Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice

• Published in: Molecular cancer therapeutics 2004-04, Vol.3 (4), p.417-424
• Main Authors: Lanza-Jacoby, Susan, Dicker, Adam P, Miller, Sheldon, Rosato, Francis E, Flynn, John T, Lavorgna, Stephanie N, Burd, Randy
• Format: Article
• Language: English
• Subjects: Animals; Cell Division - drug effects; Cell Division - radiation effects; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - radiation effects; Culture Media, Conditioned - metabolism; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - pharmacology; Genes, erbB-2 - genetics; Genes, erbB-2 - physiology; Isoenzymes - genetics; Isoenzymes - metabolism; Mammary Neoplasms, Animal - drug therapy; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - pathology; Mammary Neoplasms, Animal - radiotherapy; Mice; Mice, Transgenic; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - metabolism; Pyrazoles - antagonists & inhibitors; Pyrazoles - pharmacology; Radiation, Ionizing; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sulfonamides - antagonists & inhibitors; Sulfonamides - pharmacology; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - secretion
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.417.3.4

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 PGE 2 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 PGE 2 and prostacyclin (PGI 2 ). Treating NMF11.2 cells with high concentrations (20 μ m ) of SC236 for 48 h reduced the radiation-induced increase in COX-2 activity and also decreased cell growth. SC236 (20 μ m ) increased the accumulation of the cells in the radiosensitive G 2 -M phase of the cell cycle. However, a low concentration (5 μ m ) of SC236 was adequate to reduce COX-2 activity. The lower concentration of SC236 (5 μ m ) 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 G 2 -M phase. Restoring PG to control values in cells treated with 5 μ m SC236 prevented the growth inhibition and G 2 -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 μ m SC236 but not in those pretreated with 5 μ m SC236. These findings indicate that the COX-2 inhibitor SC236 reduced cell growth and arrested cells in the G 2 -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.