Combined inhibition of extracellular signal-regulated kinases and HSP90 sensitizes human colon carcinoma cells to ionizing radiation.
Indomethacin, a common nonsteroidal anti-inflammatory drug, has been shown to enhance radiation-mediated cell-killing effect through the activation of p38 mitogen-activated protein kinase (MAPK). We found that indomethacin strongly reduced the basal level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in HT-29 human colon carcinoma cells. The inhibition of ERK1/2 by indomethacin was only observed in cells with high basal activities of ERK1/2 such as HT-29 cells, but not in cells with low basal activities, such as HeLa. Cell cycle analysis of HT-29 cells exposed with indomethacin showed a partial G1/S arrest and slow DNA synthesis. However, the treatment with NS398, a specific COX-1/2 inhibitor, failed to show any effect on cell cycle, indicating that the inhibition of COX-1/2 is not responsible for cell cycle arrest. Since U0126, a specific inhibitor for MEK1/2, also induced a partial G1/S arrest, the G1/S arrest induced by indomethacin is, at least in part, caused by the inhibition of ERK1/2. Cell proliferation of HT-29 was inhibited by the treatment of U0126 but not in HeLa cells, and the treatment of HT-29 cells with U0126 enhanced radiation sensitivity possibly due to the accumulation of cells in G1 phase. We found that 17-allylamino-17-demethoxygeldanamycin, a geldanamycin delivative, radiosensitized HT-29 cells at a relatively low dose of irradiation, and indomethacin and U0126 further enhanced this effect. Therefore, tumor cells with elevated ERK1/2 activity can be effectively sensitized to radiation treatment by a combinational inhibition of HSP90 and MAPK activity.
Kobayashi
Shinichiro
S
Department of Radiation Oncology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63108, USA.
Nantz
Regan
R
Kitamura
Tetsuya
T
Higashikubo
Ryuji
R
Horikoshi
Nobuo
N
D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism / Q000532:radiotherapy*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000532:radiotherapy*; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007259:Infrared Rays; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism
D018841:HSP90 Heat-Shock Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007213:Indomethacin