NSAIDs diclofenac, indomethacin, and meloxicam highly upregulate expression of ICAM-1 and COX-2 induced by X-irradiation in human endothelial cells.
BACKGROUND
It is well known that radiation exposure to the heart and the use of non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of myocardial infarction (MI). Some NSAIDs are also known to act synergistically with ionizing radiation and have radio-sensitizing effects in radiotherapy. These evidences suggest that NSAIDs may affect the risk of MI after radiation exposure to the heart. In the present study, we investigated effects of NSAIDs on radiation-induced expression of cell adhesion molecules and COX-2, which are associated with inflammation and an increased risk of MI, in human endothelial cells.


METHODS
Effects of NSAIDs on radiation-induced expression of ICAM-1, VCAM-1, E-selectin, and COX-2 were investigated in human umbilical vein endothelial cells (HUVECs). As NSAIDs, diclofenac, etodolac, indomethacin, ketoprofen, meloxicam, and rofecoxib were used.


RESULTS
Irradiation with 10 Gy increased expression of ICAM-1 and COX-2, but it did not affect expression of VCAM-1 or E-selectin. All the NSAIDs upregulated radiation-induced expression of ICAM-1 and COX-2. The extent of upregulation varied depending on the types of NSAIDs. Indomethacin, diclofenac, and meloxicam highly upregulated radiation-induced expression of ICAM-1 and COX-2. The extent of upregulation was not related to the degree of COX-2 selectivity. An NF-κB inhibitor BAY 11-7082 suppressed radiation-induced expression of ICAM-1, but it did not suppress upregulated expression of ICAM-1 or COX-2 by combination treatment with X-irradiation and meloxicam, suggesting the existence of NF-κB-independent pathways for ICAM-1 and COX-2 induction.


CONCLUSIONS
Indomethacin, diclofenac, and meloxicam highly upregulated radiation-induced expression of ICAM-1 and COX-2 in HUVECs, which suggests that use of these NSAIDs may increase the effects of ionizing radiation and affect the risk of MI after radiation exposure to the heart.
Department of Radiation Biology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan.
Yoshihiko
Y
Uehara
Department of Radiation Biology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan.
Yasuhiko
Y
Murata
Department of Radiation Biology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan.
Soichiro
S
Shiga
Department of Radiation Biology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan. Electronic address: hosoi@med.tohoku.ac.jp.
Yoshio
Y
Hosoi
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D000075202:Contraindications; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004008:Diclofenac / Q000009:adverse effects / Q000494:pharmacology; D019040:E-Selectin / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000528:radiation effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D000077239:Meloxicam; D009203:Myocardial Infarction / Q000209:etiology; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D012307:Risk Factors; D013450:Sulfones / Q000494:pharmacology; D013843:Thiazines / Q000009:adverse effects / Q000494:pharmacology; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019040:E-Selectin; C573420:ICAM1 protein, human; D016328:NF-kappa B; D009570:Nitriles; C546936:SELE protein, human; D013450:Sulfones; D013843:Thiazines; D013844:Thiazoles; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D004008:Diclofenac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000077239:Meloxicam; D007213:Indomethacin
COX inhibitor; COX-2; Endothelial cells; ICAM-1; NSAIDs; Radiation