WEB 2086

Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086.[Pubmed:16721373]

Br J Cancer. 2006 Jun 5;94(11):1637-42.

WEB-2086 -- an antagonist of platelet-activating factor receptor (PAFR) with known anti-inflammatory, antiangiogenic and antileukaemic properties -- also proved to inhibit the proliferation in human solid tumour cell lines of different histology, and with much higher efficacy than in normal fibroblasts. A detailed analysis of WEB-2086 anticancer activity was then performed focusing on breast adenocarcinoma MCF-7 and MDA-MB-231 cells. WEB-2086-treated cells, either expressing (MCF-7) or unexpressing (MDA-MB-231) the oestrogen receptor (ER)alpha, underwent a dose-dependent growth arrest (IC(50)=0.65+/-0.09 and 0.41+/-0.07 mM, respectively) and accumulation in G(0)-G(1) phase. WEB-2086 also induced morphological and functional changes typical of mature mammary phenotype including (i) cell enlargement and massive neutral lipid deposition (best accomplished in MCF-7 cells); (ii) decrease in motility and active cathepsin D levels (mainly observed in highly invasive MDA-MB-231 cells). The expression of ERalpha was neither increased nor reactivated in treated MCF-7 or MDA-MB-231 cells, respectively. WEB-2086-induced differentiation in breast cancer cells involved the upregulation of PTEN, a key tumour suppressor protein opposing tumorigenesis, and was apparently independent of p53, PAFR, peripheral benzodiazepine receptor and ERalpha status. Overall, WEB-2086 can be proposed as an effective antiproliferative and differentiative agent with interesting translational opportunities to treat breast cancers in support to conventional chemotherapy.

Brain penetration of WEB 2086 (Apafant) and dantrolene in Mdr1a (P-glycoprotein) and Bcrp knockout rats.[Pubmed:25053619]

Drug Metab Dispos. 2014 Oct;42(10):1761-5.

Transporter gene knockout rat models are attracting increasing interest for mechanistic studies of new drugs as transporter substrates or inhibitors in vivo. However, limited data are available on the functional validity of such models at the blood-brain barrier. Therefore, the present study evaluated Mdr1a [P-glycoprotein (P-gp)], Bcrp, and combined Mdr1a/Bcrp knockout rat strains for the influence of P-gp and breast cancer resistance protein (BCRP) transport proteins on brain penetration of the selective test substrates [(14)C]WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]-diaz epin-2-yl]-1-(4-morpholinyl)-1-propanon) for P-gp and dantrolene for BCRP. Brain-to-plasma concentration ratios (BPR) were measured after intravenous coinfusions of 5.5 micromol/kg per hour [(14)C]WEB 2086 and 2 micromol/kg per hour dantrolene for 2 hours in groups of knockout or wild-type rats. Compared with wild-type controls, mean BPR of [(14)C]WEB 2086 increased 8-fold in Mdr1a knockouts, 9.5-fold in double Mdr1a/Bcrp knockouts, and 7.3-fold in zosuquidar-treated wild-type rats, but was unchanged in Bcrp knockout rats. Mean BPR of dantrolene increased 3.3-fold in Bcrp knockouts and 3.9-fold in double Mdr1a/Bcrp knockouts compared with wild type, but was unchanged in the Mdr1a knockouts. The human intestinal CaCo-2 cell bidirectional transport system in vitro confirmed the in vivo finding that [(14)C]WEB 2086 is a substrate of P-gp but not of BCRP. Therefore, Mdr1a, Bcrp, and combined Mdr1a/Bcrp knockout rats provide functional absence of these efflux transporters at the blood-brain barrier and are a suitable model for mechanistic studies on the brain penetration of drug candidates.

WEB 2086, a platelet-activating factor antagonist, inhibits prophenoloxidase-activating system and hemocyte microaggregation reactions induced by Trypanosoma rangeli infection in Rhodnius prolixus hemolymph.[Pubmed:16777137]

J Insect Physiol. 2006 Jul;52(7):685-92.

The effects of the triazolodiazepine WEB 2086, a platelet-activating factor (PAF) antagonist, on hemocyte microaggregation and prophenoloxidase (proPO)-activating system in the hemolymph, hemocoelic infection and mortality in fifth-instar larvae of Rhodnius prolixus inoculated with Trypanosoma rangeli were investigated. Hemocoelic injection of short T. rangeli epimastigotes (1x10(4) parasites/insect) in R. prolixus that were previously fed with blood containing 1muM of WEB 2086 resulted in (i) reduced hemocyte microaggregations as well as an attenuated proPO system in the hemolymph and (ii) greater parasitemia and mortality among the insects. In vitro assays using hemolymph from insects previously fed with blood containing WEB 2086 exhibited attenuated hemocyte microaggregations when T. rangeli was employed as the inducer of the reaction, and this effect was not counteracted by PAF treatment. In vitro assays using hemolymph from insects previously fed with blood, regardless of WEB 2086 presence increased the PO activity when incubated with the parasites. However, the PO activity was drastically inhibited when hemolymph from insects fed with blood, whether or not it contained WEB 2086, was incubated with fat body homogenates from insects fed with blood containing WEB 2086. The addition of PAF did not enhance the PO activity. These analyses did not reveal any PAF influence on WEB 2086 effects in the two defense reactions.

