Assessment of the Effect of Sorafenib on Omega-6 and Omega-3 Epoxyeicosanoid Formation in Patients with Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death. The multikinase inhibitor sorafenib is widely used for systemic therapy in advanced HCC. Sorafenib might affect epoxyeicosanoids, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of epoxides derived from long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding diols. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) showed 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 pilot study, we assessed the effect of sorafenib treatment on the presence of lipid mediators, such as EETs, in blood of the patients with HCC using the lipidomics technology. We found a significant increase in 11,12-EET and 14,15-EET levels in HCC patients treated with sorafenib. Furthermore, while not significant in this small sample set, the data presented indicate that sorafenib can also increase the level of omega-3 DHA-derived 19,20-EDP. While the effect on EETs might hamper the anti-tumor effect of sorafenib, we hypothesize that supplementation of DHA in sorafenib-treated HCC patients could increase the level of 19,20-EDP and thereby enhance its anti-tumor effect.

Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

“…In comparison, 13,14-EpDPE is anti-angiogenic and is metabolized by both sEH and mEH. Use of selective inhibitors in animal models and in human has shown that sEH inhibition results in an increased level of EpFAs, supporting the significant role of this enzyme for EpFAs metabolism in vivo [ 5 , 7 , 34 , 35 ]. No inhibitor sufficiently effective in vivo exists for mEH yet.…”

Carcinogenesis: Failure of resolution of inflammation?

“…A diet high in omega-3 fatty acids opposes the western diet, high in omega-6 fatty acids, which promotes inflammatory macrophage- and colitis-associated colon carcinogenesis ( Kim et al, 2010 ). Importantly, DHA supplementation may increase the efficacy of HCC patients receiving sorafenib via increased anti-angiogenic and anti-tumorigenic lipids such as 19,20-epoxydocosapentaenoic acid (EDP) ( Leineweber et al, 2020 ; Zhang, Panigrahy, et al, 2013 ). Additionally, diets, based off elite crop varieties containing anticancer effects have been demonstrated to reduce hepatocarcinogenesis from NDEA by downregulating TNF-α/IL-6, increasing antioxidants, and increasing apoptosis without stimulating regenerative proliferation ( Zheng et al, 2019 ).…”

The Consequences of Soluble Epoxide Hydrolase Deletion on Tumorigenesis and Metastasis in a Mouse Model of Breast Cancer

“…The levels of PUFA epoxides in cells and tissues are usually tightly controlled by the activity of the soluble epoxide hydrolase (sEH), which metabolizes them to vicinal diols [3]. Thus, a decrease in sEH expression, as has been observed in some tumors [10][11][12], would be expected to shift the epoxide-diol balance towards that of the epoxides. Such considerations led to the proposal that increasing epoxide levels could predispose patients to tumor development and that this process could be promoted and maybe even accelerated following the inhibition or downregulation of the sEH.…”