Disease relevance of bromoenol lactone (BEL)

• Both the iPLA(2)beta inhibitor bromoenol lactone and the CaMKIIbeta inhibitor KN93 reduced arachidonate release from INS-1 insulinoma cells, and both inhibit insulin secretion [1].
• METHODS: Isolated rat hearts were treated for 10 min with 0.3-6 microM bromoenol lactone and then subjected to 25 min ischemia and 30 min reperfusion [2].
• During global ischemia, time to contracture was significantly increased from vehicle group values in the presence of the bromoenol lactone (EC50 = 1.2 microM) [2].
• In the experimental condition used, pertussis toxin, staurosporine, H7, ATK or bromoenol lactone did not induce cytotoxic effects, according to MTT assay [3].

High impact information on bromoenol lactone (BEL)

• Inhibition of PAP-1 by bromoenol lactone, propranolol, or ethanol resulted in a decrease in LPS-induced COX-2 mRNA transcript production, COX-2 protein expression, and prostaglandin E(2) release from U937 macrophages [4].
• Inhibition of iPLA(2) activity by bromoenol lactone (BEL) was sufficient to entirely block endothelial cell growth [5].
• Bromoenol lactone (BEL), a suicide substrate inhibitor of iPLA2, inhibits the activity of both isoforms at low micromolar concentrations [6].
• In addition to sPLA(2), mitochondria contain another phospholipase A(2) that is Ca(2+)-independent and sensitive to bromoenol lactone, associated with the outer mitochondrial membrane [7].
• Spermatozoa from iPLA(2)beta(-/-) mice have reduced motility and impaired ability to fertilize mouse oocytes in vitro and in vivo, and inhibiting iPLA(2)beta with a bromoenol lactone suicide substrate reduces motility of wild-type spermatozoa in a time- and concentration-dependent manner [8].
• bromoenol lactone inhibits voltage-gated Ca2+ channels, transient receptor potential canonical (TRPC1-TRPC5, TRPC5, TRPC6) channels, and phospholipase C (PLC) [9].

Chemical compound and disease context of bromoenol lactone

• Moreover, co-incubation of cardiac myocytes with urocortin, or the specific phospholipase A2 inhibitor bromoenol lactone, reduces the cytotoxicity produced by lysophosphatidylcholine or ischemia/reperfusion [10].

Biological context of bromoenol lactone

• Similarly, PKC activation with PMA and diacylglycerol enhanced phagocytosis in the absence, but not in the presence, of bromoenol lactone [11].
• A group VI PLA(2) (iPLA(2)) that is sensitive to a bromoenol lactone inhibitor catalyzes arachidonate hydrolysis from phospholipids in some cells and facilitates arachidonate incorporation into glycerophosphocholine (GPC) lipids in others, but it is not known whether U937 cells express iPLA(2) [12].
• MAFP and BEL prevented pp125FAK phosphorylation and platelet spreading on fibrinogen having no effect on pp125FAK phosphorylation or platelet spreading on immobilized IgG [13].
• Group VIA PLA2 (iPLA2beta) has a GTSTG serine lipase consensus sequence, and studies with a bromoenol lactone (BEL) suicide substrate inhibitor have been taken to suggest that iPLA2beta participates in a wide variety of biological processes [14].
• Here we report that the SERCA inhibitor thapsigargin induces apoptosis in INS-1 insulinoma cells and that this is inhibited by a bromoenol lactone (BEL) inhibitor of group VIA calcium-independent phospholipase A(2) (iPLA(2)beta) [15].

Anatomical context of bromoenol lactone

• Bromoenol lactone (BEL), a selective inhibitor of the calcium-independent phospholipase A(2) (iPLA(2)), prevents dsRNA- and virus-induced iNOS expression by RAW 264.7 cells and mouse macrophages [16].
• Addition of the iPLA(2) inhibitors, bromoenol lactone, or arachidonyl trifluoromethyl ketone (AAOCF(3)), inhibited both mitogen-induced PBL as well as Jurkat T cell proliferation [17].
• The PLA2 activators mastoparan and melittin restored phagocytosis to PKC-inhibited cells, but were ineffective in monocytes pretreated with the pPL inhibitor bromoenol lactone [11].
• Calcium-independent sn-2-acylhydrolytic activity was measurable in PBL cytosols and could be inhibited by the selective iPLA(2) inhibitor bromoenol lactone [17].
• CONCLUSIONS: The bromoenol lactone protects ischemic myocardium at concentrations which also inhibit calcium-independent PLA2 [2].

Associations of bromoenol lactone with other chemical compounds

• Inhibition of PAP-1 activity by three different strategies (i.e. use of bromoenol lactone, propranolol, and ethanol) resulted in inhibition of COX-2 expression and hence of PGE(2) production [18].
• Identical inhibition of TG-induced Ca(2+) and Mn(2+) influx (but not Ca(2+) release) was observed in SMC, human platelets, and Jurkat T-lymphocytes when functional activity of iPLA(2) was inhibited by its mechanism-based suicidal substrate, bromoenol lactone (BEL) [19].
• Co-application of the DAG antagonist and a phospholipase A(2) (PLA(2)) inhibitor such as aristolochic acid, arachidonyltrifluoromethyl ketone, or bromoenol lactone inhibited the purinergic receptor-mediated translocation of PKC epsilon although each PLA(2) inhibitor alone did not block the translocation [20].
• Bromoenol lactone (BEL), an inhibitor of the Group VI Ca2+-independent phospholipase A2 (iPLA2), diminished both lysophosphatidylcholine levels and the incorporation of AA into phospholipids [21].
• PLD activation was fully blocked by the cytosolic phospholipase A(2) (PLA(2)) inhibitor ONO-RS-082 and partially attenuated by the selective Ca(2+)-dependent cytosolic PLA(2) inhibitor, arachidonyl trifluoromethylketone (AACOCF(3)), or by bromoenol lactone, an inhibitor of Ca(2+)-independent cytosolic PLA(2) [22].

Gene context of bromoenol lactone

• In contrast, bromoenol lactone (BEL), a specific inhibitor of iPLA2 had no effect on the release of AA [13].
• The present study shows that the iPLA2 inhibitor bromoenol lactone, when introduced into hippocampal CA1 pyramidal cells through a patch pipette, generated a dose-dependent increase in the amplitude of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) [23].
• Although a significant inhibitory effect of MAFP on both TNF-induced AA release and PLA(2) activity in MCF7 was observed, BEL had no effect [24].
• The selective iPLA(2) suicide substrate inhibitor bromoenol lactone prevents dsRNA- and EMCV-stimulated inducible NO synthase expression; however, bromoenol lactone does not attenuate dsRNA- or EMCV-induced COX-2 expression by macrophages [25].
• Based on the use of the Group VI Ca2+-independent phospholipase A2 (iPLA2) inhibitor bromoenol lactone (BEL), we previously suggested a role for the iPLA2 in mediating phospholipid fatty acid turnover (Balsinde, J., Bianco, I. D., Ackermann, E. J., Conde-Frieboes, K., and Dennis, E. A. (1995) Proc. Natl. Acad. Sci. U. S. A. 92: 8527-8531) [26].

Analytical, diagnostic and therapeutic context of bromoenol lactone

• During reperfusion, 5-HD abolished the protective effects of the bromoenol lactone on cardiac function and LDH release [2].
• The rate of appearance of arachidonate-containing phosphatidylethanolamine species visualized by ESI mass spectrometry is also similar in iPLA2beta-overexpressing and parental INS-1 cells incubated with supplemental arachidonic acid, and this process is unaffected by BEL [27].

References