The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review.
OBJECTIVE
Microtubules are important cytoskeletal components involved in many cellular events. Antimicrotubule agents including polymerizing agents (paclitaxel 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 family genes in the regulation of apoptosis, and summarize effects of microtubule targeting agents on apoptotic signal transduction pathways.


CONCLUSIONS
Disruption of microtubule structure by antimicrotubule drugs results in induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein kinases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These protein kinases are associated directly or indirectly with phosphorylation of bcl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to apoptosis. New pathways of antitumor agents could be directed at this p53, p21 and bcl-2/bax function, and may enhance the effect of existing agents.
Wang
L G
LG
Don Monti Division of Medical Oncology, Department of Medicine, New York University School of Medicine, North Shore University Hospital, Manhasset, New York 11030, USA.
Liu
X M
XM
Kreis
W
W
Budman
D R
DR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000077143:Docetaxel; D004961:Estramustine / Q000494:pharmacology; D019254:Genes, bcl-2; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D005810:Multigene Family; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D043823:Taxoids; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D014750:Vincristine; D014747:Vinblastine; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D000077235:Vinorelbine