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Review

Minimizing Membrane Arachidonic Acid Content as a Strategy for Controlling Cancer: A Review

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Pages 840-850 | Received 13 Dec 2017, Accepted 27 Feb 2018, Published online: 01 Oct 2018

References

  • Wang D and DuBois RN: Eicosanoids and cancer. Nat Rev Cancer 10, 181–193, 2010.
  • Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, et al.: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376, 1741–1750, 2010.
  • Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, et al.: Effect of daily aspirin on long-term risk of death due to cancer: Analysis of individual patient data from randomised trials. Lancet 377, 31–41, 2011.
  • Algra AM and Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: A systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol 13, 518–527, 2012.
  • Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, et al.: Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: Analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 379, 1602–1612, 2012.
  • O'Callaghan G and Houston A: Prostaglandin E2 and the EP receptors in malignancy: Possible therapeutic targets? Br J Pharmacol 172, 5239–5250, 2015.
  • Fujino H: The roles of EP4 prostanoid receptors in cancer malignancy signaling. Biol Pharm Bull 39, 149–155, 2016.
  • Ruan D and So SP: Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo. Life Sci 116, 43–50, 2014.
  • Reader J, Holt D, and Fulton A: Prostaglandin E2 EP receptors as therapeutic targets in breast cancer. Cancer Metastasis Rev 30, 449–463, 2011.
  • Holt D, Ma X, Kundu N, and Fulton A: Prostaglandin E(2) (PGE (2)) suppresses natural killer cell function primarily through the PGE(2) receptor EP4. Cancer Immunol Immunother 60, 1577–1586, 2011.
  • Zhang Y and Daaka Y: PGE2 promotes angiogenesis through EP4 and PKA Cγ pathway. Blood 118, 5355–5364, 2011.
  • Bishayee K and Khuda-Bukhsh AR: 5-lipoxygenase antagonist therapy: A new approach towards targeted cancer chemotherapy. Acta Biochim Biophys Sin (Shanghai) 45, 709–719, 2013.
  • Ghosh J and Myers CE: Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci USA 95, 13182–13187, 1998.
  • Chen X, Wang S, Wu N, Sood S, Wang P, et al.: Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis. Clin Cancer Res 10, 6703–6709, 2004.
  • Poff CD and Balazy M: Drugs that target lipoxygenases and leukotrienes as emerging therapies for asthma and cancer. Curr Drug Targets Inflamm Allergy 3, 19–33, 2004.
  • Cianchi F, Cortesini C, Magnelli L, Fanti E, Papucci L, et al.: Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells. Mol Cancer Ther 5, 2716–2726, 2006.
  • Tong WG, Ding XZ, Talamonti MS, Bell RH, and Adrian TE: LTB4 stimulates growth of human pancreatic cancer cells via MAPK and PI-3 kinase pathways. Biochem Biophys Res Commun 335, 949–956, 2005.
  • Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, et al.: Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: A potential target for prevention. Carcinogenesis 26, 785–791, 2005.
  • Bachi AL, Kim FJ, Nonogaki S, Carneiro CR, Lopes JD, et al.: Leukotriene B4 creates a favorable microenvironment for murine melanoma growth. Mol Cancer Res 7, 1417–1424, 2009.
  • Faronato M, Muzzonigro G, Milanese G, Menna C, Bonfigli AR, et al.: Increased expression of 5-lipoxygenase is common in clear cell renal cell carcinoma. Histol Histopathol 22, 1109–1118, 2007.
  • Park SW, Heo DS, and Sung MW: The shunting of arachidonic acid metabolism to 5-lipoxygenase and cytochrome p450 epoxygenase antagonizes the anti-cancer effect of cyclooxygenase-2 inhibition in head and neck cancer cells. Cell Oncol (Dordr) 35, 1–8, 2012.
  • Steinhilber D, Fischer AS, Metzner J, Steinbrink SD, Roos J, et al.: 5-lipoxygenase: Underappreciated role of a pro-inflammatory enzyme in tumorigenesis. Front Pharmacol 1, 143, 2010.
  • Ishii K, Zaitsu M, Yonemitsu N, Kan Y, Hamasaki Y, et al.: 5-lipoxygenase pathway promotes cell proliferation in human glioma cell lines. Clin Neuropathol 28, 445–452, 2009.
