Benzenesulfonamide indole inhibitors of cytosolic phospholipase A2α: Optimization of in vitro potency and rat pharmacokinetics for oral efficacy

2008 ◽  
Vol 16 (3) ◽  
pp. 1345-1358 ◽  
Author(s):  
Katherine L. Lee ◽  
Mark L. Behnke ◽  
Megan A. Foley ◽  
Lihren Chen ◽  
Weiheng Wang ◽  
...  
Keyword(s):  
Cytosolic Phospholipase ◽  
Cytosolic Phospholipase A2α

scholarly journals Critical Involvement of Calcium-Dependent Cytosolic Phospholipase A2α in Aortic Valve Interstitial Cell Calcification

2020 ◽  
Vol 21 (17) ◽  
pp. 6398
Author(s):  
Antonella Bonetti ◽  
Lorenzo Allegri ◽  
Federica Baldan ◽  
Magali Contin ◽  
Claudio Battistella ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Interstitial Cell ◽  
Attractive Potential ◽  
Dystrophic Calcification ◽  
Calcium Dependent ◽  
Enzyme Content ◽  
Cytosolic Phospholipase ◽  
Cytosolic Phospholipase A2α ◽  
Novel Therapeutic Strategies

The involvement of calcium-dependent cytosolic phospholipase A2α (cPLA2α) in aortic valve calcification is not exhaustively elucidated. Here, cPLA2α expression in aortic valve interstitial cell (AVIC) pro-calcific cultures simulating either metastatic or dystrophic calcification was estimated by qPCR, Western blotting, and counting of cPLA2α-immunoreactive cells, with parallel ultrastructural examination of AVIC calcific degeneration. These evaluations also involved pro-calcific AVIC cultures treated with cPLA2α inhibitor dexamethasone. cPLA2α over-expression resulted for both types of pro-calcific AVIC cultures. Compared to controls, enzyme content was found to increase by up to 300% and 186% in metastatic and dystrophic calcification-like cultures, respectively. Increases in mRNA amounts were also observed, although they were not as striking as those in enzyme content. Moreover, cPLA2α increases were time-dependent and strictly associated with mineralization progression. Conversely, drastically lower levels of enzyme content resulted for the pro-calcific AVIC cultures supplemented with dexamethasone. In particular, cPLA2α amounts were found to decrease by almost 88% and 48% in metastatic and dystrophic calcification-like cultures, respectively, with mRNA amounts showing a similar trend. Interestingly, these drastic decreases in cPLA2α amounts were paralleled by drastic decreases in mineralization degrees, as revealed ultrastructurally. In conclusion, cPLA2α may be regarded as a crucial co-factor contributing to AVIC mineralization in vitro, thus being an attractive potential target for designing novel therapeutic strategies aimed to counteract onset or progression of calcific aortic valve diseases.

scholarly journals Zymosan-induced glycerylprostaglandin and prostaglandin synthesis in resident peritoneal macrophages: roles of cyclo-oxygenase-1 and -2

2006 ◽  
Vol 399 (1) ◽  
pp. 91-99 ◽  
Author(s):  
Carol A. Rouzer ◽  
Susanne Tranguch ◽  
Haibin Wang ◽  
Hao Zhang ◽  
Sudhansu K. Dey ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Peritoneal Macrophages ◽  
Prostaglandin Synthesis ◽  
Wild Type ◽  
Cytosolic Phospholipase ◽  
Cytosolic Phospholipase A2α ◽  
Cox 2 ◽  
Cox 1 ◽  
Exogenous Substrates

COX [cyclo-oxygenase; PG (prostaglandin) G/H synthase] oxygenates AA (arachidonic acid) and 2-AG (2-arachidonylglycerol) to endoperoxides that are converted into PGs and PG-Gs (glycerylprostaglandins) respectively. In vitro, 2-AG is a selective substrate for COX-2, but in zymosan-stimulated peritoneal macrophages, PG-G synthesis is not sensitive to selective COX-2 inhibition. This suggests that COX-1 oxygenates 2-AG, so studies were carried out to identify enzymes involved in zymosan-dependent PG-G and PG synthesis. When macrophages from COX-1−/− or COX-2−/− mice were treated with zymosan, 20–25% and 10–15% of the PG and PG-G synthesis observed in wild-type cells respectively was COX-2 dependent. When exogenous AA and 2-AG were supplied to COX-2−/− macrophages, PG and PG-G synthesis was reduced as compared with wild-type cells. In contrast, when exogenous substrates were provided to COX-1−/− macrophages, PG-G but not PG synthesis was reduced. Product synthesis also was evaluated in macrophages from cPLA2α (cytosolic phospholipase A2α)−/− mice, in which zymosan-induced PG synthesis was markedly reduced, and PG-G synthesis was increased approx. 2-fold. These studies confirm that peritoneal macrophages synthesize PG-Gs in response to zymosan, but that this process is primarily COX-1-dependent, as is the synthesis of PGs. They also indicate that the 2-AG and AA used for PG-G and PG synthesis respectively are derived from independent pathways.

