Epoxyeicosatrienoic acid

Chemical structure of 14,15-epoxyeicosatrienoic acid.

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases.[1] These nonclassic eicosanoids are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, Soluble epoxide hydrolase (sEH, also termed Epoxide hydrolase 2). The EETs consequently often function as transiently acting, short-range hormones; that is, they work locally to regulate the function of the cells that produce them (i.e. they are autocrine agents) or of nearby cells (i.e. they are paracrine agents). The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by stimulating arterial vasorelaxation and inhibit the kidney's retention of salts and water. In these models, EETs also prevent arterial occlusive diseases such as heart attack and strokes possibly by their anti-inflammatory, pro-fibrinolytic, and anti-hypertensive actions.[2] With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various cardiovascular diseases, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of neuropathic pain. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETS in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.

Structure

EETS are epoxide eicosatrienoic acid metabolites of the straight chain Eicosatetraenoic acid, arachidonic acid. Arachidonic acid has 4 cis (see Cis–trans isomerism; the cis configureation is termed Z in the IUPAC Chemical nomenclature used here) Double bonds located between carbons 5-6, 8-9, 11-12, and 14-15. It is therefore 5Z,8Z,11Z,14Z-eicosatetraenoic acid. Cytochrome P450 epoxygenases attack these double bounds to form their respective eicosatrienoic acid epoxide regioisomers (see Structural isomer, section on position isomerism (regioisomerism)) viz., 5,6-EET (i.e. 5,6-epoxy-8Z,11Z,14Z-eicosatetrienoic acid), 8,9-EET (i.e. 5,6-epoxy-8Z,11Z,14Z-eicosatetrienoic acid), 11,12-EET (i.e. 11,12-epoxy-5Z,8Z,14Z-eicosatetrienoic acid), or, as drawn in the attached figure, 14,15-EET (i.e. 14,15-epoxy-5Z,8Z,11Z-eicosatetrainoic acid) . The enzymes generally form both R/S enantiomers at each former double bound position; for example, cytochrome P450 epoxidases metabolize arachidonic acid to a mixture of 14R,15S-ETE and 14S,15R-ETE.[3]

Production

The cytochrome P450 (CYP) superfamily of enzymes is distributed broadly throughout bacteria, archaea, fungi, plants, animals, and even viruses (see Cytochrome P450). The superfamily comprises more than 11,000 genes categorized into 1,000 families. Humans have 57 putatively active CYP genes and 58 CYP pseudogenes; only a relatively few of the active CYP genes code for EET-forming epoxygenases, i.e. protein enzymes with the capacity to attach atomic oxygen (see Allotropes of oxygen#Atomic oxygen) to the carbon-carbon double bonds of unsaturated long chain fatty acids such as arachidonic acid.[4][5] The CYP epoxygenases fall into several subfamilies including CYP1A, CYP2B, CYP2C, CYP2E, CYP2J, and within the CYP3A sub family, CYP3A4; in humans, CYP2C8, CYP2C9, CYP2C19, CYP2J2, and CYP231 isoforms are the main producers of EETs.[3][4][6] The CYP epoxygenases can epoxidize any of the double bounds in arachidonic acid but most of them are relatively selective in that they make appreciable amounts of only one or two EETs with 11,12-EET and 14,15-EET accounting for 67%-80% of the product made by the cited CYP epoxidases as well as the main EETs made by mammalian tissues.[3] CYP2C9, CYP2JP, and possibly the more recently characterized CYP2S1 appear to be the main produces of the EETs in humans with CYPP2C9 being the main EET producer in vascular endothelial cells and CYP2JP being highly expressed (although less catalytically active than CYP2C) in heart muscle, kidneys, pancreas, lung, and brain.[7] CYP2S1 is expressed in macrophages, liver, lung, intestine, and spleen and is abundant in human and mouse atherosclerosis (i.e. Atheroma) plaques as well as inflamed tonsils.[5]

ETEs are commonly produced by the stimulation of specific cell types. The stimulation causes arachidonic acid to be released form the sn-2 position of cellular phospholipids through the action of Phospholipase A2-type enzymes and subsequent attack of the released arachidonic acid by a CYP epoxidase.[3] In a typical example of this mechanism, bradykinin or acetylcholine acting through their respective Bradykinin receptor B2 and muscarinic acetylcholine receptor M1 or muscarinic acetylcholine receptor M3 stimulate vascular endothelial cells to make and release EETs.[7]

