title: Indomethacin-induced radiosensitization and inhibition of ionizing radiation-induced NF-kappaB activation in HeLa cells occur via a mechanism involving p38 MAP kinase.
abstract: Although ionizing radiation (IR) activates multiple cellular factors that vary depending on dose and tissue specificity, the activation of NF-kappaB 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-kappaB activation and act as radiosensitizing agents. These observations reinforce the growing notion that NF-kappaB 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-kappaB 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-kappaB 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-kappaB and diminished the indomethacin radiosensitizing effect. In addition, the transient genetic activation of p38(MAPK) inhibited IR induction of NF-kappaB gene expression in the absence of indomethacin. Finally, permanently transfected cell lines genetically unable to activate NF-kappaB, because of expression of a dominant negative I-kappaBalpha 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-kappaB may be one downstream target in this process.
authors.affiliation: Radiation Oncology Branch, Radiation Oncology Sciences Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Bradbury
authors.forename: S
authors.initials: S
authors.lastname: Markovina
authors.forename: S J
authors.initials: SJ
authors.lastname: Wei
authors.forename: L M
authors.initials: LM
authors.lastname: Rene
authors.forename: I
authors.initials: I
authors.lastname: Zoberi
authors.forename: N
authors.initials: N
authors.lastname: Horikoshi
authors.forename: D
authors.initials: D
authors.lastname: Gius
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000528:radiation effects; D004247:DNA / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D012980:Sodium Salicylate / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D013467:Sulindac; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D012980:Sodium Salicylate; D007213:Indomethacin