Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Can G Leineweber; Miriam Rabehl; Anne Pietzner; Nadine Rohwer; Michael Rothe; Maciej Pech; Bruno Sangro; Rohini Sharma; Chris Verslype; Bristi Basu; Christian Sengel; Jens Ricke; Nils Helge Schebb; Karsten-H Weylandt; Julia Benckert

doi:10.3389/fphar.2023.1124214

Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Front Pharmacol. 2023 Mar 3:14:1124214. doi: 10.3389/fphar.2023.1124214. eCollection 2023.

Authors

Can G Leineweber^{1

2

3}, Miriam Rabehl^{1

2}, Anne Pietzner^{1

2}, Nadine Rohwer^{1

2

4}, Michael Rothe⁵, Maciej Pech⁶, Bruno Sangro⁷, Rohini Sharma⁸, Chris Verslype⁹, Bristi Basu¹⁰, Christian Sengel¹¹, Jens Ricke¹², Nils Helge Schebb¹³, Karsten-H Weylandt^{1

2}, Julia Benckert¹⁴

Affiliations

¹ Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, Germany.
² Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany.
³ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
⁴ Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
⁵ Lipidomix, Berlin, Germany.
⁶ Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg, Germany.
⁷ Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain.
⁸ Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
⁹ Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium.
¹⁰ Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
¹¹ Radiology Department, Grenoble University Hospital, La Tronche, France.
¹² Department of Radiology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
¹³ Chair of Food Chemistry, Faculty of Mathematics and Natural Science, University of Wuppertal, Wuppertal, Germany.
¹⁴ Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Abstract

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.

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

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Publication funded by the Brandenburg Medical School (Medizinische Hochschule Brandenburg, MHB) publication fund supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and by the Ministry of Science, Research and Culture of the State of Brandenburg.