EET metabolism

In cells, the EETs are rapidly metabolized by a cytosolic soluble epoxide hydrolase (sEH) to form their corresponding Vicinal (chemistry) diol dihydroxyeicosatrienoic acids (diHETrEs), i.e. sEH converts 14,15-ETE to 14,15-dihydroxy-eicosatrienoic acid (14,15-diHETrE), 11,12-ETE to 11,12-diHETrE, 8,9-ETE to 8,9-diHETrE, and 5,6-ETE to 5,6-diHETrE.[8] The product diHETrEs, like their epoxy precursors, are enantiomer mixtures; for instance, sEH converts 14,15-ETE to a mixture of 14(S),15(R)-diHETrE and 14(R),15(S)-diHETrE.[3] Since the diHETrE products are generally far less active than their epoxide precursors, the sEH pathway of EET metabolism is regarded as a critical EET-inactivating pathway.[8][9]

In addition to the sEH pathway, EETs may be acylated into phospholipids in an Acylation-like reaction. This pathway may serve to limit the action of EETs or store them for future release.[3]

Biological effects

Generally, EETs cause:

Other effects are specific to certain cells or locations:

Clinical significance

Regulation of blood pressure

With respect to the regulation of blood pressure as well as the kidneys' regulation of salt and water absorption (which contributes to blood pressure regulation), EETS are counterpoises to another CYP-derived arachidonic acid metabolite, 20-Hydroxyeicosatetraenoic acid (20-HETE). In humans, the major CYPs making 20-HETE are CYP4A11, CYP4F2, and CYP4F3. In animal models, 20-HETE raises blood pressure by contracting arteries and stimulating the kidney to reabsorb salt and water to increase the intravascular volume (see 20-Hydroxyeicosatetraenoic acid). EETs have the opposite effects. They are one type of Endothelium-Derived Hyperpolarizing Factor, i.e. a substance and/or electrical signal synthesized or generated in and released from the vascular endothelium that hyperpolarize nearby vascular smooth muscle cells. This causes these cells to relax and thereby lowers blood pressure. In animal (primarily rodent) models, EETs dilate smaller sized resistance arteries involved in causing hypertension as well as cardiac and renal arteries. They cause smooth muscle hyperpolarization by opening vascular smooth muscle large-conductance calcium-activated potassium channels, opening certain vascular smooth muscle transient receptor potential channels, or facilitating the movement of excitatory signals through gap junctions between endothelium and smooth muscles or between smooth muscles.[5][7] The actual mechanism(s) involved in these EET-induced effects have not been fully elucidated although some studies implicate EET binding to an unidentified Cell surface receptor and/or Gs protein-linked G protein–coupled receptor to initiate the signal pathway(s) leading to the cited channel and gap junction changes.[5][7] With respect to the kidney, studies in rodents find that 20-HETE increases sodium and water reabsorption while the EETs, which are made in the proximal tubules and cortical collecting ducts, reduce sodium ion and water transport at both sites by inhibiting kidney Sodium–hydrogen antiporter (i.e. Na+/H+ exchanger) and/or Epithelial sodium channels.[14] Mice lacking either of the EET-producing Cyp2c44 or Cyp4ac44 genes (by gene knockout) develop hypertension when fed high sodium or high potassium diets.[14] These and large number of other studies included in the cited references implicate the EETs in the control of at least certain forms of hypertension in rodents.

In humans, vascular endothelium production of EETs involves mainly CYP2C9 and numerous indirect studies have implicated CYP epoxygenase, possibly CYP2C9, in producing a product which causes vasodilation. These studies find that selective (but not entirely specific) CYP epoxygenase-inhibiting drugs reduce human vasodilation responses elicited by the vasodilators bradykinin, acetylcholine, and methacholine; this suggests that these vasodilators operate by stimulation the production of EETs. Human studies also find that Caucasian but not African American subjects who have the Lys55Arg single nucleotide polymorphism variant in the polyunsaturated fatty epoxide-inactivating enzyme, sEH, express hyperactive sEH and show reduced vasodilation responses to bradykinin. Other studies find that women with pregnancy-induced hypertension and subjects with Renovascular hypertension exhibit low plasma ETE levels.[7] Finally, 11,12-EET has been shown to relax the internal mammary artery in women, indicating that at least this EET has direct vasodilating actions in humans.[15] On the other hand, several studies in humans with single nucleotide polymorphism in CYP epxoygenase genes have given negative or confusing results. The most common variant of CYP2J2, rs890293,[16] has a -50G>T nucleotide variation at a upstream promoter region which is activated by the Sp1 transcription factor; this variant epoxygenase shows a 50% reduction in the expression of CYP2J2 as defined by in vitro assays and subjects which this variant exhibit significant reductions in plasma levels of EETs. However, bearers of this variant have no or contradictory relationships to blood pressure abnormalities in several studies;[17] similarly contradictive or negative results are reported in studies on the rs11572082 (Arg1391Lys)[18] variant of CYP2C8 and the rs1799853 (Arg144Cys)[19] and rs1057910 (Ile359Leu)[20] variants of CYP2C9, all of which code for an epoxygenase with reduced arachidonic acid-metabolizing and EET-forming activities.[21]

