Enhanced apoptotic effects of novel paclitaxel analogs on NCI/ADR-RES breast cancer cells.

This study aimed to investigate the apoptotic effects of novel paclitaxel analogs on NCI/ADR-RES breast cancer cells. Using the colony formation assay, the cytotoxicity of three novel paclitaxel analogs were evaluated on NCI/ADR-RES cells which overexpress multidrug-resistant gene (MDR1). All three novel paclitaxel analogs exhibited significantly higher cytotoxicity on NCI/ADR-RES cells than paclitaxel. One analog, TL139, was 140 times more effective than paclitaxel. Using TUNEL and DNA fragmentation assay, remarkably increased apoptosis in the paclitaxel analog-treated cells was observed at 48-72 hours, but not in paclitaxel-treated cells. Caspases-3/7 were dramatically activated at 48-72 hours by the novel paclitaxel analogs. The enhanced activity of caspases-3/7 was evidently verified by the measurement of the cleavage of poly(ADP-ribose) polymerase (PARP). The increased activity of caspases-3/7 significantly correlated with the enhanced apoptosis and cell survival data. Treatment with paclitaxel analogs resulted in a significant amount of mitotic arrest. Using Western blot, the phosphorylation of Bcl-2 protein was found in palictaxel analog-treated cells in a time-dependent manner similar to that of mitotic arrest, thereby indicating that there existed a close correlation between Bcl-2 phosphorylation and mitotic arrest that preceded apoptosis. We conclude that novel taxane analogs could effectively kill MDR1-positive breast cancer cells via the mode of apoptosis.