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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
- Source :
- Biological and Pharmaceutical Bulletin. 35:2170-2179
- Publication Year :
- 2012
- Publisher :
- Pharmaceutical Society of Japan, 2012.
-
Abstract
- 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 G(2)/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.
Details
- ISSN :
- 13475215 and 09186158
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Biological and Pharmaceutical Bulletin
- Accession number :
- edsair.doi...........7c859533844c9fa83ddbefd810a8c370