Autophagy plays an important role in Sunitinib-mediated cell death in H9c2 cardiac muscle cells

Journal Article · Fri Oct 01 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.07.007· OSTI ID:21460215

Yuqin, Zhao; Tao, Xue; Xiaochun, Yang; Hong, Zhu; Xiaofei, Ding; Liming, Lou ^[1]; Wei, Lu ^[2]

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1. Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058 (China)
2. Department of Chemistry and Institute of Medicinal Chemistry, East China Normal University, Shanghai, 200062 (China)

Sunitinib, which is a multitargeted tyrosine-kinase inhibitor, exhibits antiangiogenic and antitumor activity, and extends survival of patients with metastatic renal-cell carcinoma (mRCC) and gastrointestinal stromal tumors (GIST). This molecule has also been reported to be associated with cardiotoxicity at a high frequency, but the mechanism is still unknown. In the present study, we observed that Sunitinib showed high anti-proliferative effect on H9c2 cardiac muscle cells measured by PI staining and the MTT assay. But apoptotic markers (PARP cleavage, caspase 3 cleavage and chromatin condensation) were uniformly negative in H9c2 cells after Sunitinib treatment for 48 h, indicating that another cell death pathway may be involved in Sunitinib-induced cardiotoxicity. Here we found Sunitinib dramatically increased autophagic flux in H9c2 cells. Acidic vesicle fluorescence and high expression of LC3-II in H9c2 cells identified autophagy as a Sunitinib-induced process that might be associated with cytotoxicity. Furthermore, knocking down Beclin 1 by RNA-interference to block autophagy in H9c2 cells revealed that the death rate was decreased when treated with Sunitinib in comparison to control cells. These results confirmed that autophagy plays an important role in Sunitinib-mediated H9c2 cells cytotoxicity. Taken together, the data presented here strongly suggest that autophagy is associated with Sunitinib-induced cardiotoxicity, and that inhibition of autophagy constitutes a viable strategy for reducing Sunitinib-induced cardiomyocyte death thereby alleviating Sunitinib cardiotoxicity.

• OSTI ID: 21460215
• Journal Information: Toxicology and Applied Pharmacology, Vol. 248, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.07.007; PII: S0041-008X(10)00233-4; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTINEOPLASTIC DRUGS
APOPTOSIS
CARCINOMAS
HEART
MUSCLES
PHOSPHOTRANSFERASES
TOXICITY
TYROSINE
AMINO ACIDS
BODY
CARBOXYLIC ACIDS
CARDIOVASCULAR SYSTEM
DISEASES
DRUGS
ENZYMES
HYDROXY ACIDS
NEOPLASMS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PHOSPHORUS-GROUP TRANSFERASES
PROTEINS
TRANSFERASES