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Lookup NU author(s): Dr Allyson Campbell, Dr YuZhu Cheng, Lan Wang, Professor Nicola CurtinORCiD, Emeritus Professor Bernard Golding, Professor Roger Griffin, Dr Ian HardcastleORCiD, Andrew Henderson, Professor Herbie Newell
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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 G2-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 ∼4-fold higher than after the paclitaxel-purvalanol A combination. Moreover, an almost complete abrogation of the expression of the active, Thr34-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. Copyright © 2005 American Association for Cancer Research.
Author(s): Pennati M, Campbell AJ, Curto M, Binda M, Cheng Y, Wang L, Curtin NJ, Golding BT, Griffin RJ, Hardcastle IR, Henderson A, Zaffaroni N, Newell DR
Publication type: Article
Publication status: Published
Journal: Molecular Cancer Therapeutics
Year: 2005
Volume: 4
Issue: 9
Pages: 1328-1337
Print publication date: 01/09/2005
ISSN (print): 1535-7163
ISSN (electronic): 1538-8514
URL: http://dx.doi.org/10.1158/1535-7163.MCT-05-0022
DOI: 10.1158/1535-7163.MCT-05-0022
PubMed id: 16170024
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