Induction of hydrogen peroxide production and bax expression by caspase- 3(-like) proteases in tyrosine kinase inhibitor-induced apoptosis in human small cell lung carcinoma cells

In our previous studies (S. Simizu, et al., 1996, Cancer Res. 56, 4978- 4982), we reported that apoptosis of human small cell lung carcinoma (SCLC) cells induced by protein tyrosine kinase inhibitors, such as erbstatin and herbimycin A, was mediated by H₂O₂ via a newly synthesized protein(s). In the present study, we demonstrated that induction of apoptosis by erbstatin resulted in activation of caspase-3(like) proteases, which are interleukin- 1β-converting enzyme family proteases (caspases) and that inhibition of these protease activities reduced the extent of cell death and H₂O₂ generation. We also demonstrated that expression of apoptotic protein Bax was induced by erbstatin. Erbstatin-induced Bax expression was inhibited by the inhibitor of caspase-3(-like) proteases. These results indicate that generation of intracellular H₂O₂ and Bax expression in tyrosine kinase inhibitor-induced apoptosis were modulated by the activation of caspase-3-(- like) proteases in SCLC cells.