Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma
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 epoxygenat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1124214/full |
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| author | Can G. Leineweber Can G. Leineweber Can G. Leineweber Miriam Rabehl Miriam Rabehl Anne Pietzner Anne Pietzner Nadine Rohwer Nadine Rohwer Nadine Rohwer Michael Rothe Maciej Pech Bruno Sangro Rohini Sharma Chris Verslype Bristi Basu Christian Sengel Jens Ricke Nils Helge Schebb Karsten-H. Weylandt Karsten-H. Weylandt Julia Benckert |
| author_facet | Can G. Leineweber Can G. Leineweber Can G. Leineweber Miriam Rabehl Miriam Rabehl Anne Pietzner Anne Pietzner Nadine Rohwer Nadine Rohwer Nadine Rohwer Michael Rothe Maciej Pech Bruno Sangro Rohini Sharma Chris Verslype Bristi Basu Christian Sengel Jens Ricke Nils Helge Schebb Karsten-H. Weylandt Karsten-H. Weylandt Julia Benckert |
| author_sort | Can G. Leineweber |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T14:45:58Z |
| format | Article |
| id | doaj.art-630cda002caf4e259f38d949754a2b84 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-08T14:45:58Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-630cda002caf4e259f38d949754a2b842024-01-11T08:51:30ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-03-011410.3389/fphar.2023.11242141124214Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinomaCan G. Leineweber0Can G. Leineweber1Can G. Leineweber2Miriam Rabehl3Miriam Rabehl4Anne Pietzner5Anne Pietzner6Nadine Rohwer7Nadine Rohwer8Nadine Rohwer9Michael Rothe10Maciej Pech11Bruno Sangro12Rohini Sharma13Chris Verslype14Bristi Basu15Christian Sengel16Jens Ricke17Nils Helge Schebb18Karsten-H. Weylandt19Karsten-H. Weylandt20Julia Benckert21Medical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, GermanyFaculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, GermanyInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainMedical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, GermanyFaculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, GermanyMedical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, GermanyFaculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, GermanyMedical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, GermanyFaculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, GermanyDepartment of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, GermanyLipidomix, Berlin, GermanyDepartment of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg, GermanyLiver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, SpainDepartment of Surgery and Cancer, Imperial College London, London, United KingdomDepartment of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium0Department of Oncology, University of Cambridge, Cambridge, United Kingdom1Radiology Department, Grenoble University Hospital, La Tronche, France2Department of Radiology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany3Chair of Food Chemistry, Faculty of Mathematics and Natural Science, University of Wuppertal, Wuppertal, GermanyMedical Department B, Division of Hepatology, Gastroenterology, Oncology, Hematology, Palliative Care, Endocrinology, and Diabetes, Brandenburg Medical School, University Hospital Ruppin-Brandenburg, Neuruppin, GermanyFaculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany4Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Berlin, GermanyHepatocellular 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.https://www.frontiersin.org/articles/10.3389/fphar.2023.1124214/fullhepatocellular carcinomacytochrome P450sorafenibEETEDPomega-3 fatty acids |
| spellingShingle | Can G. Leineweber Can G. Leineweber Can G. Leineweber Miriam Rabehl Miriam Rabehl Anne Pietzner Anne Pietzner Nadine Rohwer Nadine Rohwer Nadine Rohwer Michael Rothe Maciej Pech Bruno Sangro Rohini Sharma Chris Verslype Bristi Basu Christian Sengel Jens Ricke Nils Helge Schebb Karsten-H. Weylandt Karsten-H. Weylandt Julia Benckert Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma Frontiers in Pharmacology hepatocellular carcinoma cytochrome P450 sorafenib EET EDP omega-3 fatty acids |
| title | Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma |
| title_full | Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma |
| title_fullStr | Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma |
| title_full_unstemmed | Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma |
| title_short | Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma |
| title_sort | sorafenib increases cytochrome p450 lipid metabolites in patient with hepatocellular carcinoma |
| topic | hepatocellular carcinoma cytochrome P450 sorafenib EET EDP omega-3 fatty acids |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1124214/full |
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