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Induction of apoptosis by taxol (paclitaxel) was investigated on
human leukemic HL-60 and U937 cells. In HL-60 cells, treatment
with 20-nM taxol for 1 hr showed a mitotic block without a
subsequent increase in apoptosis, and cells treated with 10 nM
taxol for 12 hr showed an increase in apoptotic ratio within
several hours without an increase in mitotic block. It shows
that apoptosis does not necessarily result from mitotic block
and these two phenomena can occur independently of each other.
Studies from the synchronized cells indicated that the cells in
S phase are also sensitive to the taxol, suggesting that the
apoptotic programs can be initiated either in G2/M or S phases
and which represent two different cytotoxic mechanisms of taxol.
In U937 taxol-induced apoptosis initiated in G1 and S phases,
but not for G2/M stage. Taxol accelerates the cell cycle
progression of treated cells, which facilitate the onset of
apoptosis in G2/M phase. This acceleration may result from
transient activation of p42/44 MAPK, because inhibition of
upstream MEK1/2 by PD98059 reversed this effect. In contrast,
inhibitors of CaMKII are capable of protecting U937 cells from
taxol-induced apoptosis, especial in G2/M stage. At the dosage
that abolishes 80% of the apoptosis induced by taxol, KN-62
effectively inhibits both the Bcl-2 phosphorylation and ICE
activation in cells at S phase; while only ICE activation can be
suppressed for cells at G2/M stage. It is also found that ICE
is spontaneously activated in G2/M stage but deactivated rapidly
after cells exit the M phase. This phenomenon provides a
rational explanation for the M phase-specific cytotoxicity of
paclitaxel.
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