Apoptotic cell death induced by baccatin III, a precursor of paclitaxel, may occur without G(2)/M arrest.
OBJECTIVE
Paclitaxel has been demonstrated to possess significant cell-killing activity in a variety of tumor cells by induction of apoptosis, but the mechanism by which paclitaxel leads to cell death and its relationship with mitotic arrest is not entirely clear. In this study, baccatin III, a synthetic precursor of paclitaxel, was used to analyze whether paclitaxel-induced apoptosis can be a separate event from microtubule bundling and G(2)/M arrest.


METHODS
Several different methods including DNA fragmentation, flow cytometric analyses, TdT-mediated dUTP nick end labeling (TUNEL) and time-lapse video microscopy were used to analyze apoptotic cell death induced by baccatin III and its possible correlation with cell cycle distribution.


RESULTS
Our results demonstrated that baccatin III could also cause apoptotic cell death in both BCap37 (a human breast cancer cell line) and KB cells (derived from human epidermoid carcinoma), but had less effect on microtubule bundling and G(2)/M arrest. Furthermore, we demonstrated that most apoptotic events induced by baccatin III were not coupled with G(2)/M arrest. Instead, these apoptotic events occurred predominantly in the cells in other phases of the cell cycle.


CONCLUSIONS
Baccatin III, which contains the core taxane ring, is the fundamental piece of paclitaxel structure. The finding of baccatin III-induced apoptosis independent of cell cycle arrest, on the one hand, implies that the core taxane ring may play a critical role in inducing cell death and, on the other hand, suggests that paclitaxel might induce apoptosis from other phases of the cell cycle by a similar mechanism.
Miller
M C
MC
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA.
Johnson
K R
KR
Willingham
M C
MC
Fan
W
W
D000470:Alkaloids / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000633:toxicity*; D005260:Female; D016195:G2 Phase; D006801:Humans; D007624:KB Cells; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis; D009707:Nucleosomes / Q000187:drug effects / Q000235:genetics; D017239:Paclitaxel / Q000633:toxicity; D000091402:Prohibitins; D043823:Taxoids; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D004273:DNA, Neoplasm; D004365:Drugs, Chinese Herbal; D009707:Nucleosomes; C000717331:PHB2 protein, human; D000091402:Prohibitins; D043823:Taxoids; C073950:baccatin III; D017239:Paclitaxel