title: Involvement of mitochondrial and Akt signaling pathways in augmented apoptosis induced by a combination of low doses of celecoxib and N-(4-hydroxyphenyl) retinamide in premalignant human bronchial epithelial cells.
abstract: Celecoxib is being evaluated as a chemopreventive agent. However, its mechanism of action is not clear because high doses were used for in vitro studies to obtain antitumor effects. We found that celecoxib inhibited the growth of premalignant and malignant human bronchial epithelial cells with IC(50) values between 8.9 and 32.7 micromol/L, irrespective of cyclooxygenase-2 (COX-2) expression. Normal human bronchial epithelial cells were less sensitive to celecoxib. Because these concentrations were higher than those attainable in vivo (<or=5.6 micromol/L), we surmised that combining celecoxib with the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HPR) might improve its efficacy. Treatment of premalignant lung cell lines with combinations of clinically relevant concentrations of celecoxib (<or=5 micromol/L) and 4HPR (<or=0.25 micromol/L) resulted in greater growth inhibition, apoptosis induction, and suppression of colony formation than did either agent alone. This combination also decreased the levels of Bcl-2, induced the release of mitochondrial cytochrome c, activated caspase-9 and caspase-3, and induced cleavage of poly(ADP-ribose)polymerase at concentrations at which each agent alone showed no or minimal effects. Furthermore, combinations of celecoxib and 4HPR suppressed the phosphorylation levels of serine/threonine kinase Akt and its substrate glycogen synthase kinase-3beta more effectively than the single agents did. Accordingly, overexpression of constitutively active Akt protected bronchial epithelial cells from undergoing apoptosis after incubation with both celecoxib and 4HPR. These findings indicate that activation of the mitochondrial apoptosis pathway and suppression of the Akt survival pathway mediate the augmented apoptosis and suggest that this combination may be useful for lung cancer chemoprevention.
authors.affiliation: Department of Thoracic, Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Schroeder
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.forename: Dafna
authors.initials: D
authors.lastname: Lotan
authors.forename: Jong K
authors.initials: JK
authors.lastname: Woo
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects*; D001982:Bronchial Diseases / Q000473:pathology*; D000068579:Celecoxib; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control; D008928:Mitochondria / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011230:Precancerous Conditions / Q000473:pathology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D017313:Fenretinide; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib