RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage
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RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastineinduced myocardial damage Huiling Zhou1,2 · Lijun Liu1,2 · Xiaolong Ma1 · Jian Wang1,2 · Jinfu Yang1,2 · Xinmin Zhou1 · Yifeng Yang1 · Haidan Liu1,2 Received: 7 May 2020 / Accepted: 16 November 2020 © The Author(s) 2020
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. Keywords Vinblastine · Necroptosis · Cardiotoxicity · MLKL
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. Meanwhile, the chemotherapy-induced cardiac complications including cardiotoxicity in patients receiving anti-cancer drug treatment also appear [2], which severely affect the life quality of patients. It is urgent clinical needs to elucidate the underlying mechanisms of chemotherapeutic agent-caused myocardial damage, optimize treatment strategies, minimize and finally prevent the risk of anti-cancer therapy-associated cardiovascular toxicities. * Haidan Liu [email protected] 1
Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
2
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. Molecular targeted therapy agents, including tyrosine kinase inhibitors (TKIs) lapatinib, sorafenib, imatinib and humanized monoclonal antibodies trastuzumab, bevacizumab, are known to cause cardiovascular t
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