Loss of cell cycle control allows selective microtubule-active drug-induced Bcl-2 phosphorylation and cytotoxicity in autonomous cancer cells

Lack of selectivity in the killing of tumor and normal cells is a major obs tacle in cancer therapy. By inhibiting normal but not autonomous cell growt h, we exploited the differences in cell cycle regulation to achieve a selec tive protection of nonautonomous cells against paclitaxel and other microtu bule-active drugs. Tubulin polymerization, a primary effect of paclitaxel, can be dissociated from Eel-a, phosphorylation and cytotoxicity in HL-60 ce lls. Growth arrest prevented paclitaxel-induced Bcl-2 phosphorylation and a poptosis without affecting paclitaxel-induced tubulin polymerization, We ab rogated the effects of paclitaxel on MCF-10A immortalized breast cells, whi le preserving its effects on MCF-7 cancer cells. Unlike MCF-7 cells, MCF-10 A cells were arrested by epidermal growth factor withdrawal, precluding pac litaxel-induced Bcl-2 phosphorylation, Furthermore, the inhibition of the e pidermal growth factor receptor kinase with low doses of AG1478 arrested gr owth of MCF-10A but not MCF-7 cells. Pretreatment with AG1478 did not affec t paclitaxel-induced Bcl-2/Raf-1 phosphorylation in MCF-7 but abrogated suc h phosphorylation in MCF-10A. Exploitation of growth factor dependency may allow the protection of normal cells from microtubule-active drugs.