Role of prostaglandins in colorectal tumorigenesis: Localization and expression of COX-1, COX-2, microsomal Prostaglandin E Synthase-1 and the EP2 receptor

Avicenna ◽  
2013 ◽  
pp. 5
Author(s):  
Lars Hedin ◽  
Katarina Rask ◽  
Yihong Zhu ◽  
Anna Wickman ◽  
Wanzhong Wang ◽  
...  
Keyword(s):  
Prostaglandin E ◽  
Colorectal Tumorigenesis ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Ep2 Receptor ◽  
Cox 1 ◽  
Microsomal Prostaglandin E Synthase

scholarly journals SAT0315 INHIBITION OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES-1) BY GS-248 REDUCES PROSTAGLANDIN E2 BIOSYNTHESIS WHILE INCREASING PROSTACYCLIN IN HUMAN SUBJECTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1103.2-1103
Author(s):  
C. Edenius ◽  
G. Ekström ◽  
J. Kolmert ◽  
R. Morgenstern ◽  
P. Stenberg ◽  
...  
Keyword(s):  
Whole Blood ◽  
Vascular Tone ◽  
Ex Vivo ◽  
Prostaglandin E ◽  
Maximum Plasma ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Oral Doses ◽  
Microsomal Prostaglandin E Synthase

Background:Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the formation prostaglandin (PG) E2from cyclooxygenase derived PGH2(1, 2). Inhibition of mPGES-1 leads to reduction of pro-inflammatory PGE2, while in vessels there is a concomitant increase of vasoprotective prostacyclin (PGI2) via shunting of PGH2(3,4). Apart from relieving symptoms in experimental animal models of inflammation, inhibitors of mPGES-1 cause relaxation of human medium sized arteries(4)and resistance arteries(5). The prostaglandin profile following mPGES-1 inhibition, explains the anti-inflammatory effects and also opens for the possibility of treating inflammatory diseases with concomitant vasculopathies. GS-248 is a potent and selective inhibitor of mPGES-1 exhibiting sub-nanomolar IC50in human whole bloodex vivo.Objectives:To evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of GS-248.Methods:Healthy males and females (age 18–73 years) were included in the study. Six cohorts were administrated single oral doses of 1-300mg GS-248 (n=36) or placebo (n=12), three cohorts were administered once daily doses of 20-180mg GS-248 (n=18) or placebo (n=12) over ten days. In addition, 8 subjects were treated in a separate cohort with 200mg celecoxib bid for ten days. Blood samples were drawn for measurement of GS-248 exposure and production of PGE2after LPS incubationex vivo. The content of PGE2and PGI2metabolites was measured in urine. All analyses were performed by LC-MS/MS.Results:GS-248 was safe and well tolerated at all tested dose levels. Maximum plasma concentration was achieved 1 - 2.5 hours after dosing, and half-life was about 10 hours. Induced PGE2formationex vivo,catalyzed by mPGES-1, was completely inhibited for 24 hours after a single low dose (40mg) of GS-248. In urine, GS-248 dose-dependently reduced the excretion of PGE2metabolite by more than 50% whereas the excretion of PGI2metabolite increased more than twice the baseline levels. In the celecoxib cohort urinary metabolites of both PGE2and PGI2were reduced with approx 50%.Conclusion:GS-248 at investigated oral doses was safe and well tolerated. There was a sustained inhibition of LPS induced PGE2formation in whole blood. In urine, there was a metabolite shift showing reduced PGE2and increased PGI2, while celecoxib reduced both PGE2and PGI2metabolites. This suggests that selective inhibition of mPGES-1 results in systemic shunting of PGH2to PGI2formation, leading to anti-inflammatory and vasodilatory effects, while preventing platelet activation. The results warrant further evaluation of GS-248 in inflammatory conditions with vasculopathies such as Digital Ulcers and Raynaud’s Phenomenon in Systemic Sclerosis.References:[1]Korotkova M, Jakobsson PJ. Persisting eicosanoid pathways in rheumatic diseases. Nat Rev Rheumatol. 2014;10:229-41[2]Bergqvist F, Morgenstern R, Jakobsson PJ. A review on mPGES-1 inhibitors: From preclinical studies to clinical applications. Prostaglandins Other Lipid Mediat. 2019;147:106383[3]Kirkby NS, et al. Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis. Cardiovasc Res. 2020[4]Ozen G, et al. Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2: a safer alternative to COX-2 inhibition. Br J Pharmacol. 2017;174:4087-98[5]Larsson K, et al. Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone. Br J Pharmacol. 2019;176:4625-38Disclosure of Interests:Charlotte Edenius Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Gunilla Ekström Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Johan Kolmert Consultant of: Gesynta Pharma,, Ralf Morgenstern Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Patric Stenberg Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca,, Göran Tornling Shareholder of: Gesynta Pharma, Vicore Pharma,, Consultant of: Gesynta Pharma, Vicore Pharma, AnaMar

