The mode of action of taxol: apoptosis at low concentration and necrosis at high concentration.
The cytotoxicity of Taxol represents both inhibition of cell proliferation and cell death. The drug blocked cells in the G2/M phase of the cell cycle. It has also been reported that Taxol induced cell apoptosis; however, the mode of action of Taxol is far from clear. In this communication, the cytotoxicity of Taxol in various breast cancer cell lines was carefully examined. We showed that Taxol treatment induced a biphasic decrease of viable cells. While the first phase of decrease occurred over concentrations ranging from 0.005 to 0.05 microM and the second phase of decrease occurred at concentrations ranging from 5 to 50 microM, there was a plateau between these ranges. We determined that the biphasic response was due to two different mechanisms. In the lower concentration range (0.005-0.05 microM), Taxol stabilized the spindle during mitosis, thereby blocking mitosis. This mitotic block led to the inhibition of cell proliferation and the induction of apoptosis. In the higher concentration range (5-50 microM), Taxol mainly increased the polymerization of microtubule and stimulated the formation of microtubule bundles, which blocked entry into S phase. This inhibition of S phase entry led to the inhibition of cell proliferation and the induction of necrosis. These findings may have profound clinical implications.
Yeung
T K
TK
Northeastern Ontario Regional Cancer Centre, Sudbury, Ontario, P3E 5J1, Canada.
Germond
C
C
Chen
X
X
Wang
Z
Z
D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D009336:Necrosis; D017239:Paclitaxel / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects; D014407:Tumor Cells, Cultured
D017239:Paclitaxel