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Effect of cell cycle inhibition on cisplatin-induced cytotoxicity

Lookup NU author(s): Professor Herbie Newell, Professor Roger Griffin, Richard Davison, Lan Wang, Professor Nicola Curtin

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Abstract

Pharmacological inhibitors of cyclin-dependent kinase (CDK)2 are currently in preclinical and clinical development. The purpose of our work was to evaluate a series of guanine derivatives for their ability to inhibit CDK2, affect cell cycle progression, and enhance the cytotoxic and apoptotic effects of cisplatin. A panel of guanine derivatives, including O6-benzylguanine (O 6-BG), S6-benzyl-6-thioguanine (S6-BG), S 6-[(cyclohexyl)methyl]-6-thioguanine (S6-CMG), O 6-[(cyclohexyl)methyl]guanine (O6-CMG), O 6-benzyl-9-methylguanine (9-CH3-BG), O6- [(cyclohexyl)methyl]-9-methylguanine (9-CH3-CMG), and 7-benzylguanine (N7-BG), exhibited varying degrees of CDK2 inhibition with O6-CMG being the most potent and 9-CH3-BG, 9-CH3-CMG, and N7-BG the least potent compounds. Treatment with S6-CMG and O 6-CMG significantly decreased the percentage of cells in S phase. In SQ20b and SCC61 head and neck cancer cell lines, the most potent CDK2 inhibitor, O6-CMG, was also the most effective at enhancing cisplatin-induced cytotoxicity and apoptosis. Cisplatin-induced DNA platination increased in SQ20b cells pretreated with S6-BG, S6-CMG, and O 6-CMG. Treatment with both O6-BG and trichostatin A, an indirect cell cycle inhibitor, demonstrated additive effects on cisplatin-induced cytotoxicity. In summary, we have identified a group of guanine derivatives that were effective modulators of cisplatin-induced cytotoxicity and apoptosis.


Publication metadata

Author(s): Fishel M, Newell D, Griffin R, Davison R, Wang L, Curtin NJ, Zuhowski E, Kasza K, Egorin M, Moschel R, Dolan M

Publication type: Article

Publication status: Published

Journal: Journal of Pharmacology and Experimental Therapeutics

Year: 2005

Volume: 312

Issue: 1

Pages: 206-213

Print publication date: 01/01/2005

ISSN (print): 0022-3565

ISSN (electronic): 1521-0103

URL: http://dx.doi.org/10.1124/jpet.104.073924

DOI: 10.1124/jpet.104.073924

PubMed id: 15304523


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