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Indomethacin-induced Radiosensitization and Inhibition of Ionizing Radiation-induced NF-B Activation in HeLa Cells Occur via a Mechanism Involving p38 MAP Kinase¹

Section of Cancer Biology, Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri [S. M., S. J. W., L. M. R., I. Z., N. H.], and Radiation Oncology Branch, Radiation Oncology Sciences Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892 [C. M. B., D. G.]

Although ionizing radiation (IR) activates multiple cellular factors that vary depending on dose and tissue specificity, the activation of NF-B appears to be a well-conserved response in tumor cells exposed to IR. Recently, it also has been demonstrated that nonsteroidal anti-inflammatory agents inhibit tumor necrosis factor and interleukin-1-induced NF-B activation and act as radiosensitizing agents. These observations reinforce the growing notion that NF-B may be a protective cellular factor responding to the cytotoxicity of IR and other damaging stimuli. As such, we addressed the idea and mechanism that NF-B is a downstream target of the nonsteroidal anti-inflammatory agent indomethacin and is involved in the process of radiosensitization. In this study, we report that indomethacin inhibited IR-induced activation of NF-B and sensitized HeLa cells to IR-induced cytotoxicity at similar concentrations. Pretreatment of HeLa cells with SB 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (MAPK), abrogated the ability of indomethacin to inhibit IR-induced activation of NF-B and diminished the indomethacin radiosensitizing effect. In addition, the transient genetic activation of p38^MAPK inhibited IR induction of NF-B gene expression in the absence of indomethacin. Finally, permanently transfected cell lines genetically unable to activate NF-B, because of expression of a dominant negative I-B gene, demonstrated increased sensitivity to IR-induced cytotoxicity. Taken together, these results suggest that p38 MAPK is a target involved in indomethacin-induced radiosensitization and that NF-B may be one downstream target in this process.

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