Paclitaxel-induced apoptosis may occur without a prior G2/M-phase arrest

Paclitaxel, a naturally occurring antineoplastic agent, can cause both mitotic arrest and apoptotic cell death, but the relationship between these two events is not entirely clear. The focus of this study was to determine whether apoptosis induced by paclitaxel may occur independent of mitotic arrest and to examine the underlying molecular mechanisms of paclitaxel-induced apoptosis.

Two paclitaxel-sensitive tumor cell lines, human breast cancer BCap37 and human epidermoid carcinoma KB cells, were pulsed exposed to various concentrations of paclitaxel. Multiple methods were used to analyze the possible correlation between paclitaxel-induced apoptosis and paclitaxel-induced mitotic arrest. A series of assays were also performed in which we utilized parthenolide, a specific inhibitor of NF-kappaB, to analyze the possible role that the NF-kappaB/IkappaB signaling pathway has in mediating paclitaxel-induced apoptosis.

Both tumor cell lines treated with pulsed paclitaxel exposures exhibited a significant number of cells undergoing apoptosis, however many fewer cells were arrested at the G2/M-phase of the cell cycle when compared to the continuous paclitaxel exposures. Short exposures to paclitaxel also induced the phosphorylation and degradation of IkappaB-alpha, which in turn caused the activation of NF-kappaB in both cell lines. Parthenolide was found to inhibit paclitaxel-induced activation of the NF-kappaB/IkappaB signal pathway as well as apoptotic cell death.

These findings suggest that paclitaxel-induced apoptosis might occur independent of a prior G2/M-phase arrest and be mediated or regulated by the NF-kappaB/IkappaB signal pathway.