Inhibition Of Prostaglandin E2 Biosynthesis Research Articles

Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy

Immune checkpoint inhibitors (ICIs) such as anti-PD-L1 antibodies are widely used to treat human cancers, and growing evidence suggests that ICIs are promising treatments for canine malignancies. However, only some canine oral malignant melanoma (OMM) cases respond to ICIs. To explore biomarkers predictive of survival in dogs with pulmonary metastatic OMM receiving the anti-PD-L1 antibody c4G12 (n = 27), serum concentrations of prostaglandin E2 (PGE2), cytokines, chemokines, and growth factors were measured prior to treatment initiation. Among 12 factors tested, PGE2, interleukin (IL)-12p40, IL-8, monocyte chemotactic protein-1 (MCP-1), and stem cell factor (SCF) were higher in OMM dogs compared to healthy dogs (n = 8). Further, lower baseline serum PGE2, MCP-1, and vascular endothelial growth factor (VEGF)-A concentrations as well as higher IL-2, IL-12, and SCF concentrations predicted prolonged overall survival. These observations suggest that PGE2 confers resistance against anti-PD-L1 therapy through immunosuppression and thus is a candidate target for combination therapy. Indeed, PGE2 suppressed IL-2 and interferon (IFN)-γ production by stimulated canine peripheral blood mononuclear cells (PBMCs), while inhibition of PGE2 biosynthesis using the COX-2 inhibitor meloxicam in combination with c4G12 enhanced Th1 cytokine production by PBMCs. Thus, serum PGE2 may be predictive of c4G12 treatment response, and concomitant use of COX-2 inhibitors may enhance ICI antitumor efficacy.

Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis.

Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE2 biosynthesis. We show that low-dose aspirin inhibits systemic PGE2 biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE2 biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2 production by the platelet-tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2 biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855-65. ©2016 AACR.

Unraveling the moleculr interactions between PGE2 signaling and pain pathways in endometriosis

Prostaglandin E2 (PGE2) is the principal mediator in inflammation and pain hypersensitivity and plays important roles in the pathogenesis of endometriosis. PGE2 produced at the site of inflammation acts on the nociceptors of peripheral terminals through EP1, EP2, EP3, and EP4 receptors. Inhibition of PGE2 biosynthesis using NSAIDs and COX-2 inhibitors has emerged as the main class analgesics. Selective inhibition of PGE2 signaling down-stream of COX-2 may provide an opportunity to inhibit pronociceptive actions of PGE2 in endometriosis.

Entamoeba histolytica suppresses gamma interferon-induced macrophage class II major histocompatibility complex Ia molecule and I-A beta mRNA expression by a prostaglandin E2-dependent mechanism.

The surface expression of class II major histocompatibility complex immune-associated (Ia) antigen is a principal accessory function of macrophages for antigen-specific T-cell activation and immunoregulation. To explore the mechanisms of impaired cell-mediated immunity in invasive amebiasis, we investigated the effects of Entamoeba histolytica proteins on gamma interferon (IFN-gamma)-induced Ia expression by murine bone marrow-derived macrophages. Pretreatment of macrophages with secreted (conditioned medium) or whole soluble amebic proteins inhibited the induction of IFN-gamma-induced surface Ia antigen expression by 30 to 61% but had no effect on surface Ia molecules already expressed. By Northern (RNA) blot analysis, amebic proteins suppressed IFN-gamma-induced macrophage I-A beta mRNA accumulation by 36% but did not alter the constitutive levels of actin mRNA expression. E. histolytica stimulated macrophages to produce high levels of prostaglandin E2 (PGE2) as determined by reverse-phase high-pressure liquid chromatography and quantification by PGE2-specific radioimmunoassay. Inhibition of PGE2 biosynthesis with the cyclooxygenase inhibitor indomethacin abrogated ameba-induced suppression of Ia antigen by 60%, whereas exogenously added PGE2 decreased IFN-gamma-induced macrophage Ia expression by 44%. Our results suggest that the mechanism whereby E. histolytica suppresses IFN-gamma-induced macrophage surface Ia molecule synthesis and I-A beta mRNA expression is by stimulating the production of PGE2, which acts in an autocrine fashion for immunoregulation. E. histolytica subverting critical macrophage accessory function via PGE2 biosynthesis is a novel strategy which the parasite uses to suppress host defenses.

