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.
Yang
Li-Xi
LX
Radiobiology Laboratory, California Pacific Medical Center Research Institute, St. Mary's Medical Center, San Francisco, CA 94118, USA. Yang@cooper.cpmc.org
Zhu
Jun
J
Wang
Hui-Juan
HJ
Holton
Robert A
RA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D017239:Paclitaxel