  • Chatterjee M, Das S, Roy K, and Chatterjee M: Overexpression of 5-lipoxygenase and its relation with cell proliferation and angiogenesis in 7,12-dimethylbenz(alpha)anthracene-induced rat mammary carcinogenesis. Mol Carcinog 52, 359–369, 2013.
  • Knab LM, Schultz M, Principe DR, Mascarinas WE, Gounaris E, et al.: Ablation of 5-lipoxygenase mitigates pancreatic lesion development. J Surg Res 194, 481–487, 2015.
  • Hayashi T, Nishiyama K, and Shirahama T: Inhibition of 5-lipoxygenase pathway suppresses the growth of bladder cancer cells. Int J Urol 13, 1086–1091, 2006.
  • Shi HY, Lv FJ, Zhu ST, Wang QG, and Zhang ST: Dual inhibition of 5-LOX and COX-2 suppresses esophageal squamous cell carcinoma. Cancer Lett 309, 19–26, 2011.
  • Ye YN, Wu WK, Shin VY, Bruce IC, Wong BC, et al.: Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke. Carcinogenesis 26, 827–834, 2005.
  • Klil-Drori AJ and Ariel A: 15-Lipoxygenases in cancer: A double-edged sword? Prostaglandins Other Lipid Mediat 106, 16–22, 2013.
  • Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM, et al.: Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol 40–41, 48–81, 2016.
  • Chang HH and Meuillet EJ: Identification and development of mPGES-1 inhibitors: Where we are at? Future Med Chem 3, 1909–1934, 2011.
  • DiNicolantonio JJ, McCarty MF, Chatterjee S, Lavie CJ, and O'Keefe JH: A higher dietary ratio of long-chain omega-3 to total omega-6 fatty acids for prevention of COX-2-dependent adenocarcinomas. Nutr Cancer 66, 1279–1284, 2014.
  • Dong L, Zou H, Yuan C, Hong YH, Kuklev DV, et al.: Different fatty acids compete with arachidonic acid for binding to the allosteric or catalytic subunits of cyclooxygenases to regulate prostanoid synthesis. J Biol Chem 291, 4069–4078, 2016.
  • Vecchio AJ, Simmons DM, and Malkowski MG: Structural basis of fatty acid substrate binding to cyclooxygenase-2. J Biol Chem 285, 22152–22163, 2010.
  • Lands WE, Libelt B, Morris A, Kramer NC, Prewitt TE, et al.: Maintenance of lower proportions of (n - 6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n - 3) fatty acids. Biochim Biophys Acta 1180, 147–162, 1992.
  • Funahashi H, Satake M, Hasan S, Sawai H, Newman RA, et al.: Opposing effects of n-6 and n-3 polyunsaturated fatty acids on pancreatic cancer growth. Pancreas 36, 353–362, 2008.
  • Hawcroft G, Loadman PM, Belluzzi A, and Hull MA: Effect of eicosapentaenoic acid on E-type prostaglandin synthesis and EP4 receptor signaling in human colorectal cancer cells. Neoplasia 12, 618–627, 2010.
  • Yang P, Chan D, Felix E, Cartwright C, Menter DG, et al.: Formation and antiproliferative effect of prostaglandin E(3) from eicosapentaenoic acid in human lung cancer cells. J Lipid Res 45, 1030–1039, 2004.
  • Yang P, Cartwright C, Chan D, Ding J, Felix E, et al.: Anticancer activity of fish oils against human lung cancer is associated with changes in formation of PGE2 and PGE3 and alteration of Akt phosphorylation. Mol Carcinog 53, 566–577, 2014.
  • Yang P, Jiang Y, and Fischer SM: Prostaglandin E3 metabolism and cancer. Cancer Lett 348, 1–11, 2014.
  • Lee TH, Mencia-Huerta JM, Shih C, Corey EJ, Lewis RA, et al.: Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils. J Clin Invest 74, 1922–1933, 1984.
  • Kobayashi J, Yokoyama S, and Kitamura S: Eicosapentaenoic acid modulates arachidonic acid metabolism in rat alveolar macrophages. Prostaglandins Leukot Essent Fatty Acids 52, 259–262, 1995.
