Dual cytotoxic mechanisms of submicromolar taxol on human leukemia HL-60 cells.

Taxol-induced mitotic block and apoptosis were investigated using taxol-sensitive human leukemia HL-60 cells at submicromolar concentrations of the drug. Cells exposed to either 20 nM taxol for 1 hr or 10 nM taxol for 12 hr were able to resume normal growth, whereas cells exposed to 60 nM taxol for 1 hr or 10 nM taxol for 24 hr failed to proliferate after drug removal. Progressive changes in the percentage of mitotic block and apoptosis induced by these four treatment protocols were monitored continuously for 3-5 days after drug removal. Cells treated with 20 nM taxol for 1 hr showed a mitotic block without a subsequent increase in apoptosis, whereas cells treated with 10 nM taxol for 12 hr showed an increase in apoptotic ratio within several hours without an increase in mitotic block. These results indicate that apoptosis does not necessarily result from mitotic block and that these two phenomena can occur independently of each other. Drug sensitivity at progressive stages of the cell cycle was also investigated. The results showed that, in addition to the cells in G2/M phase, the cells in S phase were also sensitive to the drug, especially to a prolonged treatment. These results suggest that, in HL-60 cells, the apoptotic programs can be initiated in either the G2/M or S phase and represent two different cytotoxic mechanisms of taxol.