Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice.
Cyclooxygenase (COX)-2-derived prostaglandins (PGs) are thought to contribute to tumor growth and resistance to radiation therapy. COX-2 protein expression is increased in many tumors including those of the breast. COX-2-derived PGs have been shown to protect cells from radiation damage. This study evaluated the role of COX-2-derived PG in radiation treatment by using the NMF11.2 mammary tumor cell line originally obtained from HER-2/neu mice that overexpress HER-2/neu. We determined whether the effects of the COX-2 inhibitor SC236 on cell growth, radiation-induced PGE2 production and COX expression, cell cycle redistribution, and vascular endothelial growth factor (VEGF) were acting through COX-2-dependent mechanisms. The NMF11.2 cells expressed both COX-1 and COX-2 protein and mRNA. The radiation treatment alone led to a dose-dependent increase in the levels of COX-2 mRNA and COX-2 protein, which was associated with an increase in the production of PGE2 and prostacyclin (PGI2). Treating NMF11.2 cells with high concentrations (20 microM) of SC236 for 48 h reduced the radiation-induced increase in COX-2 activity and also decreased cell growth. SC236 (20 microM) increased the accumulation of the cells in the radiosensitive G2-M phase of the cell cycle. However, a low concentration (5 microM) of SC236 was adequate to reduce COX-2 activity. The lower concentration of SC236 (5 microM) also decreased cell growth after a longer incubation period (96 h) and, in combination with a 2 or 5 Gy dose, led to an accumulation of cells in G2-M phase. Restoring PG to control values in cells treated with 5 microM SC236 prevented the growth inhibition and G2-M cell cycle arrest. Radiation treatment of NMF11.2 cells also increased VEGF protein expression and VEGF secretion in a dose-dependent manner, which was blocked in those cells pretreated with 20 microM SC236 but not in those pretreated with 5 microM SC236. These findings indicate that the COX-2 inhibitor SC236 reduced cell growth and arrested cells in the G2-M phase of the cell cycle by mechanisms that are both dependent and independent of PG production while its effects on VEGF appear to be independent of COX-2.
Lanza-Jacoby
Susan
S
Department of Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. Susan.Lanza-Jacoby@jefferson.edu
Dicker
Adam P
AP
Miller
Sheldon
S
Rosato
Francis E
FE
Flynn
John T
JT
Lavorgna
Stephanie N
SN
Burd
Randy
R
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D017077:Culture Media, Conditioned / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D018734:Genes, erbB-2 / Q000235:genetics* / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D008822:Mice, Transgenic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000096926:Benzenesulfonamides
D017077:Culture Media, Conditioned; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007527:Isoenzymes; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C467480:vascular endothelial growth factor A, mouse