期刊
MOLECULAR AND CELLULAR BIOCHEMISTRY
卷 476, 期 2, 页码 1233-1243出版社
SPRINGER
DOI: 10.1007/s11010-020-03985-3
关键词
Vinblastine; Necroptosis; Cardiotoxicity; MLKL
类别
资金
- Natural Science Foundation of Hunan Province [2019JJ40420]
- National Natural Science Foundation of China [82073260, 81572280]
Vinblastine, a first-line anti-tumor drug, has been associated with myocardial damage, the underlying molecular mechanism of which remains unknown. This study demonstrates that necroptosis is involved in vinblastine-induced myocardial damage, and targeting necroptosis could potentially alleviate chemotherapy-related myocardial injury.
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.
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