4-oxo-6-((pyrimidin-2-ylthio)methyl)-4h-pyran-3-yl-4-nitrobenzoate and Bile-Duct-Neoplasms

Cholangiocarcinoma (CCA) is a malignancy of the biliary epithelium that is associated with low five-year survival. The apelin receptor (APLNR), which is activated by the apelin peptide, has not been studied in CCA. The purpose of this study is to determine if inhibition of the apelin/APLNR axis can inhibit CCA growth.. Immunohistochemistry, rtPCR, immunofluorescence, flow cytometry, and ELISA was used to measure APLNR expression in human CCA cells and tissues. Mz-ChA-1 cells were treated with increasing concentrations of apelin and ML221, an APLNR antagonist. Expression of proliferative and angiogenic genes were measured via rtPCR. In vivo, Mz-ChA-1 cells were injected into the flanks of nu/nu mice, which were treated with ML221 (150 μg/kg) via tail vein injection.. Expression of the apelin/APLNR axis was increased in CCA. In vitro, CCA proliferation and angiogenesis was inhibited by ML221 treatment. ML221 treatment significantly decreased tumor growth in nu/nu mice.. The apelin/APLNR axis regulates CCA proliferation and angiogenesis. Inhibition of the apelin/APLNR axis decreases tumor growth in our xenograft model. Targeting APLNR signaling has the potential to serve as a novel, tumor directed therapy for CCA.

Topics: Adult; Aged, 80 and over; Angiogenesis Inhibitors; Animals; Apelin; Apelin Receptors; Bile Duct Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neovascularization, Pathologic; Nitrobenzoates; Pyrans; Receptors, G-Protein-Coupled; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays