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Experimental Therapeutics

Inhibition of ATM and ATR Kinase Activities by the Radiosensitizing Agent, Caffeine

Jann N. Sarkaria, Ericka C. Busby, Randal S. Tibbetts, Pia Roos, Yoichi Taya, Larry M. Karnitz and Robert T. Abraham
Jann N. Sarkaria
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. N. S., E. C. B., L. M. K., R. S. T., P. R., R. T. A.], and National Cancer Research Institute, Biology Division, Tokyo, Japan 104-0045 [Y. T.]
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Ericka C. Busby
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. N. S., E. C. B., L. M. K., R. S. T., P. R., R. T. A.], and National Cancer Research Institute, Biology Division, Tokyo, Japan 104-0045 [Y. T.]
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Randal S. Tibbetts
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. N. S., E. C. B., L. M. K., R. S. T., P. R., R. T. A.], and National Cancer Research Institute, Biology Division, Tokyo, Japan 104-0045 [Y. T.]
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Pia Roos
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. N. S., E. C. B., L. M. K., R. S. T., P. R., R. T. A.], and National Cancer Research Institute, Biology Division, Tokyo, Japan 104-0045 [Y. T.]
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Yoichi Taya
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. N. S., E. C. B., L. M. K., R. S. T., P. R., R. T. A.], and National Cancer Research Institute, Biology Division, Tokyo, Japan 104-0045 [Y. T.]
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Larry M. Karnitz
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. N. S., E. C. B., L. M. K., R. S. T., P. R., R. T. A.], and National Cancer Research Institute, Biology Division, Tokyo, Japan 104-0045 [Y. T.]
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Robert T. Abraham
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. N. S., E. C. B., L. M. K., R. S. T., P. R., R. T. A.], and National Cancer Research Institute, Biology Division, Tokyo, Japan 104-0045 [Y. T.]
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DOI:  Published September 1999
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Abstract

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 cell 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 G2 fail to arrest progression into mitosis, and S-phase-irradiated cells exhibit radioresistant DNA synthesis. Similar concentrations of caffeine also inhibit γ- and UV radiation-induced phosphorylation of p53 on Ser15, 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 G2 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.

  • Received February 23, 1999.
  • Accepted July 7, 1999.
  • ©1999 American Association for Cancer Research.
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September 1999
Volume 59, Issue 17
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Inhibition of ATM and ATR Kinase Activities by the Radiosensitizing Agent, Caffeine
Jann N. Sarkaria, Ericka C. Busby, Randal S. Tibbetts, Pia Roos, Yoichi Taya, Larry M. Karnitz and Robert T. Abraham
Cancer Res September 1 1999 (59) (17) 4375-4382;

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Inhibition of ATM and ATR Kinase Activities by the Radiosensitizing Agent, Caffeine
Jann N. Sarkaria, Ericka C. Busby, Randal S. Tibbetts, Pia Roos, Yoichi Taya, Larry M. Karnitz and Robert T. Abraham
Cancer Res September 1 1999 (59) (17) 4375-4382;
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