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

• Published in: Anticancer research Vol. 23; no. 4; p. 3295
• Main Authors: Yang, Li-Xi, Zhu, Jun, Wang, Hui-Juan, Holton, Robert A
• Format: Journal Article
• Language: English
• Published: Greece 01-07-2003
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Caspase 3; Caspase 7; Caspases - metabolism; Enzyme Activation - drug effects; Humans; Paclitaxel - analogs & derivatives; Paclitaxel - pharmacology; Phosphorylation - drug effects; Poly(ADP-ribose) Polymerases - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Tumor Cells, Cultured
• ISSN: 0250-7005

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.