Frontiers in Pharmacology (Mar 2023)

Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

  • 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

DOI
https://doi.org/10.3389/fphar.2023.1124214
Journal volume & issue
Vol. 14

Abstract

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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.

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