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.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 2005|
ASJC Scopus subject areas
- Molecular Medicine