Effect of cell cycle inhibition on cisplatin-induced cytotoxicity

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 O-6-benzylguanine (O-6-BG), S-6-benzyl-6-thioguanine (S-6-BG), S-6-[(cyclohexyl)methyl]-6-thioguanine (S-6-CMG), O-6-[(cyclohexyl) methyl] guanine (O-6-CMG), O-6-benzyl-9-methylguanine (9-CH3-BG), O-6-[(cyclohexyl)methyl]-9-methylguanine (9-CH3-CMG), and 7-benzylguanine (N7-BG), exhibited varying degrees of CDK2 inhibition with O-6-CMG being the most potent and 9-CH3-BG, 9-CH3-CMG, and N7-BG the least potent compounds. Treatment with S-6-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, O-6-CMG, was also the most effective at enhancing cisplatin-induced cytotoxicity and apoptosis. Cisplatin-induced DNA platination increased in SQ20b cells pretreated with S-6-BG, S-6-CMG, and O-6-CMG. Treatment with both O-6-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.