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-CH(3)-BG), O(6)-[(cyclohexyl)methyl]-9-methyl-guanine (9-CH(3)-CMG), and 7-benzylguanine (N7-BG), exhibited varying degrees of CDK2 inhibition with O(6)-CMG being the most potent and 9-CH(3)-BG, 9-CH(3)-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.
Department of Medicine, Committe on Cancer Biology and Cancer Research Center, University of Chicago, Chicago, IL 60637, USA.
Melissa L
ML
Fishel
David R
DR
Newell
Roger J
RJ
Griffin
Richard
R
Davison
Lan-Zhen
LZ
Wang
Nicola J
NJ
Curtin
Eleanor G
EG
Zuhowski
Kristen
K
Kasza
Merrill J
MJ
Egorin
Robert C
RC
Moschel
M Eileen
ME
Dolan
D000970:Antineoplastic Agents / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004338:Drug Combinations; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C116701:9-methylguanine; C012589:trichostatin A; D006147:Guanine; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D002945:Cisplatin