title: Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma.
abstract: BACKGROUND
  Pancreatico-biliary malignancies exhibit similar characteristics, including obesity-related features and poor prognosis, and require new treatment strategies. Oxidative stress is known to induce DNA damage and carcinogenesis, and its reduction is viewed as being favorable. However, it also has anti-infection and anti-cancer functions that need to be maintained. To reveal the effect of oxidative stress on cancer progression, we evaluated oxidative stress and anti-oxidative balance in pancreatic cancer (PC) and cholangiocarcinoma (CC) patients, as well as the effect of add-on antioxidant treatment to chemotherapy in a mouse cholangiocarcinoma model.
  
  
  METHODS
  We recruited 84 CC and 80 PC patients who were admitted to our hospital. Serum levels of reactive oxygen metabolites (ROM) and the anti-oxidative OXY-adsorbent test were determined and the balance of these tests was defined as an oxidative index. A diabetic mouse-based cholangiocarcinoma model was utilized to evaluate the effects of add-on antioxidant therapy on cholangiocarcinoma chemotherapy.
  
  
  RESULTS
  Serum ROM was higher and anti-oxidant OXY was lower in CC patients with poor outcomes. These parameters were not significantly different in PC patients. In mice, vitamin E administration induced antioxidant hemeoxygenase (HO)-1 protein expression in cancer tissue, while the number of stem-like cells increased. l-carnitine administration improved intestinal microbiome and biliary acid balance, upregulated the hepatic mitochondrial membrane uptake related gene Cpt1 in non-cancerous tissue, and did not alter stem-like cell numbers.
  
  
  CONCLUSIONS
  Oxidative stress balance was dysregulated in cholangiocarcinoma with poor outcome. The mitochondrial function-supporting agent l-carnitine is a good candidate to control oxidative stress conditions.
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Uchida
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Akinobu
authors.initials: A
authors.lastname: Takaki
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishikawa
authors.affiliation: b Shigei Medical Research Institute , Okayama , Japan ;
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Tomono
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Hironari
authors.initials: H
authors.lastname: Kato
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsutsumi
authors.affiliation: c Department of Preventive Dentistry , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;|d Department of Preventive Dentistry Institute of Health Biosciences , Tokushima University Graduate School , Tokushima , Japan ;
authors.forename: Naofumi
authors.initials: N
authors.lastname: Tamaki
authors.affiliation: c Department of Preventive Dentistry , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: c Department of Preventive Dentistry , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Takaaki
authors.initials: T
authors.lastname: Tomofuji
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Tsuzaki
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yasunaka
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Kazuko
authors.initials: K
authors.lastname: Koike
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsushita
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Fusao
authors.initials: F
authors.lastname: Ikeda
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyake
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Hidenori
authors.initials: H
authors.lastname: Shiraha
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nouso
authors.affiliation: e Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Yoshida
authors.affiliation: e Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Umeda
authors.affiliation: e Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Shinoura
authors.affiliation: e Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Yagi
authors.affiliation: e Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: c Department of Preventive Dentistry , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Manabu
authors.initials: M
authors.lastname: Morita
authors.affiliation: b Shigei Medical Research Institute , Okayama , Japan ;
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukushima
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: a Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan ;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002331:Carnitine / Q000494:pharmacology; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000975:Antioxidants; D002331:Carnitine
keywords: Anti-oxidative; cancer; l-carnitine; mitochondria; steatosis