title: Antiproliferative effects of carbon monoxide on pancreatic cancer.
abstract: BACKGROUND
  Carbon monoxide, the gaseous product of heme oxygenase, is a signalling molecule with a broad spectrum of biological activities. The aim of this study was to investigate the effects of carbon monoxide on proliferation of human pancreatic cancer.
  
  
  METHODS
  In vitro studies were performed on human pancreatic cancer cells (CAPAN-2, BxPc3, and PaTu-8902) treated with a carbon monoxide-releasing molecule or its inactive counterpart, or exposed to carbon monoxide gas (500 ppm/24h). For in vivo studies, pancreatic cancer cells (CAPAN-2/PaTu-8902) were xenotransplanted subcutaneously into athymic mice, subsequently treated with carbon monoxide-releasing molecule (35 mg/kg b.w. i.p./day), or exposed to safe doses of carbon monoxide (500 ppm 1h/day; n = 6 in each group).
  
  
  RESULTS
  Both carbon monoxide-releasing molecule and carbon monoxide exposure significantly inhibited proliferation of human pancreatic cancer cells (p<0.05). A substantial decrease in Akt phosphorylation was observed in carbon monoxide-releasing molecule compared with inactive carbon monoxide-releasing molecule treated cancer cells (by 30-50%, p<0.05). Simultaneously, carbon monoxide-releasing molecule and carbon monoxide exposure inhibited tumour proliferation and microvascular density of xenotransplanted tumours (p<0.01), and doubled the survival rates (p<0.005). Exposure of mice to carbon monoxide led to an almost 3-fold increase in carbon monoxide content in tumour tissues (p=0.006).
  
  
  CONCLUSIONS
  These data suggest a new biological function for carbon monoxide in carcinogenesis, and point to the potential chemotherapeutic/chemoadjuvant use of carbon monoxide in pancreatic cancer.
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague 2, Czech Republic; 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University in Prague, Prague 2, Czech Republic. Electronic address: vitek@cesnet.cz.
authors.forename: Libor
authors.initials: L
authors.lastname: Vítek
authors.affiliation: Department of Biochemistry and Microbiology, Institute of Chemical Technology, Prague 6, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Gbelcová
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague 2, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Muchová
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague 2, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Váňová
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague 2, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Zelenka
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague 2, Czech Republic.
authors.forename: Renata
authors.initials: R
authors.lastname: Koníčková
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague 2, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Suk
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University in Prague, Prague 2, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Zadinova
authors.affiliation: Department of Biochemistry and Microbiology, Institute of Chemical Technology, Prague 6, Czech Republic.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Knejzlík
authors.affiliation: Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK; School of Life & Health Sciences, Aston University, Birmingham, UK.
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujisawa
authors.affiliation: Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK; School of Life & Health Sciences, Aston University, Birmingham, UK.
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Department of Biochemistry and Microbiology, Institute of Chemical Technology, Prague 6, Czech Republic. Electronic address: Tomas.Ruml@vscht.cz.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Ruml
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal; D049109:Cell Proliferation / Q000187:drug effects*; D064426:Gasotransmitters / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000494:pharmacology*; D010190:Pancreatic Neoplasms; D010766:Phosphorylation / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D064426:Gasotransmitters; D009942:Organometallic Compounds; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D051057:Proto-Oncogene Proteins c-akt
keywords: Anticancer effects; Heme catabolic pathway; Heme oxygenase