Celecoxib enhances radiosensitivity in medulloblastoma-derived CD133-positive cells.
OBJECTIVE
Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins, is overexpressed in a variety of tumors, including medulloblastoma (MB). CD133, a transmembrane glycoprotein, has been suggested as a marker for cancer stem cells in brain tumors. The aim of the present study was to investigate the role of celecoxib, a selective COX-2 inhibitor, in enhancing the effects of ionizing radiotherapy (IR) on medulloblastoma-derived CD133-positive cells (MB-CD133(+)).


METHODS
MB-CD133(+) were isolated from two medulloblastoma cell lines (Daoy and UW228). Then, they were treated with celecoxib in different concentrations, and cell viability was assessed. The assays of cell survival, soft agar, radiosensitivity, colony formation, and apoptotic activity in MB-CD133(+) treated with celecoxib alone, radiation alone, or celecoxib combined with radiation were further evaluated.


RESULTS
MB-CD133(+) showed the self-renew ability to form sphere bodies in vitro and regenerate tumors in vivo. The levels of COX-2 mRNA and protein in MB-CD133(+) were significantly higher than those in MB-CD133(-). The treatment of 30 μM celecoxib could effectively inhibit the abilities of cell proliferation and colony formation and increase IR-induced apoptosis in treated MB-CD133(+). Furthermore, in vivo study demonstrated that celecoxib significantly enhanced radiosensitivity in MB-CD133(+)-transplanted grafts. Notably, xenotransplantation analysis demonstrated that the treatment of celecoxib could further suppress the expressions of angiogenic and stemness-related genes in treated MB-CD133(+) grafts of SCID mice.


CONCLUSIONS
Celecoxib presents the potential of radiosensitizing effect in MB-derived cancer stem cells. Therefore, it should be warranted in future trials to enhance the radiotherapeutic effects in MB patients.
Chen
Kuan-Hsuan
KH
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Hsu
Chuan-Chih
CC
Song
Wen-Shin
WS
Huang
Chi-Shuan
CS
Tsai
Chia-Chen
CC
Kuo
Cheng-Deng
CD
Hsu
Han-Shui
HS
Tsai
Tung-Hu
TH
Tsai
Ching-Yao
CY
Woung
Lin-Chung
LC
Chiou
Shih-Hwa
SH
Lu
Kai-Hsi
KH
Chen
Yi-Wei
YW
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000473:pathology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000032:analysis*; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000528:radiation effects*; D010455:Peptides / Q000032:analysis*; D011720:Pyrazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D000071916:AC133 Antigen; D015703:Antigens, CD; D052246:Cyclooxygenase 2 Inhibitors; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011720:Pyrazoles; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; D000068579:Celecoxib