title: In vitro and in vivo effects and mechanisms of celecoxib-induced growth inhibition of human hepatocellular carcinoma cells.
abstract: OBJECTIVE
  Cyclooxygenase-2 (COX-2) inhibitors cause growth inhibition of human hepatocellular carcinoma cells but it remains unclear whether this is both COX-2 dependent and independent. The related mechanisms remain to be determined. The present study was aimed to determine the effect of celecoxib on growth of hepatocellular carcinoma cells and xenografts and the related mechanisms.
  
  
  METHODS
  Both low COX-2 expressing PLC/PRF/5 and high COX-2 expressing HuH7 cells, and nude mice bearing hepatocellular carcinoma xenografts were used to study the effect and mechanisms of celecoxib on hepatocellular carcinoma cell growth.
  
  
  RESULTS
  Celecoxib resulted in a comparable growth inhibition of both hepatocellular carcinoma cells that was associated with decreased production of prostaglandin E(2) and increased peroxisome proliferator-activated receptor gamma in both cells. Addition of prostaglandin E(2) only partially counteracted the effect of celecoxib on both cells. Celecoxib resulted in a significant reduction of retinoblastoma phosphorylation and DP1/E2F1 complex in both cells. Celecoxib caused a significant increase of apoptosis and activation of caspase-3 and caspase-9 in both cells. In nude mice inoculated with HuH7 cells, celecoxib resulted in decreased frequency and mean weight of hepatocellular carcinoma xenografts.
  
  
  CONCLUSIONS
  The present study showed that celecoxib causes COX-2-dependent and COX-2-independent growth inhibition of hepatocellular carcinoma cells and xenografts by (a) decreased retinoblastoma phosphorylation and DP1/E2F1 complex; (b) increased activation of caspase-3 and caspase-9; and (c) increased expression of proliferator-activated receptor gamma. The present study significantly extended our knowledge on the effect and mechanisms of celecoxib-induced inhibition of hepatocellular carcinoma cell growth.
authors.affiliation: Division of Gastroenterology and Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, California 92868, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Chang-Hong
authors.initials: CH
authors.lastname: Yu
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016861:Cyclooxygenase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; D015232:Dinoprostone