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Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.

Published version
Peer-reviewed

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Authors

Leineweber, Can G 
Rabehl, Miriam 
Pietzner, Anne 
Rohwer, Nadine 
Rothe, Michael 

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.

Description

Peer reviewed: True


Acknowledgements: We thank the SORAMIC research group for providing the samples, recruiting patients, collecting patient information, and processing blood samples, and the patients for their participation. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).

Keywords

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

Journal Title

Front Pharmacol

Conference Name

Journal ISSN

1663-9812
1663-9812

Volume Title

Publisher

Frontiers Media SA
Sponsorship
National Institute for Health and Care Research (IS-BRC-1215-20014)