TY - JOUR
T1 - Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice
AU - Lanza-Jacoby, Susan
AU - Dicker, Adam P.
AU - Miller, Sheldon
AU - Rosato, Francis E.
AU - Flynn, John T.
AU - Lavorgna, Stephanie N.
AU - Burd, Randy
PY - 2004/4
Y1 - 2004/4
N2 - 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 μM) of SC236 for 48 h reduced the radiation-induced increase in COX-2 activity and also decreased cell growth. SC236 (20 μM) increased the accumulation of the cells in the radiosensitive G2-M phase of the cell cycle. However, a low concentration (5 μM) of SC236 was adequate to reduce COX-2 activity. The lower concentration of SC236 (5 μM) 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 μM 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 μM SC236 but not in those pretreated with 5 μM 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.
AB - 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 μM) of SC236 for 48 h reduced the radiation-induced increase in COX-2 activity and also decreased cell growth. SC236 (20 μM) increased the accumulation of the cells in the radiosensitive G2-M phase of the cell cycle. However, a low concentration (5 μM) of SC236 was adequate to reduce COX-2 activity. The lower concentration of SC236 (5 μM) 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 μM 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 μM SC236 but not in those pretreated with 5 μM 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.
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U2 - 10.1158/1535-7163.417.3.4
DO - 10.1158/1535-7163.417.3.4
M3 - Article
C2 - 15078985
AN - SCOPUS:4444235839
SN - 1535-7163
VL - 3
SP - 417
EP - 424
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 4
ER -