title: Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Clobenpropit enhanced the anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of the epithelial-mesenchymal transition process.
authors.affiliation: Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea.
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Paik
authors.affiliation: Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea.
authors.forename: Ji Kon
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea.
authors.forename: Kyoung-Sin
authors.initials: KS
authors.lastname: Jeong
authors.affiliation: Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea.
authors.forename: Jin Myung
authors.initials: JM
authors.lastname: Park
authors.affiliation: Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea.
authors.forename: Byeong Jun
authors.initials: BJ
authors.lastname: Song
authors.affiliation: Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea.
authors.forename: Sang Hyub
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea.
authors.forename: Yong-Tae
authors.initials: YT
authors.lastname: Kim
authors.affiliation: Woo Hyun Paik, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Koyang 411-706, South Korea.
authors.forename: Yong Bum
authors.initials: YB
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D017442:Histamine Agonists / Q000008:administration & dosage; D054828:Histamine H3 Antagonists / Q000008:administration & dosage; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C418607:HRH4 protein, human; D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D007093:Imidazoles; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D003841:Deoxycytidine; D013890:Thiourea; C086108:clobenpropit; D000093542:Gemcitabine
keywords: Clobenpropit; Epithelial-mesenchymal transition; Histamine; Histamine receptors; Pancreatic neoplasm