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

dc.bibliographicCitation.firstPage8854432eng
dc.bibliographicCitation.journalTitleCanadian journal of gastroenterology & hepatologyeng
dc.bibliographicCitation.volume2021eng
dc.contributor.authorDiesinger, Torsten
dc.contributor.authorLautwein, Alfred
dc.contributor.authorBergler, Sebastian
dc.contributor.authorBuckert, Dominik
dc.contributor.authorRenz, Christian
dc.contributor.authorDvorsky, Radovan
dc.contributor.authorBuko, Vyacheslav
dc.contributor.authorKirko, Siarhei
dc.contributor.authorSchneider, Edith
dc.contributor.authorKuchenbauer, Florian
dc.contributor.authorKumar, Mukesh
dc.contributor.authorGünes, Cagatay
dc.contributor.authorGenze, Felicitas
dc.contributor.authorBüchele, Berthold
dc.contributor.authorSimmet, Thomas
dc.contributor.authorHaslbeck, Martin
dc.contributor.authorMasur, Kai
dc.contributor.authorBarth, Thomas
dc.contributor.authorMüller-Enoch, Dieter
dc.contributor.authorWirth, Thomas
dc.contributor.authorHaehner, Thomas
dc.contributor.editorGranito, Alessandro
dc.date.accessioned2022-03-22T11:25:06Z
dc.date.available2022-03-22T11:25:06Z
dc.date.issued2021
dc.description.abstractCytochrome 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. © 2021 Torsten Diesinger et al.eng
dc.description.versionpublishedVersioneng
dc.identifier.urihttps://oa.tib.eu/renate/handle/123456789/8318
dc.identifier.urihttps://doi.org/10.34657/7356
dc.language.isoengeng
dc.publisher[Cairo] : Hindawieng
dc.relation.doihttps://doi.org/10.1155/2021/8854432
dc.relation.essn1916-7237
dc.rights.licenseCC BY 4.0 Unportedeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/eng
dc.subject.ddc610eng
dc.subject.other12 Imidazolyl 1 dodecanoleng
dc.subject.othercaspaseeng
dc.subject.othercyclin dependent kinase inhibitor 1Beng
dc.subject.othercytochrome P450 2E1 inhibitoreng
dc.subject.othereosineng
dc.subject.otherhematoxylineng
dc.subject.otherKi 67 antigeneng
dc.subject.otherlauryl alcoholeng
dc.subject.otherprotein p27eng
dc.subject.othercytochrome P450 2E1eng
dc.subject.otherlauryl alcoholeng
dc.subject.otheranimal experimenteng
dc.subject.otheranimal modeleng
dc.subject.othercachexiaeng
dc.subject.othercarcinogenesiseng
dc.subject.othercaspase assayeng
dc.subject.othercell cycle assayeng
dc.subject.othercell cycle progressioneng
dc.subject.othercell cycle regulationeng
dc.subject.othercell cycle S phaseeng
dc.subject.othercell viabilityeng
dc.subject.otherchorioallantoiseng
dc.subject.othercolorectal adenocarcinoma cell lineeng
dc.subject.othercytotoxicityeng
dc.subject.otherDLD-1 cell lineeng
dc.subject.otherfatty livereng
dc.subject.otherHep-G2 cell lineeng
dc.subject.otherimmunoblottingeng
dc.subject.otherimmunofluorescenceeng
dc.subject.otherimmunohistochemistryeng
dc.subject.otherliver cell carcinomaeng
dc.subject.othermouseeng
dc.subject.othernonalcoholic fatty livereng
dc.subject.othernonalcoholic steatohepatitiseng
dc.subject.otherprotein expressioneng
dc.subject.otherRNA extractioneng
dc.subject.othertumor xenografteng
dc.subject.otherTUNEL assayeng
dc.subject.otherliver tumoreng
dc.subject.otheroxidative stresseng
dc.subject.otherCarcinoma, Hepatocellulareng
dc.subject.otherCytochrome P-450 CYP2E1eng
dc.subject.otherDodecanoleng
dc.subject.otherLiver Neoplasmseng
dc.titleA New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinomaeng
dc.typeArticleeng
dc.typeTexteng
tib.accessRightsopenAccesseng
wgl.contributorINPeng
wgl.subjectMedizin, Gesundheiteng
wgl.typeZeitschriftenartikeleng
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