  • Xia S, Lu Y, Wang J, He C, Hong S, et al.: Melanoma growth is reduced in fat-1 transgenic mice: Impact of omega-6/omega-3 essential fatty acids. Proc Natl Acad Sci USA 103, 12499–12504, 2006.
  • Jia Q, Lupton JR, Smith R, Weeks BR, Callaway E, et al.: Reduced colitis-associated colon cancer in Fat-1 (n-3 fatty acid desaturase) transgenic mice. Cancer Res 68, 3985–3991, 2008.
  • Lu Y, Nie D, Witt WT, Chen Q, Shen M, et al.: Expression of the fat-1 gene diminishes prostate cancer growth in vivo through enhancing apoptosis and inhibiting GSK-3 beta phosphorylation. Mol Cancer Ther 7, 3203–3211, 2008.
  • Lim K, Han C, Dai Y, Shen M, and Wu T: Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2. Mol Cancer Ther 8, 3046–3055, 2009.
  • Griffitts J, Saunders D, Tesiram YA, Reid GE, Salih A, et al.: Non-mammalian fat-1 gene prevents neoplasia when introduced to a mouse hepatocarcinogenesis model: Omega-3 fatty acids prevent liver neoplasia. Biochim Biophys Acta 1801, 1133–1144, 2010.
  • Weylandt KH, Krause LF, Gomolka B, Chiu CY, Bilal S, et al.: Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-alpha. Carcinogenesis 32, 897–903, 2011.
  • Song KS, Jing K, Kim JS, Yun EJ, Shin S, et al.: Omega-3-polyunsaturated fatty acids suppress pancreatic cancer cell growth in vitro and in vivo via downregulation of Wnt/Beta-catenin signaling. Pancreatology 11, 574–584, 2011.
  • MacLennan MB, Clarke SE, Perez K, Wood GA, Muller WJ, et al.: Mammary tumor development is directly inhibited by lifelong n-3 polyunsaturated fatty acids. J Nutr Biochem 24, 388–395, 2013.
  • Algamas-Dimantov A, Yehuda-Shnaidman E, Hertz R, Peri I, Bar-Tana J, et al.: Prevention of diabetes-promoted colorectal cancer by (n-3) polyunsaturated fatty acids and (n-3) PUFA mimetic. Oncotarget 5, 9851–9863, 2014.
  • Yao L, Han C, Song K, Zhang J, Lim K, et al.: Omega-3 polyunsaturated fatty acids upregulate 15-PGDH expression in cholangiocarcinoma cells by inhibiting mir-26a/b expression. Cancer Res 75, 1388–1398, 2015.
  • Han YM, Park JM, Cha JY, Jeong M, Go EJ, et al.: Endogenous conversion of omega-6 to omega-3 polyunsaturated fatty acids in fat-1 mice attenuated intestinal polyposis by either inhibiting COX-2/beta-catenin signaling or activating 15-PGDH/IL-18. Int J Cancer 138, 2247–2256, 2016.
  • Zheng H, Tang H, Liu M, He M, Lai P, et al.: Inhibition of endometrial cancer by n-3 polyunsaturated fatty acids in preclinical models. Cancer Prev Res (Phila) 7, 824–834, 2014.
  • Chen Z, Zhang Y, Jia C, Wang Y, Lai P, et al.: mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression. Oncogene 33, 4548–4557, 2014.
  • Zou Z, Bellenger S, Massey KA, Nicolaou A, Geissler A, et al.: Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice. J Lipid Res 54, 3453–3463, 2013.
  • Zou Z, Bidu C, Bellenger S, Narce M, and Bellenger J: n-3 polyunsaturated fatty acids and HER2-positive breast cancer: Interest of the fat-1 transgenic mouse model over conventional dietary supplementation. Biochimie 96, 22–27, 2014.
  • Mohammed A, Janakiram NB, Brewer M, Duff A, Lightfoot S, et al.: Endogenous n-3 polyunsaturated fatty acids delay progression of pancreatic ductal adenocarcinoma in Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice. Neoplasia 14, 1249–1259, 2012.
