Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma

Daisuke Uchida, Akinobu Takaki, Hisashi Ishikawa, Yasuko Tomono, Hironari Katou, Koichiro Tsutsumi, Naofumi Tamaki, Takayuki Maruyama, Takaaki Tomofuji, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Hiroshi Matsushita, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Kazuhiro Nouso, Ryuichi Yoshida, Yuzo Umeda, Susumu ShinouraTakahito Yagi, Toshiyoshi Fujiwara, Manabu Morita, Masaki Fukushima, Kazuhide Yamamoto, Hiroyuki Okada

Research output: Contribution to journalArticle

5 Citations (Scopus)

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. Conclusion: 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.

Original languageEnglish
Pages (from-to)732-743
Number of pages12
JournalFree Radical Research
Volume50
Issue number7
DOIs
Publication statusPublished - Jul 2 2016

Fingerprint

Oxidative stress
Cholangiocarcinoma
Oxidative Stress
Chemotherapy
Carnitine
Antioxidants
Pancreatic Neoplasms
Metabolites
Tissue
Oxygen
Heme Oxygenase-1
Neoplasms
Stem Cells
Vitamin E
Oxidants
Adsorbents
Drug Therapy
Mitochondrial Membranes
Genes
Serum

Keywords

  • Anti-oxidative
  • cancer
  • l-carnitine
  • mitochondria
  • steatosis

ASJC Scopus subject areas

  • Biochemistry

Cite this

Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma. / Uchida, Daisuke; Takaki, Akinobu; Ishikawa, Hisashi; Tomono, Yasuko; Katou, Hironari; Tsutsumi, Koichiro; Tamaki, Naofumi; Maruyama, Takayuki; Tomofuji, Takaaki; Tsuzaki, Ryuichiro; Yasunaka, Tetsuya; Koike, Kazuko; Matsushita, Hiroshi; Ikeda, Fusao; Miyake, Yasuhiro; Shiraha, Hidenori; Nouso, Kazuhiro; Yoshida, Ryuichi; Umeda, Yuzo; Shinoura, Susumu; Yagi, Takahito; Fujiwara, Toshiyoshi; Morita, Manabu; Fukushima, Masaki; Yamamoto, Kazuhide; Okada, Hiroyuki.

In: Free Radical Research, Vol. 50, No. 7, 02.07.2016, p. 732-743.

Research output: Contribution to journalArticle

Uchida, Daisuke ; Takaki, Akinobu ; Ishikawa, Hisashi ; Tomono, Yasuko ; Katou, Hironari ; Tsutsumi, Koichiro ; Tamaki, Naofumi ; Maruyama, Takayuki ; Tomofuji, Takaaki ; Tsuzaki, Ryuichiro ; Yasunaka, Tetsuya ; Koike, Kazuko ; Matsushita, Hiroshi ; Ikeda, Fusao ; Miyake, Yasuhiro ; Shiraha, Hidenori ; Nouso, Kazuhiro ; Yoshida, Ryuichi ; Umeda, Yuzo ; Shinoura, Susumu ; Yagi, Takahito ; Fujiwara, Toshiyoshi ; Morita, Manabu ; Fukushima, Masaki ; Yamamoto, Kazuhide ; Okada, Hiroyuki. / Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma. In: Free Radical Research. 2016 ; Vol. 50, No. 7. pp. 732-743.
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T1 - Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma

AU - Uchida, Daisuke

AU - Takaki, Akinobu

AU - Ishikawa, Hisashi

AU - Tomono, Yasuko

AU - Katou, Hironari

AU - Tsutsumi, Koichiro

AU - Tamaki, Naofumi

AU - Maruyama, Takayuki

AU - Tomofuji, Takaaki

AU - Tsuzaki, Ryuichiro

AU - Yasunaka, Tetsuya

AU - Koike, Kazuko

AU - Matsushita, Hiroshi

AU - Ikeda, Fusao

AU - Miyake, Yasuhiro

AU - Shiraha, Hidenori

AU - Nouso, Kazuhiro

AU - Yoshida, Ryuichi

AU - Umeda, Yuzo

AU - Shinoura, Susumu

AU - Yagi, Takahito

AU - Fujiwara, Toshiyoshi

AU - Morita, Manabu

AU - Fukushima, Masaki

AU - Yamamoto, Kazuhide

AU - Okada, Hiroyuki

PY - 2016/7/2

Y1 - 2016/7/2

N2 - 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. Conclusion: 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.

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