cytochrome-c-t and taxane

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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; bcl-2-Associated X Protein; Bridged-Ring Compounds; Caspase 3; Caspase 9; Cell Cycle Checkpoints; Cell Line, Tumor; Cytochromes c; DNA Fragmentation; Drug Resistance, Neoplasm; Fas Ligand Protein; fas Receptor; Female; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; Microtubules; Mitochondria; Neoplasms; Paclitaxel; Poly(ADP-ribose) Polymerases; Polymerization; Proto-Oncogene Proteins c-bcl-2; Taxoids; Xenograft Model Antitumor Assays