title: Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids.
abstract: OBJECTIVE
  Celecoxib, an inhibitor of cyclooxygenase-2 (COX2), was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs), as well as elucidate the underlying mechanisms.
  
  
  METHODS
  The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway.
  
  
  RESULTS
  MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 μmol/L) plus 5-fluorouracil (8.1 × 10(-3) g/L) or sorafenib (4.4 μmol/L) increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR) and phosphorylated (p)-AKT expression. Gefitinib (5 μmol/L), which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 μmol/L) plus celecoxib (21.8 μmol/L) increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited.
  
  
  CONCLUSIONS
  Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2 MCSs. Our results provided molecular evidence to support celecoxib combination-treatment strategies for patients with human hepatocellular carcinoma. MCSs provided a good model to evaluate the interaction of anticancer drugs.
authors.affiliation: Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China ; Department of Oncology, Yan'an University Affiliated Hospital, Yan'an, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Oncology, Shaanxi Province Cancer Hospital, Xi'an, People's Republic of China.
authors.forename: Ya-Huan
authors.initials: YH
authors.lastname: Guo
authors.affiliation: Department of Urology, Yan'an University Affiliated Hospital, Yan'an, People's Republic of China.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Jiang
authors.affiliation: Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Jie-Qun
authors.initials: JQ
authors.lastname: Ma
authors.affiliation: Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Min-Cong
authors.initials: MC
authors.lastname: Wang
authors.affiliation: Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Ke-Jun
authors.initials: KJ
authors.lastname: Nan
authors.affiliation: Department of Radiotherapy, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Song
keywords: 5-fluorouracil; celecoxib; gefitinib; hepatocellular carcinoma; multicellular spheroids; sorafenib