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

Susan Lanza-Jacoby, Adam P. Dicker, Sheldon Miller, Francis E. Rosato, John T. Flynn, Stephanie N. Lavorgna, Randy M Burd

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)417-424
Number of pages8
JournalMolecular Cancer Therapeutics
Volume3
Issue number4
StatePublished - Apr 2004
Externally publishedYes

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Cyclooxygenase 2
Ionizing Radiation
Breast Neoplasms
Prostaglandins
Radiation
Vascular Endothelial Growth Factor A
G2 Phase
Growth
Cell Division
Cell Cycle
Cyclooxygenase 2 Inhibitors
Epoprostenol
Dinoprostone
4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
Proteins
G2 Phase Cell Cycle Checkpoints
Cyclooxygenase 1
Messenger RNA
Prostaglandin-Endoperoxide Synthases
Tumor Cell Line

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice. / Lanza-Jacoby, Susan; Dicker, Adam P.; Miller, Sheldon; Rosato, Francis E.; Flynn, John T.; Lavorgna, Stephanie N.; Burd, Randy M.

In: Molecular Cancer Therapeutics, Vol. 3, No. 4, 04.2004, p. 417-424.

Research output: Contribution to journalArticle

Lanza-Jacoby, Susan ; Dicker, Adam P. ; Miller, Sheldon ; Rosato, Francis E. ; Flynn, John T. ; Lavorgna, Stephanie N. ; Burd, Randy M. / Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice. In: Molecular Cancer Therapeutics. 2004 ; Vol. 3, No. 4. pp. 417-424.
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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.",
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AU - Dicker, Adam P.

AU - Miller, Sheldon

AU - Rosato, Francis E.

AU - Flynn, John T.

AU - Lavorgna, Stephanie N.

AU - Burd, Randy M

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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.

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