Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Frontiers in Pharmacology

Pharmacology

Nils Helge Schebb¹  Chris Verslype²  Julia Benckert³  Bristi Basu⁴  Maciej Pech⁵  Jens Ricke⁶  Rohini Sharma⁷  Michael Rothe⁸  Bruno Sangro⁹  Miriam Rabehl^1,10  Karsten-H. Weylandt^1,10  Anne Pietzner^1,10  Nadine Rohwer^1,11  Can G. Leineweber^1,12  Christian Sengel^1,13 

[1] Chair of Food Chemistry, Faculty of Mathematics and Natural Science, University of Wuppertal, Wuppertal, Germany;Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium;Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Berlin, Germany;Department of Oncology, University of Cambridge, Cambridge, United Kingdom;Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg, Germany;Department of Radiology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany;Department of Surgery and Cancer, Imperial College London, London, United Kingdom;Lipidomix, Berlin, Germany;Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain;Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany;Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany;Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany;Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany;Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany;Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany;Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany;Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;Radiology Department, Grenoble University Hospital, La Tronche, France;

关键词: hepatocellular carcinoma;    cytochrome P450;    sorafenib;    EET;    EDP;    omega-3 fatty acids;    oxylipins;    lipidomics;   

DOI  :  10.3389/fphar.2023.1124214

 received in 2022-12-14, accepted in 2023-02-15,  发布年份 2023

来源: Frontiers

【 摘 要 】

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.

【 授权许可】

Unknown   
Copyright © 2023 Leineweber, Rabehl, Pietzner, Rohwer, Rothe, Pech, Sangro, Sharma, Verslype, Basu, Sengel, Ricke, Schebb, Weylandt and Benckert.