SS-31 Attenuates Doxorubicin-induced Cardiomyoblast H9C2 Cell Senescence

衰老 细胞 细胞凋亡 阿霉素 细胞生长 活力测定 细胞周期 化学 分子生物学 生物 癌症研究 细胞生物学 医学 内科学 化疗 生物化学
作者
Huiliang Zhang,Jiaojiao Fan,Shuoqiu Deng,Lixin Xie,Jinzi J. Wu,Christoph Mora,Peter S. Rabinovitch,Nancy J. Rusch
出处
期刊:Journal of Pharmacology and Experimental Therapeutics [American Society for Pharmacology & Experimental Therapeutics]
卷期号:: 463-463
标识
DOI:10.1124/jpet.463.926200
摘要

Abstract ID 92620 Poster Board 463 Background: Doxorubicin (DOX), an effective drug for many types of cancer, is associated with substantial cardiotoxicity. A 3-hour treatment of cardiomyoblast H9C2 cells with a low concentration of DOX (100 nM) can induce senescence-associated β-galactosidase (SA β-gal) staining, the gold standard of cell senescence. Here, we comprehensively characterized the phenotype of the DOX-induced senescent cardiomyocytes for the first time. We plan to use this cell model to search for effective treatments for DOX-induced cell senescence. Methods and Results: Using SA β-gal staining and cell growth rate as readouts, we assessed the concentration-dependent effect of DOX on H9C2 cell senescence. The cells were treated with DOX for 3 hours and subsequently cultured for 3 days. We found that a 50 nM concentration of DOX induced ∼ 50% SA β-gal staining and completely inhibited cell growth. The DOX-induced H9C2 cell senescence was further confirmed by several well-accepted senescence markers including cell hypertrophy, increased p16 and p21 expression, increased Senescence Associated Secretory Phenotype (SASP) markers, arrested cell cycle at S phase and G2 phase, and increased ROS production. Interestingly, we found that 50 nM DOX increased mitochondrial respiration. Translationally, we found that mitochondrial-targeted tetrapeptide SS-31 (elamipretide, 1 μM), which is in clinical trials for heart failure and other diseases associated with mitochondrial dysfunction, partially attenuated 50 nM DOX-induced SA β-gal staining from 51.4% to 35.8%. SS-31 also prevented increases of the p16, p21, and SASP markers and mitigated mitochondrial ROS production. SS-31 also reversed the 50 nM DOX-induced elevation of mitochondrial respiration. However, 1 μM SS-31 failed to prevent the cell cycle arrest and cell growth retardation induced by 50 nM DOX. Conclusion: We determined that a 3-hour treatment with 50 nM DOX establishes a H9C2 cell senescence model. Treatment with mitochondrial-targeted SS-31 reverses the 50 nM DOX-induced cell senescence but not the cell cycle arrest. These data suggest that SS-31 is a promising drug to treat DOX-induced cardiomyocyte senescence. Keywords: Doxorubicin; H9C2 cell; Senescence; Mitochondria; SS-31 H.Z. received support from NIH (R35GM151226) and UAMS (Development Enhancement Awards for Proposals).

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