While many of the cited studies suggest that one or more of the EETs released by vascular endothelial cells are responsible for the actions of the vasodilators and that deficiencies in EET production or excessive EET inactivation by sEH underlie certain types of hypertension in humans, they are not conclusive. They do not exclude a possibility that other polyunsaturated fatty acid epoxides such as those derived from eicosatetraenoic, docosatetraenoic, or linoleic acids made by CYP2C9 or other CYP epoxygenases (see epoxygenase) contribute in small or large part to vasodilation responses and by this action promote blood flow to tissues and function in lowering high blood pressures. Furthermore, the genetic studies conducted to date on SNP variants do not give strong support for an antihypertensive role for the EETs or EET-forming epoxygenases in humans. Recently developed drugs which are metabolically stable analogs of the EETs and thereby mimic the EETs actions or, alternatively of drugs which inhibit sEH and thereby increase EET levels are in the Pre-clinical development stage for treating human hypertension.[22] Testing for their usefulness in treating human hypertension is made difficult because of: 1) the large number of CYP epoxygenases along with their differing tissue distributions and sensitivities to drug inhibitors; 2) the diversity of EETs made by the CYP epoxygenases, some of which differ in activities; 3) the diversity of fatty acid substrates metabolized by the CYP epoxygenases some of which are converted to epoxides (e.g. the epoxide metabolites of linoleic, docosahexaenoic, eicosapentaenoic acids) with have different activities than the EETs or may even be overtly toxic to humans (see Coronaric acid); 4) the sEH-derived dihydroxy metabolites of the EETs some of which have potent vasodilating effects in the certain vascular networks in rodents and therefore potentially in humans; and 5) the non-specificity and side effects of the latter drugs.[23][24][25]

As indicated on the ClinicalTrials.gov web sit, an National Institutes of Health-sponsored clinical trial entitled "Evaluation of Soluble Epoxide Hydrolase (s-EH) Inhibitor in Patients With Mild to Moderate Hypertension and Impaired Glucose Tolerance" has not been completed or reported on although started in 2009.[26]

Heart disease

As indicated elsewhere on this page, EETs inhibit inflammation, inhibit blood clot formation, inhibit platelet activation, dilate blood vessels including the coronary arteries, reduce certain types of hypertension, stimulate the survival of vascular endothelial and cardiac muscle cells by inhibiting apoptosis, promote blood vessel growth (i.e. angiogenesis), and stimulate smooth muscle cell migration; these activities may protect the heart. Indeed, studies on in vivo animal and in vitro animal and human cell model systems indicate that the ETEs reduce infarct (i.e. injured tissue]] size, reduce cardiac arrhythmias, and improve the strength of left ventricle contraction immediately after blockade of coronary artery blood flow in animal models of ischemia-reperfusion injury; EETs also reduce the size of heart enlargement that occurs long after these experiment-induced injuries.[27]

Humans with established coronary artery disease have higher levels of plasma EETs and higher ratios of 14,15-EET to 14,15-diHETrE (14,15-diHETrE is the less active or inactive metabolite 14,15-EET). This suggests that the EETs serve a protective role in this setting and that these plasma changes were a result of a reduction in cardiac sEH activity. Furthermore, coronary artery disease patients who had lower levels of EETs/14,15-di-ETE ratios exhibited evidence of a poorer prognosis based on the presence of poor prognostic indicators, cigarette smoking, obesity, old age, and elevation in inflammation markers.[27][28]

