title: Anti-LeY antibody enhances therapeutic efficacy of celecoxib against gastric cancer by downregulation of MAPKs/COX-2 signaling pathway: correlation with clinical study.
abstract: BACKGROUND
  Helicobacter pylori (H. pylori) is a major causative agent for the induction of chronic gastritis, gastric ulcer and gastric cancer. Celecoxib (COX-2 inhibitor) inhibits gastric cancer cell proliferation, but with low treatment efficacy, limiting its applications. It is important to develop a better strategy to improve the efficacy of celecoxib. Lewis Y (LeY) is a difucosylated oligosaccharide, highly expressed in 60-90% of human epithelial cancers, including gastric cancer. We previously found that H. pylori infection was associated with high level of LeY in gastric cancer.
  
  
  METHODS
  Herein, we analyzed the correlation between H. pylori and cyclo-oxygenase-2 (COX-2), LeY, gastric markers (CA724 and GRN) in gastric patient's tissue and serum samples by IHC and ELISA. Furthermore, we treated the primary gastric cancer cells with celecoxib, anti-LeY antibody or the combination, and analyzed their therapeutic efficacy on CA724, GRN and COX-2 expression by Western blot, flow cytometry and ELISA.
  
  
  RESULTS
  We found that gastric cancer had significantly high expression of H. pylori, COX-2, CA724, and GRN compared to gastric ulcers and chronic gastritis (P < 0.0001). H. pylori level showed significant correlation with COX-2 (R--0.552), LeY (R--0.861), CA724 (R--0.714) and GRN (R--0.664) (P < 0.0001). Additionally, the combination therapy led to impressive inhibition of gastric cancer cell proliferation, with decreased expression of COX-2, CA724 and GRN through downregulation of MAPKs/COX-2 pathway (P < 0.01).
  
  
  CONCLUSIONS
  Our findings suggest that anti-LeY antibody enhances the cancer cell proliferation inhibitory effects of celecoxib, which might be a new feasible way for gastric cancer therapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian, 116044, People's Republic of China.
authors.forename: Faisal
authors.initials: F
authors.lastname: Aziz
authors.forename: Xuesong
authors.initials: X
authors.lastname: Yang
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Wang
authors.forename: Qiu
authors.initials: Q
authors.lastname: Yan
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D016481:Helicobacter Infections / Q000378:metabolism / Q000473:pathology; D016480:Helicobacter pylori; D006801:Humans; D007983:Lewis Blood Group Antigens / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008875:Middle Aged; D011720:Pyrazoles / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013276:Stomach Ulcer / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib