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标题：Lx2-32c, a Novel Taxane Derivative, Exerts Anti-resistance Activity by Initiating Intrinsic Apoptosis Pathway in Vitro and Inhibits the Growth of Resistant Tumor in Vivo
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作者：Qing Zhou ; Yan Li ; Jing Jin 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2012
卷号：35
期号：12
页码：2170-2179
DOI：10.1248/bpb.b12-00513
出版社：The Pharmaceutical Society of Japan
摘要：Resistance to anticancer drugs is a major obstacle to successful chemotherapy. Thus, the exploration of new drugs and strategies in combating resistance is of great importance. In this study, we investigated the anti-tumor drug resistance (anti-resistance for short) activity of Lx2-32c, a novel taxane, and its possible mechanisms. Lx2-32c was cytotoxic to various drug-resistant tumor cell lines, and significantly suppressed the growth of tumor xenografts in paclitaxel-resistant MX-1 nude mice. It promoted microtubule polymerization and G₂/M phase arrest in MX-1/T cells. Moreover, it induced typical apoptotic characteristics indicated by morphological changes and DNA fragmentation. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c and apoptosis-inducing factor (AIF) release, elevation of the Bax/Bcl-2 ratio, activation of caspase-9,-3 but not caspase-8 and Fas/FasL, and degradation of poly(ADP-ribose) polymerase (PARP). In conclusion, Lx2-32c is an effective microtubule-stabilizing agent in overcoming paclitaxel resistance by inducing apoptosis via the intrinsic apoptotic pathway. It also displayed robust anti-paclitaxel-resistance activity in vivo . Therefore, these findings provide new insight into the strategy to overcome resistance by manipulating dysregulated apoptosis pathway.
关键词：Lx2-32c;anti-resistance activity;taxane;microtubule;apoptosis