RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage

Huiling Zhou,Xiaolong Ma,Jinfu Yang,Xinmin Zhou,Jian Wang,Yifeng Yang,Lijun Liu,Haidan Liu

doi:10.1007/s11010-020-03985-3

Abstract

Vinblastine (VBL) has been considered as a first-line anti-tumor drug for many years. However, vinblastine-caused myocardial damage has been continually reported. The underlying molecular mechanism of the myocardial damage remains unknown. Here, we show that vinblastine induces myocardial damage and necroptosis is involved in the vinblastine-induced myocardial damage both in vitro and in vivo. The results of WST-8 and flow cytometry analysis show that vinblastine causes damage to H9c2 cells, and the results of animal experiments show that vinblastine causes myocardial cell damage. The necrosome components, receptor-interacting protein 1 (RIP1) receptor-interacting protein 3 (RIP3), are significantly increased in vinblastine-treated H9c2 cells, primary neonatal rat ventricular myocytes and rat heart tissues. And the downstream substrate of RIP3, mixed lineage kinase domain like protein (MLKL) was also increased. Pre-treatment with necroptosis inhibitors partially inhibits the necrosome components and MLKL levels and alleviates vinblastine-induced myocardial injury both in vitro and in vivo. This study indicates that necroptosis participated in vinblastine-evoked myocardial cell death partially, which would be a potential target for relieving the chemotherapy-related myocardial damage.

Highlights

Cancer is a leading threat to human health all over the world [1]
Daunorubicin and vinblastine caused a significant cell death of H9c2 at 1 μM (Fig. 1a)
The results indicated that the expressions of necrosome components receptor-interacting protein 1 (RIP1), receptor-interacting protein 3 (RIP3) were increased upon vinblastine treatment, and the substrate of RIP3, mixed lineage kinase domain like protein (MLKL) was increased (Fig. 4a and b)

Summary

Introduction

Cancer is a leading threat to human health all over the world [1]. Owing to the advances in anti-cancer therapies, the number of long-term cancer survivors has significantly increased. It is urgent clinical needs to elucidate the underlying mechanisms of chemotherapeutic agent-caused myocardial damage, optimize treatment strategies, minimize and prevent the risk of anti-cancer therapy-associated cardiovascular toxicities. Emerging experimental and clinical data indicate that many anti-neoplastic drugs have side effects on the heart Traditional chemotherapeutic drugs, such as platinum, doxorubicin, have historically been a major problem that causes cardiotoxicity. The recent immunotherapeutic agents such as checkpoint inhibitors (e.g., ipilimumab, nivolumab and atezolizumab), though exhibiting a highly promising therapeutic effect with durable anti-cancer responses and long-term remission in a broad spectrum of cancers, have been found to cause cardiac dysfunction [5]. The common cardiac toxic effects caused by anti-cancer therapies include left ventricular dysfunction (LVD), heart failure (HF), stoke, myocardial ischemia, myocarditis, cardiomyopathy [3,4,5] and so on. Doxorubicin has been found to cause irreversible cardiotoxicity in 30–40% of

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Results

Conclusion