Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34(cdc2) kinase

Siu Long Yao, Adil J. Akhtar, Karen A. Mckenna, Gauri C. Bedi, David Sidransky, Mack Mabry, Rajani Ravi, Michael I. Collector, Richard J Jones, Saul J. Sharkis, Ephraim J Fuchs, Atul Bedi

Research output: Contribution to journalArticle

Abstract

The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because the p53 tumor suppressor gene is a critical component for induction of apoptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both the G1/S and G2/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA, the arrest at the G1 checkpoint is mediated by p53-dependent induction of p21(WAF1/CIP1), whereas the G2 arrest involves inactivation of p34(cdc2) kinase. Following DNA damage, p53-deficient cells fail to arrest at G1 and accumulate at the G2/M transition. We demonstrate that abrogation of G2 arrest by caffeine-mediated activation of p34(cdc2) kinase results in the selective sensitization of p53-deficient primary and tumor cells to irradiation-induced apoptosis. These data suggest that pharmacologic activation of p34(cdc2) kinase may be a useful therapeutic strategy for circumventing the resistance of p53-deficient cancers to genotoxic anticancer agents.

Original languageEnglish (US)
Pages (from-to)1140-1143
Number of pages4
JournalNature Medicine
Volume2
Issue number10
DOIs
StatePublished - Oct 1996
Externally publishedYes

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Caffeine
Phosphotransferases
Chemical activation
DNA Damage
Tumors
DNA
Cell death
Apoptosis
Antineoplastic Agents
Neoplasms
Cell Death
Cells
Cell Cycle Checkpoints
Tumor Suppressor Genes
Genes
Irradiation
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34(cdc2) kinase. / Yao, Siu Long; Akhtar, Adil J.; Mckenna, Karen A.; Bedi, Gauri C.; Sidransky, David; Mabry, Mack; Ravi, Rajani; Collector, Michael I.; Jones, Richard J; Sharkis, Saul J.; Fuchs, Ephraim J; Bedi, Atul.

In: Nature Medicine, Vol. 2, No. 10, 10.1996, p. 1140-1143.

Research output: Contribution to journalArticle

Yao, Siu Long ; Akhtar, Adil J. ; Mckenna, Karen A. ; Bedi, Gauri C. ; Sidransky, David ; Mabry, Mack ; Ravi, Rajani ; Collector, Michael I. ; Jones, Richard J ; Sharkis, Saul J. ; Fuchs, Ephraim J ; Bedi, Atul. / Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34(cdc2) kinase. In: Nature Medicine. 1996 ; Vol. 2, No. 10. pp. 1140-1143.
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