Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma

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.

FIGURE 1

CYP-dependent lipid metabolite formation from AA/DHA/EPA, and the potential effects of sorafenib.

FIGURE 2

Effects on the concentrations of (A) AA-, (B) DHA-, and (C) EPA-derived epoxy-PUFA EETs, EDPs, and EEQs; and (D) AA-derived epoxy-PUFA plus dihydroxy-PUFA, (E) DHA-derived epoxy-PUFA plus dihydroxy-PUFA, and (F) EPA-derived epoxy-PUFA plus dihydroxy-PUFA in the plasma of n = 43 patients with hepatocellular carcinoma (HCC) without and undergoing sorafenib treatment (ng/mL ± standard error of the mean). Statistical differences were determined using the Wilcoxon signed-rank test (**p < 0.01; ***p < 0.001; ****p < 0.0001).

FIGURE 3

(A) Relative n-3 (docosahexaenoic acid, DHA; eicosapentaenoic acid, EPA) and n-6 (arachidonic acid, AA) PUFA levels in plasma from n = 43 patients with hepatocellular carcinoma (HCC) without and during sorafenib treatment individually, summarized and as a ratio. (B) Relative content of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) in plasma from n = 43 patients with HCC without and undergoing sorafenib treatment. Statistical differences were determined using the Wilcoxon signed-rank test (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

FIGURE 4

Ratio of n-6 and n-3 PUFA-derived dihydroxy to epoxy-PUFA as a marker for sEH activity in n = 43 patients with HCC without and undergoing sorafenib treatment (***p < 0.001).

FIGURE 5

N-3 and n-6 PUFA-derived epoxides plus dihydroxy compounds as a marker for the presence of CYP metabolites in plasma from n = 43 patients with HCC without and undergoing sorafenib treatment. (A) Ratio of AA-derived products divided by AA plasma content, (B) ratio of DHA-derived products divided by DHA plasma content, (C) ratio of EPA-derived products divided by EPA plasma content (*p < 0.05, **p < 0.01; ***p < 0.001; ****p < 0.0001).