抗炎症 炎症抑制の方法論と手段 アラキドン酸カスケードの側面より

Using an air pouch type allergic inflammation model in rats, roles of arachidonate metabolites in inflammatory responses were investigated in order to define characteristics of allergic inflammation in rats, and to get further insight into a methodology for suppression of inflammation from a veiw point of arachidonic acid metabolism. Biochemical and pharmacological analysis revealed following results; (1) Peptide-leukotrienes do not play any significant role in vascular permeability increase in anaphylaxis phase. (2) Leukotriene B4 also plays no role in neutrophil infiltration, suggesting that participation of lipoxygenase products in inflammatory responses is negligible in rats. (3) In contrast, antagonists of platelet activating factor (PAF) efficiently suppressed neutrophil infiltration into the inflammatory locus indicating that PAF plays a significant role for neutrophil infiltration. (4) Prostaglandin E2 participates in vascular permeability increase at a definite period, and in stimulation of neutrophil infiltraltion by suppressing histamine production at the inflammatory locus. (5) Cyclooxygenase inhibitors suppress vascular permeability and neutrophil infiltration. Suppression of neutrophil infiltration by cyclooxygenase inhibitors is mediated by stimulation of histamine production through inhibition of prostaglandin E2 biosynthesis. Histamine suppresses neutrophil infiltration by acting on histamine H2 receptors of neutrophils.Finally, present situation and point at issue for suppression of inflammation through regulation of arachidonic acid metabolism is discussed.

Metabolism of linoleic and arachidonic acids in VX2 carcinoma tissue: identification of monohydroxy octadecadienoic acids and monohydroxy eicosatetraenoic acids.

The metabolism of arachidonic and linoleic acids by VX2 carcinoma tissue in vitro was determined. Prostaglandin E2 was the major metabolic product of arachidonic acid in the neoplastic tissue. Minor products accounting for 3- 8% of arachidonic acid metabolism were II-hydroxy-5, 8, 12, 14-eicosatetraenoic acid (II-HETE) and 15-hydroxy-5, 8, 11, 13-eicosatetraenoic acid (15-HETE). Linoleic acid was converted to a mixture of 9-hydroxy-10, 12-octadecadienoic acid (9-HODD) and 13-hydroxy-9, 11-octadecadienoic acid (13-HODD). The conversion of linoleic acid to monohydroxy C-18 fatty acids varied from 40-80% 9-HODD and 20-60% 13-HODD in tumor tissue harvested from different animals. The quantity of monohydroxy C-18 fatty acids biosynthesized by VX2 carcinoma tissue from endogenous linoleic acid equals or exceeds that of prostaglandin E2 biosynthesis from endogenous arachidonic acid. The presence of a hydroxyl group adjacent to a conjugated diene suggest that the monohydroxy C-18 and monohydroxy C-20 fatty acids were formed via the action of lipoxygenase-like enzymes. These lipoxygenase-like reactions are inhibited by indomethacin in a concentration-dependent fashion similar to the inhibition of prostaglandin E2 biosynthesis. The enzymes catalyzing the lipoxygenase-like reactions of linoleic and arachidonic acids are localized in the microsomal fraction of VX2 carcinoma tissue. These data suggest that the lipoxygenase-like reactions are catalyzed by fatty acid cyclooxygenase and that there are two major pathways of fatty acid cyclooxygenase metabolism of polyenoic fatty acids in the neoplastic tissue. One pathway involves the formation of prostaglandin E2 via cyclic endoperoxy intermediates. The second pathway involves the formation of monohydroxy C-18 fatty acids from linoleic acid via lipoxygenase-like reactions.

EFFECTS OF FOOD ANTIOXIDANTS ON PROSTAGLANDIN BIOSYNTHESIS

ABSTRACTThis study was designed to determine the influence of t‐butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and ascorbic acid on the biosynthesis of prostaglandins. Prostaglandin biosynthesis was monitored by determining the conversion of 14C‐dihomo‐gamma‐linolenic acid and 3 H‐arachidonic acid to prostaglandin E1 (PGE1), and prostaglandin E2 (PGE2), respectively, by the microsomal fraction of bovine seminal vesicles incubated under optimal conditions. The microsomal fraction converted in high yield, all‐cis 8,11,14 eicosatrienoic acid (dihomogamma linolenic acid) to PGE1 and all‐cis 5,8,11,14‐eicosatetraenoic acid (arachidonic acid) to PGE2 and in low yield, to prostaglandin F1α and F1α (PGF1α and PGF2β), respectively. Concentrations of 6.70 μM of BHA, 5.49 μM of TBHQ, and 100.6 μM of BHT resulted in a 50% inhibition of PGE1 biosynthesis, while concentrations of 3.08 μM of BHA, 6.07 μM of TBHO. and 93.0 μM of BHT resulted in a 50% inhibition of PGE2 biosynthesis in the’ systems used. 434.0 μM of ascorbic acid resulted in a 23% inhibition of PGE1 and a 43% inhibition of PGE2 biosynthesis. These results confirm that extremely low concentrations of food anti‐oxidants can interfere with prostaglandin biosynthesis.