Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2

Seno, Kaoru; Okuno, Takayuki; Nishi, Koichi; Murakami, Yasushi; Yamada, K; Nakamoto, Shozo; Ono, Takashi

doi:10.1016/s0960-894x(01)00003-8

Cited by 80 publications

(42 citation statements)

References 16 publications

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“…In our studies with CHO-K1 and HEK293 cells, it is clear that essentially all of the released [ 3 H]arachidonate is accounted for by that which accumulates in the culture medium. Also the fact that the cPLA 2 -␣ inhibitors reduce accumulation of [ 3 H]arachidonate in the medium in the present as well as in previous studies (2,26,28,42) The data presented in this paper provide a particularly clear example of cross-talk between hGIIA or hGX and cPLA 2 -␣. A second clear example of this cross-talk comes from the recent study of Han et al (15).…”

Section: Localization Of Hgiia In Hek293 Cells By Immunofluorescence-supporting

confidence: 84%

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Arachidonic Acid Release from Mammalian Cells Transfected with Human Groups IIA and X Secreted Phospholipase A2 Occurs Predominantly during the Secretory Process and with the Involvement of Cytosolic Phospholipase A2-α

Mounier

Ghomashchi

Lindsay

et al. 2004

Journal of Biological Chemistry

137

147

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Stable expression of human groups IIA and X secreted phospholipases A 2 (hGIIA and hGX) in CHO-K1 and HEK293 cells leads to serum-and interleukin-1␤-promoted arachidonate release. Using mutant CHO-K1 cell lines, it is shown that this arachidonate release does not require heparan sulfate proteoglycan-or glycosylphosphatidylinositol-anchored proteins. It is shown that the potent secreted phospholipase A 2 inhibitor Me-Indoxam is cell-impermeable. By use of Me-Indoxam and the cellimpermeable, secreted phospholipase A 2 trapping agent heparin, it is shown that hGIIA liberates free arachidonate prior to secretion from the cell. With hGX-transfected CHO-K1 cells, arachidonate release occurs before and after enzyme secretion, whereas all of the arachidonate release from HEK293 cells occurs prior to enzyme secretion. Immunocytochemical studies by confocal laser and electron microscopies show localization of hGIIA to the cell surface and Golgi compartment. Additional results show that the interleukin-1␤-dependent release of arachidonate is promoted by secreted phospholipase A 2 expression and is completely dependent on cytosolic (group IVA) phospholipase A 2 . These results along with additional data resolve the paradox that efficient arachidonic acid release occurs with hGIIAtransfected cells, and yet exogenously added hGIIA is poorly able to liberate arachidonic acid from mammalian cells.Phospholipases A 2 (PLA 2 s) 1 are a class of enzymes that release fatty acids from the sn-2 position of glycero-phospholipids. Biomedical interest in these enzymes stems from the finding that the liberation of arachidonic acid for the biosynthesis of the eicosanoids (prostaglandins, leukotrienes, and others) is mediated in mammalian cells by one or more PLA 2 s. Current evidence favors a role for cytosolic phospholipase A 2 -␣ (cPLA 2 -␣, also known as group IVA PLA 2 ) as a major component of the arachidonate releasing signal transduction pathway (1-3). Mammals also contain a large number of secreted phospholipases A 2 (sPLA 2 s) (4, 5), and the possible participation of these enzymes in arachidonate release is under active investigation. For example, group V sPLA 2 is present in the macrophage-like cell line p388D1 and contributes a portion of the arachidonate released in response to lipopolysaccharide (6). Exogenous addition of groups V and X sPLA 2 s to a variety of mammalian cells leads to arachidonate release (7-10). There is some evidence to suggest that the action of cPLA 2 -␣ is a prerequisite for sPLA 2 function in cells (11,12) and even for the vice versa scenario (13-15), but such cross-talk between PLA 2 s remains poorly understood.To assess the arachidonate releasing capacity of PLA 2 s in mammalian cells, CHO and HEK293 cell lines that stably express the various enzymes have been established (16 -20). The behavior of human group IIA (hGIIA) and human group X (hGX) sPLA 2 s when transfected in HEK293 and CHO cells has been extensively studied. hGIIA is secreted from HEK293 cells, and most of the extracellular enzyme is a...

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Section: Localization Of Hgiia In Hek293 Cells By Immunofluorescence-supporting

confidence: 84%

“…Materials-The cPLA 2 -␣ inhibitors pyrrophenone (26), pyrrolidine-1 (27), and AZ-1 (compound 22 of (28)) and the sPLA 2 inhibitor MeIndoxam (29) were prepared as described. Porcine intestinal mucosa low molecular mass heparin (ϳ3,000 Da) and heparin are from Sigma (H3400 and H3149, respectively).…”

Section: Methodsmentioning

confidence: 99%

Arachidonic Acid Release from Mammalian Cells Transfected with Human Groups IIA and X Secreted Phospholipase A2 Occurs Predominantly during the Secretory Process and with the Involvement of Cytosolic Phospholipase A2-α

Mounier

Ghomashchi

Lindsay

et al. 2004

Journal of Biological Chemistry

137

147

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“…The inhibitory activities of the ROC-0929 inhibitor and the control compound (ROC-0428) at relevant molar concentrations are shown in supplemental Table 3. Inhibition of cPLA 2 ␣ was conducted with Pyr-2 (pyrrophenone) and Wyeth-2 (giripladib) (30,31).…”

Section: Materials-chclmentioning

confidence: 99%

Eosinophil Cysteinyl Leukotriene Synthesis Mediated by Exogenous Secreted Phospholipase A2 Group X

Lü

Oslund

Bollinger

et al. 2010

Journal of Biological Chemistry

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“…1). 25 The structural motifs include activated ketones, [26][27][28][29][30] pyrrolidines, 31,32 indoles, 29,[33][34][35][36] oxamides, 37,38 and triazinetriones. 39 Seno (Shionogi) has shown that thiazolidinedione-containing pyrrolidines, as exemplified by 1, are potent cPLA 2a inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Benzhydrylquinazolinediones: Novel cytosolic phospholipase A2α inhibitors with improved physicochemical properties

Kirincich¹,

Xiang²,

Green³

et al. 2009

Bioorganic & Medicinal Chemistry

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Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2

Cited by 80 publications

References 16 publications

Arachidonic Acid Release from Mammalian Cells Transfected with Human Groups IIA and X Secreted Phospholipase A2 Occurs Predominantly during the Secretory Process and with the Involvement of Cytosolic Phospholipase A2-α

Arachidonic Acid Release from Mammalian Cells Transfected with Human Groups IIA and X Secreted Phospholipase A2 Occurs Predominantly during the Secretory Process and with the Involvement of Cytosolic Phospholipase A2-α

Eosinophil Cysteinyl Leukotriene Synthesis Mediated by Exogenous Secreted Phospholipase A2 Group X

Benzhydrylquinazolinediones: Novel cytosolic phospholipase A2α inhibitors with improved physicochemical properties

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