Portal hypertension

Portal hypertension or hypertension in the venous hepatic portal system of blood flow is defined as an increase in portal pressure above normal values of 10 Millimeter of mercury.[29] It is a serious, sometimes life-threatening complication of various diseases such as liver cirrhosis, liver fibrosis, massive Fatty liver, portal vein thrombosis, liver schistosomiasis, massive liver involvement in miliary tuberculosis or sarcoidosis, and obstruction of the venous circuit at any level between liver and right heart (see Portal hypertension). Vascular contraction in the portal system is mediated by several agents: nitric oxide, carbon monoxide, prostacyclin I2, and Endothelium-derived hyperpolarizing factors (EDHFs). EDHFs include endothelin, angiotensin II, thromboxane A2, certain leukotrienes, and the EETs. In portal hypertension, portal vein endothelium appears to be dysfunctional in that it overproduces EDHFs.[30] The EETs, particularly 11,12-EET, have a quite different effect on the Liver sinusoidal veins than on arteries of the systemic circulation: they constrict the sinusoids.[31] Levels of EETs in the plasma and liver of patients with cirrhosis and portal hypertension are reportedly elevated compared to normal subjects.[29][30][32] These and other findings have lead to the proposal that portal endothelium-derived EETs, perhaps acting in cooperation with another EDHF, endothelin, contribute to portal hypertension.[29][33]

Cancer

The forced over-expression of CYP2J2 in and/or the addition of an EET to cultured human Tca-8113 oral squamous cancer cells, lung cancer A549 cells and NCL-H446 cells, HepG2 liver cancer cells, LS-174 colon cancer cells, SiHa uterine cervix cancer cells, U251 glioblastoma cancer cells, ScaBER urinary bladder cancer cells, and K562 erythroleukemia and HL-60 promyelocyte leukemic blood cancer cells caused an increase in their survival and proliferation.[34][35] Putative inhibitors of CYP2J2 inhibit the growth in culture of several human cancer cell lines that express relatively high levels of CYP2J2 viz., Tca-8113 cells, HeLa uterine cervix cell lines, A549 cells, MDA-MB-435-239 breast cells, and HepG2 cells but they had no significant inhibitory effects on two cell lines that expressed little or no CYP2J2.[36] A putative inhibitor of CYPJ2 also inhibited the growth of human K562 erythroleukemia in an Severe combined immunodeficiency (non-human)#mice model as well as the growth of mouse el4 lymphoma cells in mice that were forced to overexpress CYP2J2 cells in their vascular epithelium. Forced expression of CYP2J2 also enhanced, while forced inhibition of its expression (using Small interfering RNA) reduced, the survival, growth, and metastasis of MDA-MB-231 human breast carcinoma cells in the mouse model and likewise enhanced or reduced, respectively, the survival and growth of these cells in culture.[37] Further studies found that the expression of CYP2J2 was in increased in the malignant cells, relative to the nearby normal cells, in the following specimens taken from humans suffering Squamous-cell carcinoma and adenocarcinoma types of Esophageal cancer and lung cancer, small cell lung carcinoma, breast cancer, stomach cancer, liver cancer, and colon adenocarcinoma; this CYP was also highly expressed in the malignant cells of patients with acute leukemia, chronic leukemia, and lymphoma.[38] As a group, patients with these cancers exhibited increased levels of EETs in their urine and blood samples.[38]

Studies of the CYP epoxygenases have not been restricted to the CYP2J subfamily. Reduction in the expression of CYP3A4 or CYP2C using small interfering RNA inhibits the growth of cultured MCF7, T47D, and MDA-MB-231 human breast cancer cells; in these studies 14,15-EET stimulated the proliferation of cultured MCF7 cells, reduction in the expression of CYP3A4 by small interference RNA methods, inhibited these cells from proliferating, and 14,15-ETE reversed the effect of CYP3A4 interference; in other studies, the forced overexpression of CYP3A4 stimulated the growth of human liver cancer (hepatoma) cell line, Hep3 .[39][40] In human breast cancer, not only CYP2J2 but also CYP2C8 and CYP2C9 levels appear elevated while sEH levels appear reduced in malignant compared to nearby normal tissues; associated with this finding, the levels of 14,15-EET as well as the levels of 14,15-EET plus 14,15-dihydroxy-EET were significantly elevated in the cancerous compared to noncancerous cells and the levels of CYP2C8 and CYP2C9 proteins correlated positively and sEH levels correlated negatively with the tumor cells rate of proliferation as accessed by their Ki67 levels while CYP2J2 levels correlated positively with poorer prognosis as predicted tumor histological grade and tumor size.[41]

The cited findings suggest that various CYP epoxygenases along with the epoxide metabolites which they make promote the growth and spread of diverse types of cancer in animals and humans. Their effects may reflect the ability of the epoxide metabolites to stimulate the proliferation and survival of the target cancer cells but perhaps also to stimulate these cells to trigger new capillary formation (see angiogenesis#Tumor angiogenesis), invade new tissues, and metastasize.[5][42][43] A series of drugs derived from Terfenadine have been shown to inhibit CYP2J2 and to suppress the proliferation and cause the apoptosis of various types of human cancer cell lines in culture as well as in animal models.[44] However, clinical studies targeting CYP epoxygenases and EETs and to successfully suppress cancer in humans have not been reported.

