Clobenpropit Enhances Anti-Tumor Effect of Gemcitabine in Pancreatic Cancer = Clobenpropit Enhances Anti-Tumor Effect of Gemcitabine in Pancreatic Cancer

다국어 초록 (Multilingual Abstract)

Objective: Histamine is associated with carcinogenesis through activation of its four membrane-specific receptors. Here, we evaluated the anti-tumor effect of clobenpropit, which is the specific H3 antagonist and H4 agonist, with gemcitabine combination in pancreatic cancer cell line. Methods: Three kinds of human pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and AsPC-1) were used in this study. Expression of H3 and H4 receptor in pancreatic cancer cell was identified with Western blotting. Effects of clobenpropit on cell proliferation, migration and apoptosis were evaluated. Alteration of epithelial and mesenchymal markers after administration of clobenpropit was analyzed. In vivo study with Panc-1 xenograft mouse model was also performed. Results: H4 receptors were present as two subunits in human pancreatic cancer cells, while there was no expression of H3 receptor. Clobenpropit inhibited cell migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine. Clobenpropit up-regulated E-cadherin, whereas down-regulated vimentin and matrix metalloproteinase 9 in real-time PCR. Also, clobenpropit inhibited tumor growth and enhanced apoptosis in combination with gemcitabine by up-regulation of E-cadherin and down-regulation of Zeb1 in Panc-1 xenograft mouse. Conclusions: Clobenpropit enhanced anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of epithelial-mesenchymal transition process.