A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma

Author:

Diesinger Torsten123ORCID,Lautwein Alfred2,Bergler Sebastian2,Buckert Dominik24,Renz Christian2,Dvorsky Radovan56,Buko Vyacheslav78,Kirko Siarhei7,Schneider Edith9,Kuchenbauer Florian10,Kumar Mukesh11,Günes Cagatay11,Genze Felicitas12,Büchele Berthold12,Simmet Thomas12,Haslbeck Martin13,Masur Kai14,Barth Thomas15,Müller-Enoch Dieter2,Wirth Thomas2,Haehner Thomas2

Affiliation:

1. Chair of Biochemistry and Molecular Medicine, Witten/Herdecke University, Faculty of Health/School of Medicine, Alfred-Herrhausen-Straße 50, 58448 Witten, Germany

2. Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany

3. Department of Internal Medicine, Neu-Ulm Hospital, Krankenhausstraße 11, 89231 Neu-Ulm, Germany

4. Department of Internal Medicine II, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany

5. Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany

6. Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany

7. Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Bulvar Leninskogo Komsomola, Dom 50, Grodno 230030, Belarus

8. Department of Biotechnology, University of Medical Sciences, Ulica Jana Kilinskiego 1, 15-089 Białystok, Poland

9. Department of Internal Medicine III, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany

10. University of British Columbia, Terry Fox Laboratory, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada

11. Department of Urology, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany

12. Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Helmholtzstraße 20, 89081 Ulm, Germany

13. Chair of Biotechnology, TUM Department of Chemistry, Technical University of Munich, Lichtenbergstraße 4, 85748 Garching, Munich, Germany

14. Leibniz Institute for Plasma Science and Technology, Felix-Hausdorff-Straße 2, 17489 Greifswald, Germany

15. Institute of Pathology, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany

Abstract

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.

Publisher

Hindawi Limited

Subject

Gastroenterology,Hepatology,General Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3