Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2014; 20(26): 8545-8557
Published online Jul 14, 2014. doi: 10.3748/wjg.v20.i26.8545
Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer
Woo Hyun Paik, Ji Kon Ryu, Kyoung-Sin Jeong, Jin Myung Park, Byeong Jun Song, Sang Hyub Lee, Yong-Tae Kim, Yong Bum Yoon
Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea
Ji Kon Ryu, Kyoung-Sin Jeong, Jin Myung Park, Byeong Jun Song, Sang Hyub Lee, Yong-Tae Kim, Yong Bum Yoon, Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110-744, South Korea
Author contributions: Paik WH performed the experiments and wrote the manuscript; Jeong KS performed the majority of the experiments; Ryu JK designed the study and revised the manuscript; Park JM and Song BJ performed the experiments; Lee SH, Kim YT and Yoon YB critically revised the manuscript.
Supported by Korean Society of Internal Medicine Research Fund (2012) and the Seoul National University College of Medicine Research Fund (2011)
Correspondence to: Ji Kon Ryu, MD, PhD, Associate Professor, Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea. jkryu@snu.ac.kr
Telephone: +82-2-20721962 Fax: +82-2-7436701
Received: December 1, 2013
Revised: February 27, 2014
Accepted: April 5, 2014
Published online: July 14, 2014
Processing time: 224 Days and 20.4 Hours
Abstract

AIM: To evaluate the anti-tumor effect of clobenpropit, which is a specific H3 antagonist and H4 agonist, in combination with gemcitabine in a 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 receptors in pancreatic cancer cells 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. An in vivo study with a Panc-1 xenograft mouse model was also performed.

RESULTS: H4 receptors were present as 2 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, but down-regulated vimentin and matrix metalloproteinase 9 in real-time polymerase chain reaction. Also, clobenpropit inhibited tumor growth (gemcitabine 294 ± 46 mg vs combination 154 ± 54 mg, P = 0.02) and enhanced apoptosis in combination with gemcitabine (control 2.5%, gemcitabine 25.8%, clobenpropit 9.7% and combination 40.9%, P = 0.001) by up-regulation of E-cadherin and down-regulation of Zeb1 in Panc-1 xenograft mouse.

CONCLUSION: Clobenpropit enhanced the anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of the epithelial-mesenchymal transition process.

Keywords: Clobenpropit; Epithelial-mesenchymal transition; Histamine; Histamine receptors; Pancreatic neoplasm

Core tip: Histamine is associated with carcinogenesis through activation of its 4 membrane-specific receptors. Clobenpropit, which is an agonist of H4 receptor, inhibited cell migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine. Clobenpropit up-regulated an epithelial marker, but down-regulated mesenchymal markers in real-time polymerase chain reaction. In addition, 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. In conclusion, clobenpropit enhanced anti-tumor effects of gemcitabine in pancreatic cancer cells through inhibition of epithelial-mesenchymal transition process.