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Radiosensitivity Enhancement by Celecoxib, a Cyclooxygenase (COX)-2 Selective Inhibitor, via COX-2–Dependent Cell Cycle Regulation on Human Cancer Cells Expressing Differential COX-2 Levels

¹ Cancer Metastasis Research Center, ² Department of Radiation Oncology, Yonsei Cancer Center, Yonsei Institute for Cancer Research, Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University; ³ Laboratory of Immunology, Korea Institute of Radiological and Medical Sciences, Korea Atomic Energy Research Institute, Seoul, Korea and ⁴ Research Institute and Hospital, National Cancer Center, Goyang-si, Gyeonggi, South Korea

Requests for reprints: Hongryull Pyo, Center for Proton Therapy, National Cancer Center, Korea, 809 Madu-1-dong, ILsan-gu, Goyang-si, Gyeonggi-do, South Korea 411-769. Phone: 82-31-920-1723; Fax: 82-31-920-0149; E-mail: quasar93{at}ncc.re.kr.

To characterize the radiation-enhancing effects on human cancer cells and underlying mechanisms of celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, and to ascertain whether its effects are COX-2 dependent. Clonogenic cytotoxicity assays and radiation survival assays after treatment with celecoxib ± radiation were done on four human cancer cell lines that expressed differential COX-2 levels. Stably COX-2 knocked down or overexpressed cell lines were developed, and clonogenic assays, apoptosis assays, or cell cycle change measurements were conducted after treatment with celecoxib ± radiation. Prostaglandin E₂ (PGE₂) was applied to medium after treatment with celecoxib ± radiation to determine whether the radiation-enhancing effect associated with celecoxib results from reduced generation of prostaglandin. Celecoxib's radiation-enhancing effect was observed in COX-2–expressing A549 and NCI-H460 cells but was not observed in the COX-2 nonexpressing MCF-7 and HCT-116 cells. Celecoxib's radiation-enhancing effects in A549 cells were shown to disappear after the administration of COX-2 knocked down. In contrast, the HCT-116 cells were radiosensitized by celecoxib after being transfected with COX-2 expression vector. The addition of PGE₂ after treatment with celecoxib ± radiation had no significant effects on celecoxib's radiation-enhancing effects in A549 and COX-2 transfected HCT-116 cells. Radiation-induced G₂-M arrest was enhanced and sustained in the COX-2–overexpressing cells compared with that seen in COX-2 low-expressing cells. Celecoxib or NS-398 effected no changes or attenuated radiation-induced G₂-M arrest in the COX-2–overexpressing cells but further enhanced the radiation-induced G₂-M arrest in the COX-2 low-expressing cells. Celecoxib's radiation-enhancing effects seem to occur in a COX-2 expression-dependent manner in the cancer cells. This effect does not seem to be the result of reduced PGE₂ generation. Celecoxib may exert an inhibitory effect on enhanced radiation-induced G₂-M arrest in the COX-2–overexpressing cells, which may allow the arrested cells to enter mitosis and die after radiation, but may also further enhance radiation-induced G₂-M arrest in the COX-2 low-expressing cells, by virtue of another mechanism.

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