Albert Einstein Cancer Center

Erlotinib induces mitochondrial-mediated apoptosis in human H3255 non-small-cell lung cancer cells

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib inducer of apoptosis in tumor cells. In this study, the effect of erlotinib on apoptotic signal pathways in H3255 cells with the EGFR(L858R) mutation was evaluated. Erlotinib induced apoptosis associated with the activation of caspases in a dose- and time-dependent manner and induced loss of the mitochondrial membrane potential and release of cytochrome c and second mitochondria-derived activator of caspases/direct IAP binding protein. Erlotinib caused BAX translocation to mitochondria, BAX and BAK conformational changes, and oligomerization. Cotreatment with inhibitors of mitochondrial oxidative phosphorylation blocked erlotinib-induced activation of BAX and BAK and cell death and overexpression of BCL-2 caused a significant attenuation of erlotinib-induced cell death, but no effect on BAX and BAK activation. Down-regulation of BAX and BAK gene expression with small interfering RNA led to an effective reduction of erlotinib-induced apoptosis. These observations indicate that activation of BAX and BAK plays a critical role in the initiation of erlotinib-induced apoptotic cascades. 

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