title: Synergic effect between 5‑fluorouracil and celecoxib on hypoxic gastric cancer cells.
abstract: 5‑fluorouracil (5‑FU) is commonly used in the treatment of gastric cancer; however, resistance to this drug occurs under hypoxic conditions. Celecoxib may be used to reverse this resistance. The aim of the present study was to elucidate the inhibitory effects and mechanisms of 5‑FU and celecoxib on the gastric cancer cell line SGC7901 under hypoxic conditions. SGC7901 cells were divided into four groups: Hypoxic control group, 5‑FU group, celecoxib group and 5‑FU/celecoxib combination group. Following treatment, the inhibition rates of cells were determined using an MTT assay. Protein and messenger RNA (mRNA) expression of hypoxia‑inducible factor 2α (HIF‑2α), adenosine triphosphate‑binding cassette sub‑family G member 2 (ABCG2) and octamer binding protein 4 (Oct‑4) were determined using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis. The results demonstrated that the 5‑FU/celecoxib combination group had a significantly higher inhibition rate than the individually treated 5‑FU and celecoxib groups (P<0.05); inhibition rates were 66.09, 52.61 and 46.1%, respectively. mRNA and protein expression levels of HIF‑2α, ABCG2 and Oct‑4 were significantly lower in the celecoxib and 5‑FU/celecoxib combination groups (P<0.01) compared with those of the hypoxia control and 5‑FU groups. The 5‑FU group demonstrated the highest levels of the respective mRNA and proteins. In conclusion, the results of the present study indicated that celecoxib had anti‑tumor effects, as it was shown to inhibit tumor cell growth via the inhibition of HIF‑2α, ABCG2 and Oct‑4. The 5‑FU/celecoxib combination had a synergic effect on tumor growth inhibition. This therefore suggested that inhibition of HIF‑2α, ABCG2 and Oct‑4 may be a potential method of reducing chemotherapy resistance and enhancing the effectiveness of chemotherapy treatment.
authors.affiliation: Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China.
authors.forename: Xiu-E
authors.initials: XE
authors.lastname: Sun
authors.affiliation: Blood Bank, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China.
authors.forename: Wen-Dong
authors.initials: WD
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China.
authors.forename: Yu-Guang
authors.initials: YG
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Shi
authors.affiliation: Department of Parasitology, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
authors.forename: Xiu-Ning
authors.initials: XN
authors.lastname: Sun
authors.affiliation: Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China.
authors.forename: Zhi-Xing
authors.initials: ZX
authors.lastname: Gao
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D000068579:Celecoxib; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D005472:Fluorouracil / Q000633:toxicity*; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000633:toxicity*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D000068579:Celecoxib; D005472:Fluorouracil; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D000099162:Endothelial PAS Domain-Containing Protein 1; C116614:ABCG2 protein, human; C494173:POU5F1 protein, human