Mitochondrial pathway-mediated apoptosis is associated with erlotinib-induced cytotoxicity in hepatic cells.

For advanced non-small-cell lung cancer (NSCLC) with mutations to the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors, including erlotinib are indicated for the first-line treatment. Liver injury is one of the multiple adverse effects of erlotinib and may affect its safety. The present study investigated the mechanism of erlotinib-induced hepatotoxicity and provided experimental evidence for the screening of potential hepatoprotectors. Erlotinib induced dose-dependent cytotoxicity in human L-02 hepatic cells 72 h after treatment. In other experiments, L-02 cells were treated with erlotinib for 48 h and thereafter exhibited typical features of apoptosis. Erlotinib caused alterations to nuclear morphology, including chromatin condensation and karyopyknosis; it also increased the fraction of late apoptotic cells and regulated apoptotic protein levels, activating caspase-3 and cleaving of poly-ADP-ribose polymerase. Furthermore, 48 h exposure to erlotinib disturbed mitochondrial function by decreasing the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-associated X proteins and reducing mitochondrial membrane potential. The results of this study indicate that erlotinib-induced hepatotoxicity may occur through mitochondrial-pathway-mediated apoptosis.