Abstract
Purpose
It has been postulated that COX-2 is related to metastasis, neovascularization and radiosensitivity of cancer cells. In addition, COX-2 over-expression is correlated to low radiosensitivity and high malignancy in neoplastic cells. Especially, high grade gliomas are known to be hypervascular and radioresistant, because of their hypoxic environment. Thus, in this study, a selective COX-2 inhibitor, celecoxib was tested to determine whether it has synergistic effects on the radiosensitivity of malignant glioma cells under hypoxic conditions.
Materials and Methods
Materials are human glioblastoma cell line A172 and mouse glioma cell line GL261. Cells were cultured under hypoxic conditions using gas pack pouches. Celecoxib ( Pfizer, US ) was used as the selective COX-2 inhibiting drug. 137Cs gamma cell was used for gamma irradiation. Various densities of celecoxib were added to the cells, and all were irradiated with 5Gy of gamma rays. After irradiation, antitumor effects were evaluated by proliferation control examination and colony formation assay, and the appearance of COX-2 and endoplasmic reticulum (ER) stress related proteins was evaluated by western blotting.
Results
Although low dose (<10 micro-M) celecoxib suppressed the expression of COX-2, significant growth suppression was not observed. High doses (>30 micro M) of celecoxib itself induced ER stress. A significant growth delay was seen in cells treated with gamma ray + celecoxib as compared to gamma ray alone. These effects were observed not only in normoxic but also in hypoxic conditions. The effect of gamma ray irradiation under the existence of celecoxib did not depend on the state of oxygen of the cell, and the growth of malignant brain tumor cells was significantly suppressed.
Conclusions and discussion
Celecoxib has been reported to upregulate ER stress related protein and induce apoptosis. On the other hand, radiation also induces ER stress. In the present study, we were able to confirm radiosensitizing effects of celecoxib in glioblastoma cells in hypoxic states as well as normoxic states. From these results, we conclude that celecoxib is a promising drug for increasing the radiosensitivity of malignant glioma cells.
