Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells
Background Niclosamide is an oral anthelminthic drug that has been used for treating tapeworm infections. Its mechanism involves the disturbance of mitochondrial membrane potential that in turn inhibits oxidative phosphorylation leading to ATP depletion. To date, niclosamide has been validated as th...
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PeerJ Inc.
2023-11-01
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| Online Access: | https://peerj.com/articles/16512.pdf |
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| author | Thanaporn Kulthawatsiri Yingpinyapat Kittirat Jutarop Phetcharaburanin Jittima Tomacha Bundit Promraksa Arporn Wangwiwatsin Poramate Klanrit Attapol Titapun Watcharin Loilome Nisana Namwat |
| author_facet | Thanaporn Kulthawatsiri Yingpinyapat Kittirat Jutarop Phetcharaburanin Jittima Tomacha Bundit Promraksa Arporn Wangwiwatsin Poramate Klanrit Attapol Titapun Watcharin Loilome Nisana Namwat |
| author_sort | Thanaporn Kulthawatsiri |
| collection | DOAJ |
| description | Background Niclosamide is an oral anthelminthic drug that has been used for treating tapeworm infections. Its mechanism involves the disturbance of mitochondrial membrane potential that in turn inhibits oxidative phosphorylation leading to ATP depletion. To date, niclosamide has been validated as the potent anti-cancer agent against several cancers. However, the molecular mechanisms underlying the effects of niclosamide on the liver fluke Opisthorchis viverrini (Ov)-associated cholangiocarcinoma (CCA) cell functions remain to be elucidated. The aims of this study were to investigate the effects of niclosamide on CCA cell proliferation and on metabolic phenoconversion through the alteration of metabolites associated with mitochondrial function in CCA cell lines. Materials and Methods The inhibitory effect of niclosamide on CCA cells was determined using SRB assay. A mitochondrial membrane potential using tetramethylrhodamine, ethyl ester-mitochondrial membrane potential (TMRE-MMP) assay was conducted. Liquid chromatography-mass spectrometry-based metabolomics was employed to investigate the global metabolic changes upon niclosamide treatment. ATP levels were measured using CellTiter-Glo® luminescent cell viability assay. NAD metabolism was examined by the NAD+/NADH ratio. Results Niclosamide strongly inhibited CCA cell growth and reduced the MMP of CCA cells. An orthogonal partial-least square regression analysis revealed that the effects of niclosamide on suppressing cell viability and MMP of CCA cells were significantly associated with an increase in niacinamide, a precursor in NAD synthesis that may disrupt the electron transport system leading to suppression of NAD+/NADH ratio and ATP depletion. Conclusion Our findings unravel the mode of action of niclosamide in the energy depletion that could potentially serve as the promising therapeutic strategy for CCA treatment. |
| first_indexed | 2024-03-09T16:28:43Z |
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| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T16:28:43Z |
| publishDate | 2023-11-01 |
| publisher | PeerJ Inc. |
| record_format | Article |
| series | PeerJ |
| spelling | doaj.art-b3670b10c86940cf978c7d275eec5e822023-11-24T15:05:21ZengPeerJ Inc.PeerJ2167-83592023-11-0111e1651210.7717/peerj.16512Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cellsThanaporn Kulthawatsiri0Yingpinyapat Kittirat1Jutarop Phetcharaburanin2Jittima Tomacha3Bundit Promraksa4Arporn Wangwiwatsin5Poramate Klanrit6Attapol Titapun7Watcharin Loilome8Nisana Namwat9Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandDepartment of Medical Sciences/Regional Medical Sciences Center 2, Ministry of Public Health, Phitsanulok, Phitsanulok, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Khon Kaen, ThailandBackground Niclosamide is an oral anthelminthic drug that has been used for treating tapeworm infections. Its mechanism involves the disturbance of mitochondrial membrane potential that in turn inhibits oxidative phosphorylation leading to ATP depletion. To date, niclosamide has been validated as the potent anti-cancer agent against several cancers. However, the molecular mechanisms underlying the effects of niclosamide on the liver fluke Opisthorchis viverrini (Ov)-associated cholangiocarcinoma (CCA) cell functions remain to be elucidated. The aims of this study were to investigate the effects of niclosamide on CCA cell proliferation and on metabolic phenoconversion through the alteration of metabolites associated with mitochondrial function in CCA cell lines. Materials and Methods The inhibitory effect of niclosamide on CCA cells was determined using SRB assay. A mitochondrial membrane potential using tetramethylrhodamine, ethyl ester-mitochondrial membrane potential (TMRE-MMP) assay was conducted. Liquid chromatography-mass spectrometry-based metabolomics was employed to investigate the global metabolic changes upon niclosamide treatment. ATP levels were measured using CellTiter-Glo® luminescent cell viability assay. NAD metabolism was examined by the NAD+/NADH ratio. Results Niclosamide strongly inhibited CCA cell growth and reduced the MMP of CCA cells. An orthogonal partial-least square regression analysis revealed that the effects of niclosamide on suppressing cell viability and MMP of CCA cells were significantly associated with an increase in niacinamide, a precursor in NAD synthesis that may disrupt the electron transport system leading to suppression of NAD+/NADH ratio and ATP depletion. Conclusion Our findings unravel the mode of action of niclosamide in the energy depletion that could potentially serve as the promising therapeutic strategy for CCA treatment.https://peerj.com/articles/16512.pdfNiclosamideCholangiocarcinomaMetabolomicsLC-MS |
| spellingShingle | Thanaporn Kulthawatsiri Yingpinyapat Kittirat Jutarop Phetcharaburanin Jittima Tomacha Bundit Promraksa Arporn Wangwiwatsin Poramate Klanrit Attapol Titapun Watcharin Loilome Nisana Namwat Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells PeerJ Niclosamide Cholangiocarcinoma Metabolomics LC-MS |
| title | Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells |
| title_full | Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells |
| title_fullStr | Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells |
| title_full_unstemmed | Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells |
| title_short | Metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells |
| title_sort | metabolomic analyses uncover an inhibitory effect of niclosamide on mitochondrial membrane potential in cholangiocarcinoma cells |
| topic | Niclosamide Cholangiocarcinoma Metabolomics LC-MS |
| url | https://peerj.com/articles/16512.pdf |
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