  • Rahm JJ, and Holman RT: Effect of linoleic acid upon the metabolism of linolenic acid. J Nutr 84, 15–19, 1964.
  • Emken EA, Adlof RO, and Gulley RM: Dietary linoleic acid influences desaturation and acylation of deuterium-labeled linoleic and linolenic acids in young adult males. Biochim Biophys Acta 1213, 277–288, 1994.
  • Chorner Z, Barbeau PA, Castellani L, Wright DC, Chabowski A, et al.: Dietary alpha-linolenic acid supplementation alters skeletal muscle plasma membrane lipid composition, sarcolemmal FAT/CD36 abundance, and palmitate transport rates. Am J Physiol Regul Integr Comp Physiol 311, R1234–R1242, 2016.
  • Horrobin DF: Fatty acid metabolism in health and disease: The role of delta-6-desaturase. Am J Clin Nutr 57, 732S–736S, 1993.
  • Rett BS and Whelan J: Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: A systematic review. Nutr Metab (Lond) 8, 36, 2011.
  • Zhao A, Yu J, Lew JL, Huang L, Wright SD, et al.: Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. DNA Cell Biol 23, 519–526, 2004.
  • Hansen-Petrik MB, McEntee MF, Johnson BT, Obukowicz MG, Masferrer J, et al.: Selective inhibition of Delta-6 desaturase impedes intestinal tumorigenesis. Cancer Lett 175, 157–163, 2002.
  • He C, Qu X, Wan J, Rong R, Huang L, et al.: Inhibiting delta-6 desaturase activity suppresses tumor growth in mice. PLoS One 7, e47567, 2012.
  • Matsuzaka T, Shimano H, Yahagi N, Amemiya-Kudo M, Yoshikawa T, et al.: Dual regulation of mouse Delta(5)- and Delta(6)-desaturase gene expression by SREBP-1 and PPARalpha. J Lipid Res 43, 107–114, 2002.
  • Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, et al.: Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14, 2819–2830, 2000.
  • Cagen LM, Deng X, Wilcox HG, Park EA, Raghow R, et al.: Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements. Biochem J 385, 207–216, 2005.
  • Serviddio G, Blonda M, Bellanti F, Villani R, Iuliano L, et al.: Oxysterols and redox signaling in the pathogenesis of non-alcoholic fatty liver disease. Free Radic Res 47, 881–893, 2013.
  • Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, et al.: Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93, 693–704, 1998.
  • Peet DJ, Janowski BA, and Mangelsdorf DJ: The LXRs: A new class of oxysterol receptors. Curr Opin Genet Dev 8, 571–575, 1998.
  • Basciano H, Miller AE, Naples M, Baker C, Kohen R, et al.: Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis. Am J Physiol Endocrinol Metab 297, E462–E473, 2009.
  • Kim HJ, Miyazaki M, Man WC, and Ntambi JM: Sterol regulatory element-binding proteins (SREBPs) as regulators of lipid metabolism: Polyunsaturated fatty acids oppose cholesterol-mediated induction of SREBP-1 maturation. Ann N Y Acad Sci 967, 34–42, 2002.
  • Beltowski J: Liver X receptors (LXR) as therapeutic targets in dyslipidemia. Cardiovasc Ther 26, 297–316, 2008.
  • Edwards JE and Moore RA: Statins in hypercholesterolaemia: A dose-specific meta-analysis of lipid changes in randomised, double blind trials. BMC Fam Pract 4, 18, 2003.
  • Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, et al.: A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6, 517–526, 2000.
  • Brendel C, Schoonjans K, Botrugno OA, Treuter E, and Auwerx J: The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity. Mol Endocrinol 16, 2065–2076, 2002.
  • Seol W, Chung M, and Moore DD: Novel receptor interaction and repression domains in the orphan receptor SHP. Mol Cell Biol 17, 7126–7131, 1997.
  • Lee YS, Chanda D, Sim J, Park YY, and Choi HS: Structure and function of the atypical orphan nuclear receptor small heterodimer partner. Int Rev Cytol 261, 117–158, 2007.
  • Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, et al.: Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113, 1408–1418, 2004.
  • Hubbert ML, Zhang Y, Lee FY, and Edwards PA: Regulation of hepatic Insig-2 by the farnesoid X receptor. Mol Endocrinol 21, 1359–1369, 2007.