Effect of platelet-activating factor antagonist WEB 2086 on microcirculatory disorders in acute experimental pancreatitis of graded severity.[Pubmed:18695628]

Pancreas. 2009 Jan;38(1):58-64.

OBJECTIVES: Platelet-activating factor (PAF) is an important mediator of inflammation and postulated to be involved in the pathogenesis of acute pancreatitis. In this study, we evaluated the therapeutic effect of PAF antagonist WEB 2086 in acute experimental pancreatitis of graded severity in rats. METHODS: According to a block design, 64 animals were randomly allocated to 8 groups. Severe necrotizing pancreatitis was induced by intraductal infusion of taurocholic acid (4%, 0.4 mL), and the combination of glycodeoxycholic acid (10 mmol/L, 1.0 mL/kg, intraductal infusion) and cerulein (5 microg/kg per hour, intravenous) was applied to induce intermediate pancreatitis, or cerulein alone (5 microg/kg per hour, intravenous) to establish edematous pancreatitis. WEB 2086 was given 15 minutes after beginning the induction of pancreatitis. Pancreatic microcirculation was analyzed in vivo with an epiluminescent microscope. Histopathology was evaluated by a validated score. Trypsinogen-activating peptide and serum amylase were analyzed sequentially. RESULTS: WEB 2086 had no significant influence on the breakdown of microcirculation, leukocyte adherence, histopathological damage, and amylase levels in severe necrotizing pancreatitis, intermediate pancreatitis, and edematous pancreatitis. Only in intermediate pancreatitis was there a significant reduction of trypsinogen-activating peptide levels. CONCLUSIONS: In our study, PAF antagonist WEB 2086 had no beneficial effect on microcirculation in acute experimental pancreatitis.

Effects of WEB 2086 on the protective role of preconditioning against arrhythmias in rats.[Pubmed:9782066]

Pharmacol Res. 1998 Sep;38(3):173-8.

The purpose of the present study was to investigate a possible role of platelet activating factor (PAF) in ischaemic preconditioning (PC). Since both PC and PAF act through protein kinase C (PKC), PAF could play a role in PC. To test this hypothesis, anaesthetized, open-chest male rats were subjected to four different protocols. Group I was subjected to 30 min of left coronary artery occlusion. In Group II, WEB 2086 (10 mg kg-1 i.v. bolus+1 mg kg-1 h-1 i.v. infusion) a selective PAF antagonist was given to non-preconditioned rats 23 min before the 30-min occlusion period. In Group III and IV ischaemic PC was elicited by one cycle of 3 min occlusion and 5 min reperfusion and also in Group IV, WEB 2086 (10 mg kg-1 i.v. bolus+1 mg kg-1 h-1 i.v. infusion) was given 23 min before the 30 min occlusion period. Ventricular ectopic beats (VEB), ventricular tachycardia (VT), and ventricular fibrillation (VF) that occurred during 30 min occlusion were determined. WEB 2086 administration or PC reduced the VEBs significantly. Incidence of VT and VF were not affected by WEB 2086 compared with control values, although PC decreased the incidence of VT and VF. WEB 2086 administration did not attenuate PC-induced improvement of arrhythmia parameters. These data demonstrated that a specific PAF antagonist, WEB 2086 did not abolish PC-induced protection against arrhythmias.

Characterization of PAF receptors on human neutrophils using the specific antagonist, WEB 2086. Correlation between receptor binding and function.[Pubmed:2537761]

FEBS Lett. 1989 Feb 27;244(2):365-8.

The antagonism of PAF effects by WEB 2086 and the receptor binding of [3H]WEB 2086 were investigated in isolated human neutrophils. WEB 2086 inhibited PAF-induced beta-glucuronidase release and [3H]WEB 2086 bound specifically to high-affinity sites on the cells. Close concordance between affinity constants for WEB 2086 from functional and radioligand-binding studies suggests that WEB 2086 interacts with the neutrophil PAF receptors and that [3H]WEB 2086 may be a useful ligand in investigation of these receptors.

Apafant (WEB 2086), a potent platelet-activating factor (PAF) antagonist, inhibits PAF binding to human PAF receptors with a Ki of 9.9 nM.

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