Autophagy plays an important role in sunitinib-mediated cell death in H9c2 cardiac muscle cells.
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.
Zhao
Yuqin
Y
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Xue
Tao
T
Yang
Xiaochun
X
Zhu
Hong
H
Ding
Xiaofei
X
Lou
Liming
L
Lu
Wei
W
Yang
Bo
B
He
Qiaojun
Q
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D007211:Indoles / Q000633:toxicity*; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000633:toxicity*; D034622:RNA Interference; D051381:Rats; D000077210:Sunitinib
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D007211:Indoles; D008869:Microtubule-Associated Proteins; D011758:Pyrroles; D000077210:Sunitinib; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat