Cyclin-dependent kinases (CDK) play a crucial role in the control of the cell cycle. Aberrations in the control of cell cycle progression occur in the majority of human
malignancies; hence, CDKs are promising targets for anticancer
therapy. Here, we define the cellular effects of the novel CDK inhibitor
NU6140, alone or in association with
paclitaxel, with respect to inhibition of cell proliferation and cell cycle progression and induction of apoptosis in HeLa cervical
carcinoma cells and in comparison with
purvalanol A. Both CDK inhibitors induced a concentration-dependent cell cycle arrest at the G(2)-M phase and an increase in the apoptotic rate, with a concomitant down-regulation of the antiapoptotic
protein survivin, a member of the inhibitors of apoptosis
protein family. Notably, the addition of
NU6140 to
paclitaxel-treated cells resulted in markedly increased cytotoxic effect and apoptotic response in comparison with the
paclitaxel-
purvalanol A combination (86 +/- 11% and 37 +/- 8%, respectively). Similarly, the extent of
caspase-9 and
caspase-3 activation in paclitaxel-NU6140-treated cells was approximately 4-fold higher than after the
paclitaxel-
purvalanol A combination. Moreover, an almost complete abrogation of the expression of the active, Thr(34)-phosphorylated form of
survivin was observed in cells exposed to the paclitaxel-NU6140 combination. A synergistic effect of the paclitaxel-NU6140 combination, as a consequence of
survivin inhibition and increased activation of
caspase-9 and
caspase-3, was also observed in OAW42/e
ovarian cancer line but not in the derived OAW42/Surv subline ectopically expressing
survivin. Results from this study indicate that
NU6140 significantly potentiates the apoptotic effect of
paclitaxel, with inhibition of
survivin expression/phosphorylation as the potential mechanism.