Association between mitotic spindle checkpoint impairment and susceptibility to the induction of apoptosis by anti-microtubule agents in human lung cancers.

Anti-microtubule agents such as vinorelbine and paclitaxel, which are extensively used in the treatment of lung cancers, activate mitotic spindle checkpoint. Although defects of the mitotic spindle checkpoint are thought to play a role in the genesis of chromosome instability, we previously reported its frequent impairment in human lung cancer cell lines. In this study, we examined a panel of 13 human cancer cell lines comprising 11 lung and 2 other cancers and found a significant difference in the resistance to apoptosis induced by anti-microtubule agents between mitotic spindle checkpoint-impaired and -proficient cancer cell lines. This finding was in marked contrast to a lack of such correlation with a DNA damaging agent, cis-platin. Interestingly, anti-microtubule agent-induced apoptosis in mitotic spindle checkpoint-proficient cell lines, NCI-H460 and A549, was shown to be markedly reduced by staurosporine treatment in association with the shortened mitotic arrest, whereas various inhibitors of caspases seemed to have very modest effects. Taken together, these findings suggest the potential involvement of mitotic spindle checkpoint in the induction of apoptosis by anti-microtubule agents in human lung cancers, warranting further studies on the underlying mechanisms.