Wang L G, Liu X M, Kreis W, Budman D R
Don Monti Division of Medical Oncology, Department of Medicine, New York University School of Medicine, North Shore University Hospital, Manhasset, New York 11030, USA.
Cancer Chemother Pharmacol. 1999;44(5):355-61. doi: 10.1007/s002800050989.
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.
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.
微管是参与许多细胞活动的重要细胞骨架成分。抗微管药物包括聚合剂（紫杉醇和多西他赛）和解聚药物（长春新碱、长春瑞滨和磷酸雌莫司汀），它们单独或与其他抗癌药物联合广泛使用。这些抗微管药物是癌细胞凋亡的促进剂。在本综述中，我们讨论了bcl-2家族基因在细胞凋亡调控中的作用，并总结了微管靶向药物对凋亡信号转导通路的影响。
抗微管药物破坏微管结构会导致肿瘤抑制基因p53和细胞周期蛋白依赖性激酶抑制剂p21WAF1/CIP1（p21）的诱导，以及包括Ras/Raf、PKC/PKA I/II、丝裂原活化蛋白激酶和p34cdc2在内的几种蛋白激酶的激活/失活。这些蛋白激酶直接或间接与bcl-2的磷酸化相关。bcl-2的磷酸化以及p53和p21的升高导致细胞凋亡。抗肿瘤药物的新途径可针对这种p53、p21和bcl-2/bax功能，可能会增强现有药物的效果。