  • Yabe D, Brown MS, and Goldstein JL: Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci U S A 99, 12753–12758, 2002.
  • Kim HJ, Takahashi M, and Ezaki O: Fish oil feeding decreases mature sterol regulatory element-binding protein 1 (SREBP-1) by down-regulation of SREBP-1c mRNA in mouse liver. A possible mechanism for down-regulation of lipogenic enzyme mRNAs. J Biol Chem 274, 25892–25898, 1999.
  • Gani OA and Sylte I: Molecular recognition of docosahexaenoic acid by peroxisome proliferator-activated receptors and retinoid-X receptor alpha. J Mol Graph Model 27, 217–224, 2008.
  • Videla LA, Fernandez V, Vargas R, Cornejo P, Tapia G, et al.: Upregulation of rat liver PPARalpha-FGF21 signaling by a docosahexaenoic acid and thyroid hormone combined protocol. Biofactors 42, 638–646, 2016.
  • Zhu H, Fan C, Xu F, Tian C, Zhang F, et al.: Dietary fish oil n-3 polyunsaturated fatty acids and alpha-linolenic acid differently affect brain accretion of docosahexaenoic acid and expression of desaturases and sterol regulatory element-binding protein 1 in mice. J Nutr Biochem 21, 954–960, 2010.
  • Lamaziere A, Wolf C, Barbe U, Bausero P, and Visioli F: Lipidomics of hepatic lipogenesis inhibition by omega 3 fatty acids. Prostaglandins Leukot Essent Fatty Acids 88, 149–154, 2013.
  • Njoroge SW, Laposata M, Katrangi W, and Seegmiller AC: DHA and EPA reverse cystic fibrosis-related FA abnormalities by suppressing FA desaturase expression and activity. J Lipid Res 53, 257–265, 2012.
  • Gronn M, Christensen E, Hagve TA, and Christophersen BO: Effects of dietary purified eicosapentaenoic acid (20:5 (n-3)) and docosahexaenoic acid (22:6(n-3)) on fatty acid desaturation and oxidation in isolated rat liver cells. Biochim Biophys Acta 1125, 35–43, 1992.
  • Yap F, Craddock L, and Yang J: Mechanism of AMPK suppression of LXR-dependent Srebp-1c transcription. Int J Biol Sci 7, 645–650, 2011.
  • Sozio MS, Lu C, Zeng Y, Liangpunsakul S, and Crabb DW: Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells. Am J Physiol Gastrointest Liver Physiol 301, G739–G747, 2011.
  • Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, et al.: Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11, 554–565, 2010.
  • Hardie DG, Ross FA, and Hawley SA: AMP-activated protein kinase: A target for drugs both ancient and modern. Chem Biol 19, 1222–1236, 2012.
  • Gong J, Kelekar G, Shen J, Shen J, Kaur S, et al.: The expanding role of metformin in cancer: An update on antitumor mechanisms and clinical development. Target Oncol 11, 447–467, 2016.
  • Wang N, Tan HY, Li L, Yuen MF, and Feng Y: Berberine and coptidis rhizoma as potential anticancer agents: Recent updates and future perspectives. J Ethnopharmacol 176, 35–48, 2015.
  • Akhtar MS, Ramzan A, Ali A, and Ahmad M: Effect of Amla fruit (Emblica officinalis Gaertn.) on blood glucose and lipid profile of normal subjects and type 2 diabetic patients. Int J Food Sci Nutr 62, 609–616, 2011.
  • Antony B, Benny M, and Kaimal TN: A Pilot clinical study to evaluate the effect of Emblica officinalis extract (Amlamax) on markers of systemic inflammation and dyslipidemia. Indian J Clin Biochem 23, 378–381, 2008.
  • Yokozawa T, Kim HY, Kim HJ, Okubo T, Chu DC, et al.: Amla (Emblica officinalis Gaertn.) prevents dyslipidaemia and oxidative stress in the ageing process. Br J Nutr 97, 1187–1195, 2007.
  • Kim HY, Okubo T, Juneja LR, and Yokozawa T: The protective role of amla (Emblica officinalis Gaertn.) against fructose-induced metabolic syndrome in a rat model. Br J Nutr 103, 502–512, 2010.
