A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma
Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final c...
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Wiley
2021-01-01
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| Series: | Canadian Journal of Gastroenterology and Hepatology |
| Online Access: | http://dx.doi.org/10.1155/2021/8854432 |
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| author | Torsten Diesinger Alfred Lautwein Sebastian Bergler Dominik Buckert Christian Renz Radovan Dvorsky Vyacheslav Buko Siarhei Kirko Edith Schneider Florian Kuchenbauer Mukesh Kumar Cagatay Günes Felicitas Genze Berthold Büchele Thomas Simmet Martin Haslbeck Kai Masur Thomas Barth Dieter Müller-Enoch Thomas Wirth Thomas Haehner |
| author_facet | Torsten Diesinger Alfred Lautwein Sebastian Bergler Dominik Buckert Christian Renz Radovan Dvorsky Vyacheslav Buko Siarhei Kirko Edith Schneider Florian Kuchenbauer Mukesh Kumar Cagatay Günes Felicitas Genze Berthold Büchele Thomas Simmet Martin Haslbeck Kai Masur Thomas Barth Dieter Müller-Enoch Thomas Wirth Thomas Haehner |
| author_sort | Torsten Diesinger |
| collection | DOAJ |
| description | Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD. |
| format | Article |
| id | doaj-art-e74a70f467514028b4d33139a1dbe072 |
| institution | Kabale University |
| issn | 2291-2789 2291-2797 |
| language | English |
| publishDate | 2021-01-01 |
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| series | Canadian Journal of Gastroenterology and Hepatology |
| spelling | doaj-art-e74a70f467514028b4d33139a1dbe0722025-02-03T00:58:55ZengWileyCanadian Journal of Gastroenterology and Hepatology2291-27892291-27972021-01-01202110.1155/2021/88544328854432A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular CarcinomaTorsten Diesinger0Alfred Lautwein1Sebastian Bergler2Dominik Buckert3Christian Renz4Radovan Dvorsky5Vyacheslav Buko6Siarhei Kirko7Edith Schneider8Florian Kuchenbauer9Mukesh Kumar10Cagatay Günes11Felicitas Genze12Berthold Büchele13Thomas Simmet14Martin Haslbeck15Kai Masur16Thomas Barth17Dieter Müller-Enoch18Thomas Wirth19Thomas Haehner20Chair of Biochemistry and Molecular Medicine, Witten/Herdecke University, Faculty of Health/School of Medicine, Alfred-Herrhausen-Straße 50, 58448 Witten, GermanyInstitute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, GermanyInstitute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, GermanyInstitute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, GermanyInstitute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, GermanyInstitute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDivision of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Bulvar Leninskogo Komsomola, Dom 50, Grodno 230030, BelarusDivision of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Bulvar Leninskogo Komsomola, Dom 50, Grodno 230030, BelarusDepartment of Internal Medicine III, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, GermanyUniversity of British Columbia, Terry Fox Laboratory, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, CanadaDepartment of Urology, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, GermanyDepartment of Urology, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, GermanyInstitute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Helmholtzstraße 20, 89081 Ulm, GermanyInstitute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Helmholtzstraße 20, 89081 Ulm, GermanyInstitute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Helmholtzstraße 20, 89081 Ulm, GermanyChair of Biotechnology, TUM Department of Chemistry, Technical University of Munich, Lichtenbergstraße 4, 85748 Garching, Munich, GermanyLeibniz Institute for Plasma Science and Technology, Felix-Hausdorff-Straße 2, 17489 Greifswald, GermanyInstitute of Pathology, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, GermanyInstitute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, GermanyInstitute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, GermanyInstitute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, GermanyCytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD.http://dx.doi.org/10.1155/2021/8854432 |
| spellingShingle | Torsten Diesinger Alfred Lautwein Sebastian Bergler Dominik Buckert Christian Renz Radovan Dvorsky Vyacheslav Buko Siarhei Kirko Edith Schneider Florian Kuchenbauer Mukesh Kumar Cagatay Günes Felicitas Genze Berthold Büchele Thomas Simmet Martin Haslbeck Kai Masur Thomas Barth Dieter Müller-Enoch Thomas Wirth Thomas Haehner A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma Canadian Journal of Gastroenterology and Hepatology |
| title | A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma |
| title_full | A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma |
| title_fullStr | A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma |
| title_full_unstemmed | A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma |
| title_short | A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma |
| title_sort | new cyp2e1 inhibitor 12 imidazolyl 1 dodecanol represents a potential treatment for hepatocellular carcinoma |
| url | http://dx.doi.org/10.1155/2021/8854432 |
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