Inflammation

Studies indicate that the EETs possess anti-inflammatory activity that is directed toward reducing or blocking the inflammation that occurs in blood vessels. They do so by limiting blood-born leukocytes from adhering to blood vessel endothelium and thereby from migrating across this endothelium into blood vessel walls; by inhibiting platelet aggregation and thereby thrombus (i.e. blood clot) formation; by promoting fibrinolysis and thereby dissolving blood clots; and by inhibiting vascular smooth muscle cell proliferation and thereby reducing blood vessel hypertrophy and narrowing.[45]

References

  1. 1 2 3 4 5 6 7 8 9 10 Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 108. ISBN 1-4160-2328-3.
  2. ↑ Spector AA, Fang X, Snyder GD, Weintraub NL (January 2004). "Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function". Prog Lipid Res 43 (1): 55–90. doi:10.1016/S0163-7827(03)00049-3. PMID 14636671.
  3. 1 2 3 4 5 6 Biochim Biophys Acta. 2015 Apr;1851(4):356-65. doi: 10.1016/j.bbalip.2014.07.020. Epub 2014 Aug 2. Review.PMID 25093613
  4. 1 2 Pharmacol Ther. 2014 Nov;144(2):134-61. doi: 10.1016/j.pharmthera.2014.05.011. Epub 2014 Jun 2. Review.PMID 24882266
  5. 1 2 3 4 5 Pharmacol Rev. 2014 Oct;66(4):1106-40. doi: 10.1124/pr.113.007781. Review.PMID 25244930
  6. ↑ Cancer Metastasis Rev. 2011 Dec;30(3-4):525-40. doi: 10.1007/s10555-011-9315-y. Review.
  7. 1 2 3 4 5 Br J Clin Pharmacol. 2015 Jul;80(1):28-44. doi: 10.1111/bcp.12603. Epub 2015 Jun 1.PMID 25655310
  8. 1 2 Gene. 2013 Sep 10;526(2):61-74. doi: 10.1016/j.gene.2013.05.008. Epub 2013 May 20. Review.PMID 23701967
  9. ↑ J Cardiovasc Pharmacol. 2013 Mar;61(3):188-96. doi: 10.1097/FJC.0b013e318273b007. Review.PMID 23011468
  10. ↑ Nithipatikom K, Moore JM, Isbell MA, Falck JR, Gross GJ (August 2006). "Epoxyeicosatrienoic acids in cardioprotection: ischemic versus reperfusion injury". Am. J. Physiol. Heart Circ. Physiol. 291 (2): H537–42. doi:10.1152/ajpheart.00071.2006. PMID 16473964.
  11. ↑ Jin L, Foss CE, Zhao X; et al. (March 2006). "Cytochrome P450 epoxygenases provide a novel mechanism for penile erection". FASEB J. 20 (3): 539–41. doi:10.1096/fj.05-4341fje. PMID 16415108.
  12. ↑ Ng VY, Huang Y, Reddy LM, Falck JR, Lin ET, Kroetz DL (July 2007). "Cytochrome P450 eicosanoids are activators of peroxisome proliferator-activated receptor alpha". Drug Metab Dispos 37 (7): 1126–34. doi:10.1124/dmd.106.013839. PMID 17431031.
  13. ↑ Prostaglandins Other Lipid Mediat. 2003 Oct;72(1-2):51-71. Review.PMID 14626496
  14. 1 2 Curr Opin Nephrol Hypertens. 2015 Jan;24(1):37-46. doi: 10.1097/MNH.0000000000000088. Review.PMID 25427230
  15. ↑ Br J Clin Pharmacol. 2015 Jul;80(1):28-44. doi:10.1111/bcp.12603. Epub 2015 Jun 1.PMID 25655310
  16. ↑ https://www.pharmgkb.org/rsid/rs890293?tabType=tabVip
  17. ↑ J Cardiovasc Pharmacol. 2013 Mar;61(3):188-96. doi: 10.1097/FJC.0b013e318273b007. Review.PMID 23011468
