Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: A possible role for survivin down-regulation

Marzia Pennati, Allyson J. Campbell, Maria Curto, Mara Binda, YuZhu Cheng, Lan Zeng Wang, Nicola Curtin, Bernard T. Golding, Roger J. Griffin, Ian R. Hardcastle, Andrew Henderson, Nadia Zaffaroni, David R. Newell

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1328-1337
Number of pages10
JournalMolecular Cancer Therapeutics
Volume4
Issue number9
DOIs
Publication statusPublished - Sep 2005

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Cyclin-Dependent Kinases
Paclitaxel
Down-Regulation
Apoptosis
Cell Cycle Checkpoints
Caspase 9
Caspase 3
Inhibitor of Apoptosis Proteins
4-(6-cyclohexylmethoxy-9H-purin-2-ylamino)-N,N-diethylbenzamide
G2 Phase
Cell Division
Ovarian Neoplasms
Cell Cycle
Phosphorylation
Cell Proliferation
Carcinoma

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140 : A possible role for survivin down-regulation. / Pennati, Marzia; Campbell, Allyson J.; Curto, Maria; Binda, Mara; Cheng, YuZhu; Wang, Lan Zeng; Curtin, Nicola; Golding, Bernard T.; Griffin, Roger J.; Hardcastle, Ian R.; Henderson, Andrew; Zaffaroni, Nadia; Newell, David R.

In: Molecular Cancer Therapeutics, Vol. 4, No. 9, 09.2005, p. 1328-1337.

Research output: Contribution to journalArticle

Pennati, M, Campbell, AJ, Curto, M, Binda, M, Cheng, Y, Wang, LZ, Curtin, N, Golding, BT, Griffin, RJ, Hardcastle, IR, Henderson, A, Zaffaroni, N & Newell, DR 2005, 'Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: A possible role for survivin down-regulation', Molecular Cancer Therapeutics, vol. 4, no. 9, pp. 1328-1337. https://doi.org/10.1158/1535-7163.MCT-05-0022
Pennati, Marzia ; Campbell, Allyson J. ; Curto, Maria ; Binda, Mara ; Cheng, YuZhu ; Wang, Lan Zeng ; Curtin, Nicola ; Golding, Bernard T. ; Griffin, Roger J. ; Hardcastle, Ian R. ; Henderson, Andrew ; Zaffaroni, Nadia ; Newell, David R. / Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140 : A possible role for survivin down-regulation. In: Molecular Cancer Therapeutics. 2005 ; Vol. 4, No. 9. pp. 1328-1337.
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AU - Curto, Maria

AU - Binda, Mara

AU - Cheng, YuZhu

AU - Wang, Lan Zeng

AU - Curtin, Nicola

AU - Golding, Bernard T.

AU - Griffin, Roger J.

AU - Hardcastle, Ian R.

AU - Henderson, Andrew

AU - Zaffaroni, Nadia

AU - Newell, David R.

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