Enhanced growth inhibition and apoptosis induction in NSCLC cell lines by combination of celecoxib and 4HPR at clinically relevant concentrations.
Celecoxib exhibits cancer preventive and therapeutic effects in animal models and clinical trials. It presumably acts through selective inhibition of cyclooxygenase-2 (COX-2) and subsequent reduction of prostaglandin (PG) synthesis. However, the concentrations of celecoxib required for growth inhibition and apoptosis induction in vitro are higher than those needed for suppression of PGs. Moreover, those concentrations are not achievable in humans raising a controversy regarding the clinical relevance of in vitro data. We investigated the activity of celecoxib alone and in combination with the pro-apoptotic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) on growth and apoptosis of human nonsmall cell lung cancer (NSCLC) cell lines. Celecoxib inhibited growth of thirteen NSCLC cell lines with IC50 values ranging from 19 to 33 microM regardless of their COX-2 expression. Apoptosis was induced in cells with high (A549) as well as low (H1792) COX-2 levels but only at a concentration of 75 microM celecoxib. However, treatment with pharmacologically feasible concentrations of celecoxib (< or = 10 microM) in combination with 4HPR (< or = 2 microM) resulted in a marked suppression of NSCLC cell growth and colony formation. Apoptosis mediated by activation of caspase-3, cleavage of PARP and lamin A was suppressed by addition of antioxidants, suggesting that the generation of reactive oxygen species was partially involved. This study indicates, that celecoxib combined with 4HPR is more effective than treatment with either agent alone in inhibition of growth and induction of apoptosis in NSCLC cells. It suggests further investigations of this combination for lung cancer treatment.
Sun
Shi-Yong
SY
Department of Thoracic, Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Schroeder
Claudia P
CP
Yue
Ping
P
Lotan
Dafna
D
Hong
Waun K
WK
Lotan
Reuben
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D017313:Fenretinide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000068579:Celecoxib