The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review

Purpose: Microtubules are important cytoskeletal components involved in man y cellular events. Antimicrotubule agents including polymerizing agents (pa clitaxel and docetaxel) and depolymerizing drugs (vincristine, vinorelbine, and estramustine phosphate) are widely used either alone or in combination with other anticancer drugs. These antimicrotubule agents are promoters of apoptosis in cancer cells. In this review, we discuss the role of bcl-2 fa mily genes in the regulation of apoptosis, and summarize effects of microtu bule targeting agents on apoptotic signal transduction pathways. Conclusion : Disruption of microtubule structure by antimicrotubule drugs results in i nduction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kin ases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein ki nases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These prot ein kinases are associated directly or indirectly with phosphorylation of b cl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to ap optosis. New pathways of antitumor agents could be directed at this p53, p2 1 and bcl-2/bax function, and may enhance the effect of existing agents.