Radiosensitization of human glioma cells by cyclooxygenase-2 (COX-2) inhibition: Independent on COX-2 expression and dependent on the COX-2 inhibitor and sequence of administration

Purpose: Patients with a malignant glioma have a very poor prognosis. Cyclooxygenase-2 (COX-2) protein is regularly upregulated in gliomas and might be a potential therapeutic target. The effects of three selective COX-2 inhibitors were studied on three human glioma cell lines. Materials and methods: The selective COX-2 inhibitors NS-398, Celecoxib and Meloxicam and three human glioma cell lines (D384, U251 and U87) were used. Cell growth was assessed by a proliferation assay, the interaction with radiation (0- 6 Gy) was studied using the clonogenic assay and cell cycle distribution was determined by FACS (fluorescenceactivated cell sorting) analysis. Results: All COX-2 inhibitors reduced proliferation of the glioma cell lines irrespective of their COX-2 expression level. Incubation with 200 mM NS-398 24 h before radiation enhanced radiation-induced cell death of D384 cells and 750 mM Meloxicam resulted in radiosensitization of D384 and U87 cells. No radiosensitization was observed with COX-2 inhibitor administration after radiotherapy. Treatment of D384 with NS-398 ( 200 mu M) or Celecoxib ( 50 mu M) and U87 with NS-398 (200 mu M) after radiation resulted even in radioprotection. Conclusions: Effectiveness of COX-2 inhibitors on cell proliferation and radio-enhancement was independent of COX-2 protein expression. The sequence of COX-2 inhibitor addition and irradiation is very important.