Conversion of eicosapentaenoic acid to chain-shortened omega–3 fatty acid metabolites by peroxisomal oxidation

Williard, Deborah E.; Kaduce, Terry L.; Harmon, Shawn D.; Spector, Arthur A.

doi:10.1016/s0022-2275(20)33865-7

Cited by 27 publications

(8 citation statements)

References 39 publications

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“…Together, this suggests that the increased production of the PIFAs is due to an increase in the availability of the substrates. Thus far, 16:4(n-3) has only been described to be formed via peroxisomal oxidation from EPA (Williard et al, 1998). Given our results, it is likely that similar to KHT, 16:4(n-3) functions downstream of the COX-TXAS pathway.…”

Section: Msc-induced Resistance Is Prevented By Intervening With the Cyclooxygenase (Cox)-1/thromboxane Synthase (Txas) Pathwaymentioning

confidence: 56%

Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids

et al. 2011

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The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients.

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Section: Msc-induced Resistance Is Prevented By Intervening With the Cyclooxygenase (Cox)-1/thromboxane Synthase (Txas) Pathwaymentioning

confidence: 56%

Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids

et al. 2011

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“…Williard et al . found that EPA can be converted to 16:4( n ‐3) by peroxisomal oxidation 42 . Because of limited sample of mouse blood plasma, we were unable to determine PIFA levels in this study.…”

Section: Discussionmentioning

confidence: 87%

Specialized nutrition improves muscle function and physical activity without affecting chemotherapy efficacy in C26 tumour‐bearing mice

Wijler

Raats

Elias

et al. 2021

J cachexia sarcopenia muscle

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Background Skeletal muscle wasting and fatigue are commonly observed in cancer patients receiving chemotherapy and associated with reduced treatment outcome and quality of life. Nutritional support may mitigate these side effects, but potential interference with chemotherapy efficacy could be of concern. Here, we investigated the effects of an ω‐3 polyunsaturated fatty acid (eicosapentaenoic acid and docosahexaenoic acid), leucine‐enriched, high‐protein (100% whey), additional vitamin D, and prebiotic fibres ‘specific nutritional composition’ (SNC) and chemotherapy on state‐of‐the‐art tumour organoids and muscle cells and studied muscle function, physical activity, systemic inflammation, and chemotherapy efficacy in a mouse model of aggressive colorectal cancer (CRC). Methods Tumour‐bearing mice received a diet with or without SNC. Chemotherapy treatment consisted of oxaliplatin and 5‐fluorouracil. Tumour formation was monitored by calliper measurements. Physical activity was continuously monitored by infrared imaging. Ex vivo muscle performance was determined by myography, muscle fatty acid composition by gas chromatography, and plasma cytokine levels by Luminex xMAP technology. Patient‐derived CRC organoids and C2C12 myotubes were used to determine whether SNC affects chemotherapy sensitivity in vitro. Results Specific nutritional composition increased muscle contraction capacity of chemotherapy‐treated tumour‐bearing mice (P < 0.05) and enriched ω‐3 fatty acid composition in muscle without affecting treatment efficacy (P < 0.0001). Mice receiving SNC maintained physical activity after chemotherapy and showed decreased systemic inflammation. Therapeutic response of CRC organoids was unaffected by SNC nutrients, while cell viability and protein synthesis of muscle cells significantly improved. Conclusions The results show that specialized nutritional support can be used to maintain muscle function and physical activity levels during chemotherapy without increasing tumour viability. Therefore, nutritional strategies have potential value in promoting cancer and chemotherapy tolerance.

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“…The most abundant epoxy-fatty acid metabolites of 11,12-and 14,15-EET produced by the fibroblasts contained 16-carbons. Likewise, 16-carbon metabolites are the most abundant products that accumulate in the medium during the ␤-oxidation of 12-, and 15-hydroxyeicosatetraenoic acids (27,33), 11,12-DHET (27), arachidonic acid (29), and eicosapentaenoic acid (34). The 16-carbon products formed from each of these compounds contain…”

Section: Discussionmentioning

confidence: 99%

“…The lipids extracted from the medium and the hydrolyzed cell lipids were converted to pentafluorobenzyl (PFB) esters by incubation for 20 min at room temperature with 5 L PFB bromide in 10 L N,N-diisopropylethylamine and 50 L methylene chloride as described previously (34). The products were separated with a Hewlett-Packard 5890A gas-liquid chromatograph containing a 15 m ϫ 0.32 mm column coated with 0.1 m DB-1 ( J. W. Scientific, Rancho Cordova, CA) at a 2 mL/min helium flow rate.…”

Section: Identification Of Eet Metabolitesmentioning

confidence: 99%

Conversion of epoxyeicosatrienoic acids (EETs) to chain-shortened epoxy fatty acids by human skin fibroblasts

Fang

Kaduce

VanRollins

et al. 2000

Journal of Lipid Research

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Epoxyeicosatrienoic acids (EETs), the eicosanoid biomediators synthesized from arachidonic acid by cytochrome P450 epoxygenases, are inactivated in many tissues by conversion to dihydroxyeicosatrienoic acids (DHETs). However, we find that human skin fibroblasts convert EETs mostly to chain-shortened epoxy-fatty acids and produce only small amounts of DHETs. Comparative studies with [5,6,8,9,11,12,14,15-3 H]11,12-EET ([ 3 H]11,12-EET) and [1-14 C]11,12-EET demonstrated that chain-shortened metabolites are formed by removal of carbons from the carboxyl end of the EET. These metabolites accumulated primarily in the medium, but small amounts also were incorporated into the cell lipids. The most abundant 11,12-EET product was 7,8-epoxyhexadecadienoic acid (7,8-epoxy-16:2), and two of the others that were identified are 9,10-epoxyoctadecadienoic acid (9,10-epoxy-18:2) and 5,6-epoxytetradecaenoic acid (5,6-epoxy-14:1). The main epoxy-fatty acid produced from 14,15-EET was 10,11-epoxyhexadecadienoic acid (10,11-epoxy-16:2). [ 3 H]8,9-EET was converted to a single metabolite with the chromatographic properties of a 16-carbon epoxy-fatty acid, but we were not able to identify this compound. Large amounts of the chain-shortened 11,12-EET metabolites were produced by long-chain acyl CoA dehydrogenase-deficient fibroblasts but not by Zellweger syndrome and acyl CoA oxidase-deficient fibroblasts. We conclude that the chain-shortened epoxy-fatty acids are produced primarily by peroxisomal ␤ -oxidation. This may serve as an alternate mechanism for EET inactivation and removal from the tissues. However, it is possible that the epoxy-fatty acid products may have metabolic or functional effects and that the purpose of the ␤ -oxidation pathway is to generate these products. -Fang, X.

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Conversion of eicosapentaenoic acid to chain-shortened omega–3 fatty acid metabolites by peroxisomal oxidation

Cited by 27 publications

References 39 publications

Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids

Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids

Specialized nutrition improves muscle function and physical activity without affecting chemotherapy efficacy in C26 tumour‐bearing mice

Conversion of epoxyeicosatrienoic acids (EETs) to chain-shortened epoxy fatty acids by human skin fibroblasts

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