Anti-LeY antibody enhances therapeutic efficacy of celecoxib against gastric cancer by downregulation of MAPKs/COX-2 signaling pathway: correlation with clinical study.

Abstract

INTRODUCTION:

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.

MATERIAL AND 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: Faisal Aziz, Xuesong Yang, Xiaoqi Wang, Qiu Yan
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 141 Issue 7 Pg. 1221-35 (Jul 2015) ISSN: 1432-1335 [Electronic] Germany
• PMID: 25527419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Lewis Blood Group Antigens
• Lewis Y antigen
• Pyrazoles
• Sulfonamides
• Cyclooxygenase 2
• PTGS2 protein, human
• Celecoxib

Topics

• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Celecoxib
• Cyclooxygenase 2 (metabolism)
• Down-Regulation (drug effects)
• Drug Synergism
• Helicobacter Infections (metabolism, pathology)
• Helicobacter pylori
• Humans
• Lewis Blood Group Antigens (immunology)
• MAP Kinase Signaling System (drug effects)
• Middle Aged
• Pyrazoles (therapeutic use)
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Stomach Ulcer (metabolism, microbiology, pathology)
• Sulfonamides (therapeutic use)
• Treatment Outcome
• Tumor Cells, Cultured