Combined gemcitabine and metronidazole is a promising therapeutic strategy for cancer stem-like cholangiocarcinoma

Makoto Kawamoto; Masayo Umebayashi; Hiroto Tanaka; Norihiro Koya; Sinichiro Nakagawa; Ken Kawabe; Hideya Onishi; Masafumi Nakamura; Takashi Morisaki

doi:10.21873/anticanres.12516

Combined gemcitabine and metronidazole is a promising therapeutic strategy for cancer stem-like cholangiocarcinoma

Makoto Kawamoto, Masayo Umebayashi, Hiroto Tanaka, Norihiro Koya, Sinichiro Nakagawa, Ken Kawabe, Hideya Onishi, Masafumi Nakamura, Takashi Morisaki

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Background/Aim: Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). Materials and Methods: We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. Results: MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). Conclusion: MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA.

Original language	English
Pages (from-to)	2739-2748
Number of pages	10
Journal	Anticancer research
Volume	38
Issue number	5
DOIs	https://doi.org/10.21873/anticanres.12516
Publication status	Published - May 2018

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.21873/anticanres.12516

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title = "Combined gemcitabine and metronidazole is a promising therapeutic strategy for cancer stem-like cholangiocarcinoma",

abstract = "Background/Aim: Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). Materials and Methods: We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. Results: MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). Conclusion: MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA.",

author = "Makoto Kawamoto and Masayo Umebayashi and Hiroto Tanaka and Norihiro Koya and Sinichiro Nakagawa and Ken Kawabe and Hideya Onishi and Masafumi Nakamura and Takashi Morisaki",

note = "Funding Information: The Authors thank M. Arico from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This study was supported by JSPS KAKENHI Grant Number 17H04283 and 16K10603. Publisher Copyright: {\textcopyright} 2018 International Institute of Anticancer Research. All rights reserved.",

year = "2018",

month = may,

doi = "10.21873/anticanres.12516",

language = "English",

volume = "38",

pages = "2739--2748",

journal = "Anticancer Research",

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publisher = "International Institute of Anticancer Research",

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}

TY - JOUR

T1 - Combined gemcitabine and metronidazole is a promising therapeutic strategy for cancer stem-like cholangiocarcinoma

AU - Kawamoto, Makoto

AU - Umebayashi, Masayo

AU - Tanaka, Hiroto

AU - Koya, Norihiro

AU - Nakagawa, Sinichiro

AU - Kawabe, Ken

AU - Onishi, Hideya

AU - Nakamura, Masafumi

AU - Morisaki, Takashi

N1 - Funding Information: The Authors thank M. Arico from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This study was supported by JSPS KAKENHI Grant Number 17H04283 and 16K10603. Publisher Copyright: © 2018 International Institute of Anticancer Research. All rights reserved.

PY - 2018/5

Y1 - 2018/5

N2 - Background/Aim: Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). Materials and Methods: We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. Results: MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). Conclusion: MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA.

AB - Background/Aim: Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). Materials and Methods: We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. Results: MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). Conclusion: MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA.

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Combined gemcitabine and metronidazole is a promising therapeutic strategy for cancer stem-like cholangiocarcinoma

Abstract

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