Celecoxib increases retinoid sensitivity in human colon cancer cell lines.
Retinoid resistance has limited the clinical application of retinoids as differentiation-inducing and apoptosis-inducing drugs. This study was designed to investigate whether celecoxib, a selective COX-2 inhibitor, has effects on retinoid sensitivity in human colon cancer cell lines, and to determine the possible mechanism of said effects. Cell viability was measured using the MTT assay. Apoptosis was detected via Annexin-V/PI staining and the flow cytometry assay. PGE(2) production was measured with the ELISA assay. The expression of RARbeta was assayed via western blotting. The results showed that celecoxib enhanced the inhibitory effect of ATRA in both COX-2 high-expressing HT-29 and COX-2 low-expressing SW480 cell lines. Further study showed the ATRA and celecoxib combination induced greater apoptosis, but that the addition of PGE(2) did not affect the enhanced growth-inhibitory and apoptosis-inducing effects of the combination. Moreover, NS398 (another selective COX-2 inhibitor) did not affect the inhibitory effects of ATRA in the two cell lines. Western blotting showed that the expression of RARbeta in HT-29 cell lines was increased by celecoxib, but not by NS398, and that the addition of PGE(2) did not affect the celecoxib-induced expression of the retinoic acid receptor beta. In conclusion, celecoxib increased the expression of RARbeta and the level of cellular ATRA sensitivity through COX-2-independent mechanisms. This finding may provide a potential strategy for combination therapy.
Liu
Jian-Pei
JP
Department of Gastrointestinopancreatic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P R China.
Wei
Hong-Bo
HB
Zheng
Zong-Heng
ZH
Guo
Wei-Ping
WP
Fang
Jia-Feng
JF
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D000068579:Celecoxib; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D009578:Nitrobenzenes / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*; D014212:Tretinoin / Q000627:therapeutic use*
D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D011720:Pyrazoles; D018168:Receptors, Retinoic Acid; D013449:Sulfonamides; C082925:retinoic acid receptor beta; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D014212:Tretinoin; D000068579:Celecoxib; D015232:Dinoprostone