  • Koshy SM, Bobby Z, Hariharan AP, and Gopalakrishna SM: Amla (Emblica officinalis) extract is effective in preventing high fructose diet-induced insulin resistance and atherogenic dyslipidemic profile in ovariectomized female albino rats. Menopause 19, 1146–1155, 2012.
  • Koshy SM, Bobby Z, Jacob SE, Ananthanarayanan PH, Sridhar MG, et al.: Amla prevents fructose-induced hepatic steatosis in ovariectomized rats: Role of liver FXR and LXRalpha. Climacteric 18, 299–310, 2015.
  • De A, De A, Papasian C, Hentges S, Banerjee S, et al.: Emblica officinalis extract induces autophagy and inhibits human ovarian cancer cell proliferation, angiogenesis, growth of mouse xenograft tumors. PLoS One 8, e72748, 2013.
  • Zhao T, Sun Q, Marques M, Witcher M: Anticancer Properties of Phyllanthus emblica (Indian Gooseberry). Oxid Med Cell Longev 2015, 950890, 2015.
  • Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, et al.: Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99, 11908–11913, 2002.
  • Kay HY, Kim WD, Hwang SJ, Choi HS, Gilroy RK, et al.: Nrf2 inhibits LXRalpha-dependent hepatic lipogenesis by competing with FXR for acetylase binding. Antioxid Redox Signal 15, 2135–2146, 2011.
  • Oh GS, Lee GG, Yoon J, Oh WK, and Kim SW: Selective inhibition of liver X receptor alpha-mediated lipogenesis in primary hepatocytes by licochalcone A. Chin Med 10, 8, 2015.
  • Yabe D, Komuro R, Liang G, Goldstein JL, and Brown MS: Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis. Proc Natl Acad Sci USA 100, 3155–3160, 2003.
  • Deng X, Yellaturu C, Cagen L, Wilcox HG, Park EA, et al.: Expression of the rat sterol regulatory element-binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1 (Sp1). J Biol Chem 282, 17517–17529, 2007.
  • Deng X, Zhang W, Sullivan I, Williams JB, Dong Q, et al.: FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 287, 20132–20143, 2012.
  • Olsen A, Christensen J, Knudsen KE, Johnsen NF, Overvad K, et al.: Prediagnostic plasma enterolactone levels and mortality among women with breast cancer. Breast Cancer Res Treat 128, 883–889, 2011.
  • Buck K, Vrieling A, Zaineddin AK, Becker S, Hüsing A, et al.: Serum enterolactone and prognosis of postmenopausal breast cancer. J Clin Oncol 29, 3730–3738, 2011.
  • Guglielmini P, Rubagotti A, and Boccardo F: Serum enterolactone levels and mortality outcome in women with early breast cancer: A retrospective cohort study. Breast Cancer Res Treat 132, 661–668, 2012.
  • Seibold P, Vrieling A, Johnson TS, Buck K, Behrens S, et al.: Enterolactone concentrations and prognosis after postmenopausal breast cancer: Assessment of effect modification and meta-analysis. Int J Cancer 135, 923–933, 2014.
  • Wang L, Chen J, and Thompson LU: The inhibitory effect of flaxseed on the growth and metastasis of estrogen receptor negative human breast cancer xenograftsis attributed to both its lignan and oil components. Int J Cancer 116, 793–798, 2005.
  • Thompson LU, Chen JM, Li T, Strasser-Weippl K, and Goss PE: Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res 11, 3828–3835, 2005.
  • Chen J, Wang L, and Thompson LU: Flaxseed and its components reduce metastasis after surgical excision of solid human breast tumor in nude mice. Cancer Lett 234, 168–175, 2006.
  • Bergman JM, Thompson LU, and Dabrosin C: Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo. Clin Cancer Res 13, 1061–1067, 2007.
  • Chen J, Saggar JK, Corey P, and Thompson LU: Flaxseed and pure secoisolariciresinol diglucoside, but not flaxseed hull, reduce human breast tumor growth (MCF-7) in athymic mice. J Nutr 139, 2061–2066, 2009.
