The Anticancer Effects of Omeprazole and Cimetidine as Inhibitors of the Endothelial Molecule sLex and its Functions in Metastatic Spread
Matossian, Margarite D.
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Tumor metastasis is one of the leading determinants of cancer deaths in the world. Tumor cell adhesion to the endothelium of the blood and lymphatic vessels mediated through the interaction between E-selectin and its main ligand, sialyl Lewis x (sLex) is the first and most critical step of the metastatic dissemination. Sialyl Lewis x is a cell surface antigen expressed by epithelial cell in response to an inflammatory environment. E-selectin is expressed in tumor cells, or other cells involved in inflammatory responses. It has been reported that cimetidine, an anti-histamine type-2 receptor antacid may alter the binding interaction of sLex by inhibiting E-selectin expressed by endothelial cells in some gastrointestinal cancers. Omeprazole is also an antacid, but functions as a proton-pump inhibitor. The objective of this study was to investigate the anticancer effects of cimetidine and omeprazole on the inhibition of the Eselectin/ sLex interaction and tumor metastasis in oral squamous cell carcinomas. MTT growth and inhibition assays were used to examine cell viability in omeprazole-treated cells. qRT-PCR and Multiplex Elisa were employed to determine the effects of the antiacid drugs in oral squamous cancer cell lines UMSCC 14A and UMSCC 14B. This study found that both cimetidine and omeprazole effectively reduced sLex RNA expression in a primary tumor UMSCC 14A cell line, but not in its corresponding recurrent tumor, the UMSCC 14B cell line, isolated from the same patient after undergoing surgical removal of the primary tumor and conventional chemotherapy. These results support the hypothesis that antacid medication may effectively reduce expression of sLex, an antigen that is associated with tumor dissemination and distant metastasis, in an in vitro study of oral squamous cell carcinoma. Protein docking analyses were also performed to observe the amino acids and molecules involved in the physical interactions between the two antacids, omeprazole and cimetidine, and the E-selectin receptor. Parallel studies are currently being conducted to assess the potential benefits of the anti-acid medication in a large cohort of patients afflicted with oral, head and neck carcinomas.