Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase

Abstract

Background/Aim: Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved. Materials and Methods: PK03-mutant Kras G12D murine pancreatic carcinoma cells were inoculated into mouse models including fat-1, sEH −/− and C57BL/6J mice. The mice were fed with AIN-76A diet with or without ω-3 PUFA supplementation or treated with sEH inhibitor. In addition to tumor growth (tumor size and weight), cell proliferation, mutant Kras-mediated signaling, inflammatory reaction and angiogenesis were analyzed immunohisto-chemically and by western blot assay. ω-3 PUFA metabolism, particularly focusing on ω-3 epoxy fatty acids (ω-3 epoxides), was measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach. Results: Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm 3 vs. 519.3±60.6 mm 3). In a separate experiment, sEH −/− mice fed ω-3 PUFA supplement and C57BL/6J mice treated with sEH inhibitor and fed ω-3 PUFA supplement exhibited a significant

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

“…In experiments with cell cultures, the invasive properties of prostate cancer cells were strongly inhibited by EDPs, in contrast to the effect of 11,12-EET [24,33]. In a recent study, besides anti-angiogenic and anti-inflammatory effects, an inhibitory effect of omega-3 epoxyeicosanoids on the RAS/RAF/ MEK/ERK pathway was also described [34].…”

Carcinogenesis: Failure of resolution of inflammation?

“…Inhibition of sEH inhibits chronic pancreatitis and the progression of pancreatic intraepithelial neoplasms (PanIN) via dual inhibition of sEH and RAF1 proto-oncogene serine/threonine kinase (c-RAF)( Liao et al, 2016 ). Omega-3 epoxy fatty acids combined with a sEH inhibitor inhibited pancreatic carcinoma via anti-inflammatory, anti-proliferation, reduced mutant Kras-activated signals, and anti-angiogenic activity ( Xia et al, 2019 ). Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators (e.g.…”

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

“…The combined use of ω-3 PUFAs with sEHIs offers a promising strategy for pancreatic cancer treatment and prevention. ω-3 epoxy metabolites prevent pancreatic ductal adenocarcinoma (PDAC) growth via inhibition of the RAS/RAF/ MEK/ERK pathway [ 168 ]. ω-3 polyunsaturated fatty acids (PUFAs) are considered immunonutrients and are commonly used in the nutritional therapy of cancer patients.…”