  • Saggar JK, Chen J, Corey P, and Thompson LU: The effect of secoisolariciresinol diglucoside and flaxseed oil, alone and in combination, on MCF-7 tumor growth and signaling pathways. Nutr Cancer 62, 533–542, 2010.
  • Mabrok HB, Klopfleisch R, Ghanem KZ, Clavel T, Blaut M, et al.: Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer. Carcinogenesis 33, 203–208, 2012.
  • Chen J, Stavro PM, and Thompson LU: Dietary flaxseed inhibits human breast cancer growth and metastasis and downregulates expression of insulin-like growth factor and epidermal growth factor receptor. Nutr Cancer 43, 187–192, 2002.
  • Truan JS, Chen JM, and Thompson LU: Flaxseed oil reduces the growth of human breast tumors (MCF-7) at high levels of circulating estrogen. Mol Nutr Food Res 54, 1414–1421, 2010.
  • Lowcock EC, Cotterchio M, and Boucher BA: Consumption of flaxseed, a rich source of lignans, is associated with reduced breast cancer risk. Cancer Causes Control 24, 813–816, 2013.
  • Demark-Wahnefried W, Polascik TJ, George SL, Switzer BR, Madden JF, et al.: Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery. Cancer Epidemiol Biomarkers Prev 17, 3577–3587, 2008.
  • Azrad M, Vollmer RT, Madden J, Dewhirst M, Polascik TJ, et al.: Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer. J Med Food 16, 357–360, 2013.
  • Lin X, Gingrich JR, Bao W, Li J, Haroon ZA, et al.: Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice. Urology 60, 919–924, 2002.
  • Park SY, Murphy SP, Wilkens LR, Henderson BE, and Kolonel LN: Fat and meat intake and prostate cancer risk: The multiethnic cohort study. Int J Cancer 121, 1339–1345, 2007.
  • Fu YQ, Zheng JS, Yang B, and Li D: Effect of individual omega-3 fatty acids on the risk of prostate cancer: A systematic review and dose-response meta-analysis of prospective cohort studies. J Epidemiol 25, 261–274, 2015.
  • Giordano C, Catalano S, Panza S, Vizza D, Barone I, et al.: Farnesoid X receptor inhibits tamoxifen-resistant MCF-7 breast cancer cell growth through downregulation of HER2 expression. Oncogene 30, 4129–4140, 2011.
  • Menendez JA, Vazquez-Martin A, Ropero S, Colomer R, and Lupu R: HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated fatty acid, alpha-linolenic acid (ALA; 18:3n-3), in breast cancer cells: The "fat features" of the "Mediterranean diet" as an "anti-HER2 cocktail". Clin Transl Oncol 8, 812–820, 2006.
  • Mason JK, Chen J, and Thompson LU: Flaxseed oil-trastuzumab interaction in breast cancer. Food Chem Toxicol 48, 2223–2226, 2010.
  • Mason JK, Fu M, Chen J, and Thompson LU: Flaxseed oil enhances the effectiveness of trastuzumab in reducing the growth of HER2-overexpressing human breast tumors (BT-474). J Nutr Biochem 26, 16–23, 2015.
  • Liu J, Tong SJ, Wang X, and Qu LX: Farnesoid X receptor inhibits LNcaP cell proliferation via the upregulation of PTEN. Exp Ther Med 8, 1209–1212, 2014.
  • Ghosh-Choudhury T, Mandal CC, Woodruff K, St Clair P, Fernandes G, et al.: Fish oil targets PTEN to regulate NFkappaB for downregulation of anti-apoptotic genes in breast tumor growth. Breast Cancer Res Treat 118, 213–228, 2009.
  • Sayanova O and Napier JA: Transgenic oilseed crops as an alternative to fish oils. Prostaglandins Leukot Essent Fatty Acids 85, 253–260, 2011.
  • Petrie JR, Shrestha P, Zhou XR, Mansour MP, Liu Q, et al.: Metabolic engineering plant seeds with fish oil-like levels of DHA. PLoS One 7, e49165, 2012.
  • Mansour MP, Shrestha P, Belide S, Petrie JR, Nichols PD, et al.: Characterization of oilseed lipids from "DHA-producing Camelina sativa": A new transformed land plant containing long-chain omega-3 oils. Nutrients 6, 776–789, 2014.
