Effect of cell cycle inhibition on cisplatin-induced cytotoxicity

Melissa Fishel, David R. Newell, Roger J. Griffin, Richard Davison, Lan Zhen Wang, Nicola J. Curtin, Eleanor G. Zuhowski, Kristen Kasza, Merrill J. Egorin, Robert C. Moschel, M. Eileen Dolan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)206-213
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume312
Issue number1
DOIs
StatePublished - Jan 2005
Externally publishedYes

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S 6
Guanine
Cisplatin
Cell Cycle
Thioguanine
trichostatin A
Cyclin-Dependent Kinase 2
Apoptosis
Head and Neck Neoplasms
S Phase
Pharmacology
Cell Line
DNA
9-methylguanine

ASJC Scopus subject areas

  • Pharmacology

Cite this

Fishel, M., Newell, D. R., Griffin, R. J., Davison, R., Wang, L. Z., Curtin, N. J., ... Dolan, M. E. (2005). Effect of cell cycle inhibition on cisplatin-induced cytotoxicity. Journal of Pharmacology and Experimental Therapeutics, 312(1), 206-213. https://doi.org/10.1124/jpet.104.073924

Effect of cell cycle inhibition on cisplatin-induced cytotoxicity. / Fishel, Melissa; Newell, David R.; Griffin, Roger J.; Davison, Richard; Wang, Lan Zhen; Curtin, Nicola J.; Zuhowski, Eleanor G.; Kasza, Kristen; Egorin, Merrill J.; Moschel, Robert C.; Dolan, M. Eileen.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 312, No. 1, 01.2005, p. 206-213.

Research output: Contribution to journalArticle

Fishel, M, Newell, DR, Griffin, RJ, Davison, R, Wang, LZ, Curtin, NJ, Zuhowski, EG, Kasza, K, Egorin, MJ, Moschel, RC & Dolan, ME 2005, 'Effect of cell cycle inhibition on cisplatin-induced cytotoxicity', Journal of Pharmacology and Experimental Therapeutics, vol. 312, no. 1, pp. 206-213. https://doi.org/10.1124/jpet.104.073924
Fishel, Melissa ; Newell, David R. ; Griffin, Roger J. ; Davison, Richard ; Wang, Lan Zhen ; Curtin, Nicola J. ; Zuhowski, Eleanor G. ; Kasza, Kristen ; Egorin, Merrill J. ; Moschel, Robert C. ; Dolan, M. Eileen. / Effect of cell cycle inhibition on cisplatin-induced cytotoxicity. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 312, No. 1. pp. 206-213.
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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.",
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AB - 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.

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