonistic properties against DOX induced cardiotoxicity, nanoparticle co-delivery system, and the iron-chelating agents [20,21,22,23,24,25,26,27,28,29] have been attempted. Numerous research works have indicated that extracts of Ginkgo biloba leaves may be beneficial for preventing from the drug-induced toxicity on non-tumour tissues such as the liver, lung, kidney, and heart due to its various pharmacological properties, including anti-inflammatory effect, anti-tumor effect, anti-apoptotic effect, and antioxidant activity [30,31,32,33,34,35]

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