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Caspase-Independent Pathway is Related to Nilotinib Cytotoxicity in Cultured Cardiomyocytes.

Caspase-Independent Pathway is Related to Nilotinib Cytotoxicity in Cultured Cardiomyocytes.
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Yang Q, Zhang C, Wei H, Meng Z, Li G, Xu Y, Chen Y,


Yang Q, Zhang C, Wei H, Meng Z, Li G, Xu Y, Chen Y, (click to view)

Yang Q, Zhang C, Wei H, Meng Z, Li G, Xu Y, Chen Y,

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Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2017 08 1542(6) 2182-2193 doi 10.1159/000479993
Abstract
BACKGROUND/AIMS
Cardiotoxicity is a predominant side-effect of nilotinib during chronic myeloid leukemia treatment. The underlying molecular mechanism remains unclear. The role of autophagy and mitochondrial signaling was investigated in nilotinib-treated cardiac H9C2 cells.

METHODS
Cytotoxicity was assessed using Cell Death Detection kit. Immunoblot and immunofluorescence staining was performed, and cathepsin B and caspase3 activity was assessed in nilotinib-treated H9C2 cells with or without distinct pathway inhibitor or specific siRNA.

RESULTS
Nilotinib time- and dose-dependently induced H9C2 apoptosis, which was not completely prevented by the pan caspase inhibitor z-VAD-fmk. Following nilotinib treatment, mitochondrial membrane potential decreased significantly accompanied with remarkable morphological changes. Nuclear translocation of mitochondrial apoptosis inducing factor (AIF) and increased p53 was detected in nilotinib-treated cells. AIF knockdown prevented nilotinib-induced increase of p53 and apoptosis. Additionally, increased cathepsin B activity was detected, and inhibition of cathepsin B by CA-074Me prevented nilotinib-induced apoptosis and nuclear translocation of AIF. Moreover, increased Atg5 and transition of LC3-I to LC3-II was revealed following nilotinib treatment. Increased cathepsin B activity and apoptosis by nilotinib was significantly prohibited by specific autophagy inhibitor bafilomycin A and Atg5 knockdown.

CONCLUSION
Our findings demonstrate that nilotinib increases autophagy and cathepsin B activity, leading to mitochondrial AIF release and nuclear translocation, which is responsible for p53 and apoptosis induction in H9C2 cells.

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