  • Ruiz-Lopez N, Haslam RP, Napier JA, and Sayanova O: Successful high-level accumulation of fish oil omega-3 long-chain polyunsaturated fatty acids in a transgenic oilseed crop. Plant J 77, 198–208, 2014.
  • Tejera N, Vauzour D, Betancor MB, Sayanova O, Usher S, et al.: A transgenic camelina sativa seed oil effectively replaces fish oil as a dietary source of eicosapentaenoic acid in mice. J Nutr 146, 227–235, 2016.
  • Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, et al.: Metformin and cancer risk and mortality: A systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila) 7, 867–885, 2014.
  • Azrad M, Zhang K, Vollmer RT, Madden J, Polascik TJ, et al.: Prostatic alpha-linolenic acid (ALA) is positively associated with aggressive prostate cancer: A relationship which may depend on genetic variation in ALA metabolism. PLoS One 7, e53104, 2012.
  • Winnik S, Lohmann C, Richter EK, Schäfer N, Song WL, et al.: Dietary alpha-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation. Eur Heart J 32, 2573–2584, 2011.
  • Fukumitsu S, Aida K, Ueno N, Ozawa S, Takahashi Y, et al.: Flaxseed lignan attenuates high-fat diet-induced fat accumulation and induces adiponectin expression in mice. Br J Nutr 100, 669–676, 2008.
  • Dupasquier CM, Dibrov E, Kneesh AL, Cheung PK, Lee KG, et al.: Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions. Am J Physiol Heart Circ Physiol 293, H2394–H2402, 2007.
  • Yamashita T, Oda E, Sano T, Yamashita T, Ijiru Y, et al.: Varying the ratio of dietary n-6/n-3 polyunsaturated fatty acid alters the tendency to thrombosis and progress of atherosclerosis in apoE-/- LDLR-/- double knockout mouse. Thromb Res 116, 393–401, 2005.
  • Hageman J, Herrema H, Groen AK, and Kuipers F: A role of the bile salt receptor FXR in atherosclerosis. Arterioscler Thromb Vasc Biol 30, 1519–1528, 2010.
  • Mencarelli A and Fiorucci S: FXR an emerging therapeutic target for the treatment of f atherosclerosis. J Cell Mol Med 14, 79–92, 2010.
  • Hartman HB, Gardell SJ, Petucci CJ, Wang S, Krueger JA, et al.: Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice. J Lipid Res 50, 1090–1100, 2009.
  • Zhang J, Grieger JA, Kris-Etherton PM, Thompson JT, Gillies PJ, et al.: Walnut oil increases cholesterol efflux through inhibition of stearoyl CoA desaturase 1 in THP-1 macrophage-derived foam cells. Nutr Metab (Lond) 8, 61, 2011.
  • Prasad K and adhav A: Prevention and treatment of atherosclerosis with flaxseed-derived compound secoisolariciresinol diglucoside. Curr Pharm Des 22, 214–220, 2015.
  • Prasad K: Regression of hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglucoside isolated from flaxseed. Atherosclerosis 197, 34–42, 2008.
  • Fischer S and Weber PC: Prostaglandin I3 is formed in vivo in man after dietary eicosapentaenoic acid. Nature 307, 165–168, 1984.
  • Kobzar G, Mardla V, Jarving I, and Samel N: Comparison of anti-aggregatory effects of PGI2, PGI3 and iloprost on human and rabbit platelets. Cell Physiol Biochem 11, 279–284, 2001.
  • Ruan CH, So SP, and Ruan KH: Inducible COX-2 dominates over COX-1 in prostacyclin biosynthesis: Mechanisms of COX-2 inhibitor risk to heart disease. Life Sci 88, 24–30, 2011.
  • Funk CD and FitzGerald GA: COX-2 inhibitors and cardiovascular risk. J Cardiovasc Pharmacol 50, 470–479, 2007.
  • Goyal A, Sharma V, Upadhyay N, Gill S, and Sihag M: Flax and flaxseed oil: An ancient medicine & modern functional food. J Food Sci Technol 51, 1633–1653, 2014.

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