SEARCHCOHORToncology, clinical nutrition

cohort·oncology, clinical nutrition, micronutrients, gastroenterology, preclinical research·PMC10020374

Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Frontiers in Pharmacology · 15 authors, 14 centres

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TL;DR

This cohort study analyzed paired blood samples from 43 hepatocellular carcinoma patients before and during sorafenib treatment. It found that sorafenib treatment significantly increased levels of cytochrome P450-derived epoxy and dihydroxy polyunsaturated fatty acid metabolites in the plasma.

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This study is a sub-analysis of the SORAMIC phase II randomized controlled trial. Blood samples were analyzed in a paired fashion, before and after 7–9 weeks of sorafenib treatment. The central results showed that relative levels of arachidonic acid and docosahexaenoic acid were significantly lower during treatment. Conversely, levels of CYP-derived epoxy metabolites, such as epoxyeicosatrienoic acids (EETs), were significantly higher, and there was a trend towards increased levels of n-3 PUFA metabolites like 19,20-epoxydocosapentaenoic acid (EDP). The authors suggest that the observed increase in n-3 PUFA-derived epoxy metabolites, which have shown anti-tumor effects in preclinical models, could be a beneficial effect of sorafenib. Limitations include the analysis of peripheral blood plasma rather than tumor tissue and potential variations in sample handling affecting epoxy-PUFA levels. The findings support the hypothesis that dietary n-3 PUFA supplementation could potentially enhance these metabolite levels during sorafenib therapy.

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cohort

SPECIALTY

oncology

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ORIGINAL PAPER

PMC10020374

Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

Frontiers in Pharmacology

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ABSTRACT

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: hepatocellular carcinoma, cytochrome P450, sorafenib, EET, EDP, omega-3 fatty acids, oxylipins, lipidomics

CITATION EXPORT

Can G Leineweber, Miriam Rabehl, Anne Pietzner et al.. Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma. Frontiers in Pharmacology. (2023). https://doi.org/10.3389/fphar.2023.1124214

AUTHORS

15 · 14 CENTRES

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

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