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

Abstract

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.

Targeting the DNA Damage Response in Cancer

“…319 When combined with radiation or chemotherapy, COX-2 inhibitors have been found to promote DNA damage-induced cell killing of cancer cells. [320][321][322][323][324][325][326][327][328][329] A potential mechanism of sensitization of COX-2 inhibitors to DNA damaging agents may be that loss of COX-2 attenuates DNA repair. 322…”

“…Because of its pro-inflammation activity, many pharmaceutical drugs have been developed to target COX-2 activity. , These inhibitors have been used in cancer treatment due to the frequent overexpression of COX-2 in cancer and to the strong link between inflammation and cancer . When combined with radiation or chemotherapy, COX-2 inhibitors have been found to promote DNA damage-induced cell killing of cancer cells. − A potential mechanism of sensitization of COX-2 inhibitors to DNA damaging agents may be that loss of COX-2 attenuates DNA repair …”

Repurposed Drugs Celecoxib and Fmoc-L-Leucine Alone and in Combination as Temozolomide-Resistant Antiglioma Agents—Comparative Studies on Normal and Immortalized Cell Lines, and on C. elegans

“…Up-regulation of COX-2 after CXB administration has been observed prior to this study [ 52 ]. Higher COX-2 production may be stimulated via a negative feedback loop that was described previously [ 53 , 54 ]. Lombardi et al observed that temozolomide, one of the three chemotherapy agents available for the treatment of glioma, also causes increase of COX-2 level in glioma cells [ 55 ].…”

Contribution of non-steroidal anti-inflammatory drugs to breast cancer treatment: In vitro and in vivo studies

“…The mouse mammary tumor virus/c-Myc model was the first transgenic breast cancer mouse model reported in 1984, in which overexpression of the Myc transcription factor in the mammary gland resulted in spontaneous mammary adenocarcinomas [ 135 ]. However, MTV/ neu and HER2/ neu have been used in the literature to evaluate NSAIDs [ 136 , 137 ]. Celecoxib was again tested.…”

“…Animals were sacrificed when the tumors reached 20 mm in diameter or 15 months old. Celecoxib decreased tumor incidence and multiplicity, prolonged tumor latency, reduced lung metastasis, and PGI2 and PGE2 concentrations in mammary tumors and their adjacent mammary glands [ 137 ].…”