Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine

JN Sarkaria, EC Busby, RS Tibbetts, Pia Roos-Mattjus, Y Taya, LM Karnitz, RT Abraham

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    Caffeine exposure sensitizes tumor cells to ionizing radiation and other genotoxic agents. The radiosensitizing effects of caffeine are associated with the disruption of multiple DNA damage-responsive cen cycle checkpoints. The similarity of these checkpoint defects to those seen in ataxia-telangiectasia (A-T) suggested that caffeine might inhibit one or more components in an A-T mutated (ATM)-dependent checkpoint pathway in DNA-damaged cells, We now show that caffeine inhibits the catalytic activity of both ATM and the related kinase, ATM and Rad3-related (ATR), at drug concentrations similar to those that induce radiosensitization, Moreover, like ATM-deficient cells, caffeine-treated A549 lung carcinoma cells irradiated in G(2) fail to arrest progression into mitosis, and S-phase-irradiated cells exhibit radioresistant DNA synthesis. Similar concentrations of caffeine also inhibit gamma- and UV radiation-induced phosphorylation of p53 on Ser(15), a modification that may be directly mediated by the ATM and ATR kinases, DNA-dependent protein kinase, another ATM-related protein involved in DNA damage repair, was resistant to the inhibitory effects of caffeine, Likewise, the catalytic activity of the G(2) checkpoint kinase, hChk1, was only marginally suppressed by caffeine but was inhibited potently by the structurally distinct radiosensitizer, UCN-01, These data suggest that the radiosensitizing effects of caffeine are related to inhibition of the protein kinase activities of ATM and ATR and that both proteins are relevant targets for the development of novel anticancer agents.
    Original languageUndefined/Unknown
    Pages (from-to)4375–4382
    Number of pages8
    JournalCancer Research
    Issue number17
    Publication statusPublished - 1999
    MoE publication typeA1 Journal article-refereed

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