scholarly journals Inhibition of Cytosolic Phospholipase A2α Induces Apoptosis in Multiple Myeloma Cells

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7447
Author(s):  
Nur Mahammad ◽  
Felicity J. Ashcroft ◽  
Astrid J. Feuerherm ◽  
Samah Elsaadi ◽  
Esten N. Vandsemb ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Cancer Cell ◽  
Plasma Cells ◽  
Cancer Cell Lines ◽  
Myeloma Cells ◽  
Cytosolic Phospholipase ◽  
Hematological Cancers ◽  
Cytosolic Phospholipase A2α

Cytosolic phospholipase A2α (cPLA2α) is the rate-limiting enzyme in releasing arachidonic acid and biosynthesis of its derivative eicosanoids. Thus, the catalytic activity of cPLA2α plays an important role in cellular metabolism in healthy as well as cancer cells. There is mounting evidence suggesting that cPLA2α is an interesting target for cancer treatment; however, it is unclear which cancers are most relevant for further investigation. Here we report the relative expression of cPLA2α in a variety of cancers and cancer cell lines using publicly available datasets. The profiling of a panel of cancer cell lines representing different tissue origins suggests that hematological malignancies are particularly sensitive to the growth inhibitory effect of cPLA2α inhibition. Several hematological cancers and cancer cell lines overexpressed cPLA2α, including multiple myeloma. Multiple myeloma is an incurable hematological cancer of plasma cells in the bone marrow with an emerging requirement of therapeutic approaches. We show here that two cPLA2α inhibitors AVX420 and AVX002, significantly and dose-dependently reduced the viability of multiple myeloma cells and induced apoptosis in vitro. Our findings implicate cPLA2α activity in the survival of multiple myeloma cells and support further studies into cPLA2α as a potential target for treating hematological cancers, including multiple myeloma.

Intracellular localisation of platelet-activating factor during mammalian embryo development in vitro: a comparison of cattle, mouse and human

2019 ◽  
Vol 31 (4) ◽  
pp. 658
Author(s):  
L. T. M. Vandenberghe ◽  
B. Heindryckx ◽  
K. Smits ◽  
M. Popovic ◽  
K. Szymanska ◽  
...  
Keyword(s):  
Platelet Activating Factor ◽  
Preimplantation Embryos ◽  
Mammalian Embryo ◽  
Developmental Potential ◽  
Nuclear Envelope Breakdown ◽  
Cytosolic Phospholipase ◽  
Carrier Molecule ◽  
Development In Vitro ◽  
Intracellular Localisation

Platelet-activating factor (PAF) is a well-known marker for embryo quality and viability. For the first time, we describe an intracellular localisation of PAF in oocytes and embryos of cattle, mice and humans. We showed that PAF is represented in the nucleus, a signal that was lost upon nuclear envelope breakdown. This process was confirmed by treating the embryos with nocodazole, a spindle-disrupting agent that, as such, arrests the embryo in mitosis, and by microinjecting a PAF-specific antibody in bovine MII oocytes. The latter resulted in the absence of nuclear PAF in the pronuclei of the zygote and reduced further developmental potential. Previous research indicates that PAF is released and taken up from the culture medium by preimplantation embryos invitro, in which bovine serum albumin (BSA) serves as a crucial carrier molecule. In the present study we demonstrated that nuclear PAF does not originate from an extracellular source because embryos cultured in polyvinylpyrrolidone or BSA showed similar levels of PAF in their nuclei. Instead, our experiments indicate that cytosolic phospholipase A2 (cPLA2) is likely to be involved in the intracellular production of PAF, because treatment with arachidonyl trifluoromethyl ketone (AACOCF3), a specific cPLA2 inhibitor, clearly lowered PAF levels in the nuclei of bovine embryos.

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