Sulforaphane, a Chemopreventive Compound, Inhibits Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Expression in Human HT-29 Colon Cancer Cells

2018 ◽  
Vol 206 (1-2) ◽  
pp. 46-53 ◽  
Author(s):  
Maryam Sadat Tafakh ◽  
Massoud Saidijam ◽  
Tayebeh Ranjbarnejad ◽  
Sara Malih ◽  
Solmaz Mirzamohammadi ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Caspase 3 ◽  
Mrna Level ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Ht 29 ◽  
Microsomal Prostaglandin E Synthase

Background: A high expression of prostaglandin E2 (PGE2) is found in colorectal cancer. Therefore, blocking of PGE2 generation has been identified as a promising approach for anticancer therapy. Sulforaphane (SFN), an isothiocyanate derived from glucosinolate, is used as the antioxidant and anticancer agents. Methods: HT-29 cells were treated with various concentrations of SFN and compared to untreated cells for the expression of microsomal prostaglandin E synthase-1 (mPGES-1), cyclooxygenase 2 (COX-2), hypoxia-inducible factor-1 (HIF-1), C-X-C chemokine receptor type 4 (CXCR4), vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP)-2 and MMP-9 at the mRNA level. The PGE2 level was measured by ELISA assay. Apoptosis was evaluated by the proportion of sub-G1 cells. The activity of caspase-3 was determined using an enzymatic assay. HT-29 cell migration was assessed using a scratch test. Results: SFN preconditioning decreased the expression of COX-2, mPGES-1, HIF-1, VEGF, CXCR4, MMP-2, and MMP-9. An apoptotic effect of SFN was preceded by the activation of caspase-3 as well as accumulation of cells in the sub-G1 phase of the cell cycle. SFN decreased PGE2 generation and inhibited the in vitro motility/wound-healing activity of HT-29 cells. Conclusions: SFN anticancer effects are associated with antiproliferative, antiangiogenic, and antimetastatic activities arising from the downregulation of the COX-2/ mPGES-1 axis.

scholarly journals Potential Role of Microsomal Prostaglandin E Synthase-1 in Tumorigenesis

2003 ◽  
Vol 278 (21) ◽  
pp. 19396-19405 ◽  
Author(s):  
Daisuke Kamei ◽  
Makoto Murakami ◽  
Yoshihito Nakatani ◽  
Yukio Ishikawa ◽  
Toshiharu Ishii ◽  
...  
Keyword(s):  
Potential Role ◽  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Microsomal Prostaglandin E Synthase

scholarly journals Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

2007 ◽  
Vol 18 (5) ◽  
pp. 1466-1475 ◽  
Author(s):  
Helene Francois ◽  
Carie Facemire ◽  
Anil Kumar ◽  
Laurent Audoly ◽  
Beverly Koller ◽  
...  
Keyword(s):  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Microsomal Prostaglandin E Synthase
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