  18. ↑ https://www.pharmgkb.org/variant/rs11572082
  19. ↑ https://www.pharmgkb.org/variant/rs1799853?previousQuery=rs1799853
  20. ↑ https://www.pharmgkb.org/variant/rs1057910?previousQuery=rs1057910
  21. ↑ Prostaglandins Other Lipid Mediat. 2012 Aug;98(3-4):75-85. doi: 10.1016/j.prostaglandins.2011.11.007. Epub 2011 Nov 30. Review
  22. ↑ J Cardiovasc Pharmacol. 2013 Mar;61(3):188-96. doi: 10.1097/FJC.0b013e318273b007. Review.PMID: 23011468
  23. ↑ Biochim Biophys Acta. 2011 Jan;1814(1):210-22. doi: 10.1016/j.bbapap.2010.09.009. Epub 2010 Sep 30.PMID 20869469
  24. ↑ J Cardiovasc Pharmacol. 2013 Mar;61(3):188-96. doi: 10.1097/FJC.0b013e318273b007. Review.PMID 23011468
  25. ↑ Br J Clin Pharmacol. 2015 Dec 1. doi: 10.1111/bcp.12855. [Epub ahead of print]PMID 26620151
  26. ↑ https://clinicaltrials.gov/ct2/archive/NCT00847899
  27. 1 2 J Mol Cell Cardiol. 2014 Sep;74:199-208. doi: 10.1016/j.yjmcc.2014.05.016. Epub 2014 Jun 2. Review.PMID 24893205
  28. ↑ Front Pharmacol. 2014 Nov 10;5:239. doi: 10.3389/fphar.2014.00239. eCollection 2014. Review.PMID 25426071
  29. 1 2 3 Prostaglandins Other Lipid Mediat. 2015 Jul;120:80-90. doi: 10.1016/j.prostaglandins.2015.05.008. Epub 2015 Jun 11. Review
  30. 1 2 Prostaglandins Other Lipid Mediat. 2012 Aug;98(3-4):129-32. doi: 10.1016/j.prostaglandins.2011.12.008. Epub 2012 Jan 10.PMID 22245571
  31. ↑ Prostaglandins Other Lipid Mediat. 2003 Oct;72(1-2):51-71. Review.PMID 14626496
  32. ↑ Prostaglandins Other Lipid Mediat, 96 (1–4) (2011), pp. 72–75
  33. ↑ Prostaglandins Other Lipid Mediat. 2011 Nov;96(1-4):72-5. doi: 10.1016/j.prostaglandins.2011.08.002. Epub 2011 Aug 11.PMID 21856435
  34. ↑ Cancer Res. 2005 Jun 1;65(11):4707-15
  35. ↑ Cancer Metastasis Rev. 2011 Dec;30(3-4):525-40. doi: 10.1007/s10555-011-9315-y. Review.
  36. ↑ J Pharmacol Exp Ther. 2009 Jun;329(3):908-18. doi: 10.1124/jpet.109.152017. Epub 2009 Mar 16
  37. ↑ J Pharmacol Exp Ther. 2011 Feb;336(2):344-55. doi: 10.1124/jpet.110.174805. Epub 2010 Oct 28
  38. 1 2 Adv Drug Deliv Rev. 2011 Jul 18;63(8):597-609. doi: 10.1016/j.addr.2011.03.006. Epub 2011 Apr 6. Review
  39. ↑ J Biol Chem. 2011 May 20;286(20):17543-59. doi: 10.1074/jbc.M110.198515. Epub 2011 Mar 14
  40. ↑ Cancer Metastasis Rev. 2011 Dec;30(3-4):525-40. doi: 10.1007/s10555-011-9315-y.Review
  41. ↑ Adv Pharmacol. 2015;74:193-221. doi: 10.1016/bs.apha.2015.04.005. Epub 2015 May 27
  42. ↑ Cancer Metastasis Rev. 2011 Dec;30(3-4):525-40. doi: 10.1007/s10555-011-9315-y. Review.PMID 22009066
  43. ↑ Adv Pharmacol. 2015;74:193-221. doi: 10.1016/bs.apha.2015.04.005. Epub 2015 May 27.PMID 26233908
  44. ↑ Adv Pharmacol. 2015;74:193-221. doi: 10.1016/bs.apha.2015.04.005. Epub 2015 May 27.PMID: 26233908
  45. ↑ Front Pharmacol. 2014 Nov 10;5:239. doi: 10.3389/fphar.2014.00239. eCollection 2014. Review.PMID: 25426071
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