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Nanoliposomal delivery of cytosolic phospholipase A2 inhibitor arachidonyl trimethyl ketone for melanoma treatment.

ABSTRACT: Drug resistance and toxicity are major limitations of cancer treatment and frequently occurs during melanoma therapy. Nanotechnology can decrease drug resistance by improving drug delivery, with limited toxicity. This study details the development of nanoparticles containing arachidonyl trifluoromethyl ketone (ATK), a cytosolic phospholipase A2 inhibitor, which can inhibit multiple key pathways responsible for the development of recurrent resistant disease. Free ATK is toxic, limiting its efficacy as a therapeutic agent. Hence, a novel nanoliposomal delivery system called NanoATK was developed, which loads 61.7% of the compound and was stable at 4oC for 12 weeks. The formulation decreased toxicity-enabling administration of higher doses, which was more effective at inhibiting melanoma cell growth compared to free-ATK. Mechanistically, NanoATK decreased cellular proliferation and triggered apoptosis to inhibit melanoma xenograft tumor growth without affecting animal weight. Functionally, it inhibited the cPLA2, AKT, and STAT3 pathways. Our results suggest the successful preclinical development of a unique nanoliposomal formulation containing ATK for the treatment of melanoma.

SUBMITTER: Gowda R

PROVIDER: S-EPMC5899023 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Cytosolic phospholipase A2 modulates TLR2 signaling in synoviocytes.

Project description:Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis leading to destruction of cartilage and bone. PLA2 enzymes are key players in inflammation regulating the release of unsaturated fatty acids such as arachidonic acid (AA), a precursor of pro-inflammatory eicosanoids. Several lines of evidence point to toll-like receptors (TLRs) as drivers of synovitis and joint destruction in RA. However, few studies have addressed the implication of PLA2 activity downstream TLR activation in the synovium. Here, we aimed to characterize PLA2 enzyme involvement in TLR2-induced signaling in synovial fibroblast-like cells. TLRs1-7 and a range of sPLA2, iPLA2 and cPLA2 enzymes were found to be transcriptionally expressed in cultured synoviocytes. Activation of TLR2/1 and TLR2/6 led to phosphorylation of cPLA2? at Ser505, and induced AA release and PGE2 production; effects that were attenuated by cPLA2? inhibitors. In contrast, sPLA2 inhibitors did not affect AA or PGE2 release. cPLA2? inhibitors furthermore attenuated TLR-induced expression of IL-6, IL-8 and COX2. COX1/2 inhibitors attenuated TLR2/6-induced IL-6 transcription and protein production comparable to cPLA2? inhibition. Moreover, exogenously PGE2 added alone induced IL-6 production and completely rescued IL-6 transcription when added simultaneously with FSL-1 in the presence of a cPLA2? inhibitor. Our results demonstrate for the first time that cPLA2? is involved in TLR2/1- and TLR2/6-induced AA release, PGE2 production and pro-inflammatory cytokine expression in synoviocytes, possibly through COX/PGE2-dependent pathways. These findings expand our understanding of cPLA2? as a modulator of inflammatory molecular mechanisms in chronic diseases such as RA.

| S-EPMC4404349 | biostudies-literature

New potent and selective polyfluoroalkyl ketone inhibitors of GVIA calcium-independent phospholipase A2.

Project description:Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as an important pharmaceutical target. Selective and potent GVIA iPLA2 inhibitors can be used to study its role in various neurological disorders. In the current work, we explore the significance of the introduction of a substituent in previously reported potent GVIA iPLA2 inhibitors. 1,1,1,2,2-Pentafluoro-7-(4-methoxyphenyl)heptan-3-one (GK187) is the most potent and selective GVIA iPLA2 inhibitor ever reported with a XI(50) value of 0.0001, and with no significant inhibition against GIVA cPLA2 or GV sPLA2. We also compare the inhibition of two difluoromethyl ketones on GVIA iPLA2, GIVA cPLA2, and GV sPLA2.

| S-EPMC3883354 | biostudies-literature

Inhibition of cyclooxygenases 1 and 2 by the phospholipase-blocker, arachidonyl trifluoromethyl ketone.

Project description:Arachidonyl trifluoromethyl ketone (ATK) is widely used as an inhibitor of cytosolic group IV phospholipase A(2) (cPLA(2)) and calcium-independent group VI phospholipase A(2) (iPLA(2)). ATK thus reduces arachidonic acid (AA) substrate for cyclooxygenase (COX; also known as prostaglandin H synthase) and attenuates prostaglandin (PG) synthesis. It has been shown previously, that ATK blocks thromboxane B(2) production induced by exogenous AA in human platelets. It remains, however, unknown whether ATK also directly modulates the activity of cyclooxygenase (COX).Time courses for inhibition of COX by ATK was obtained using osteoblast-like MC3T3-E1 cells, with exogenous AA as substrate and the pure enzymes COX-1 and COX-2. PGE(2) was measured by GC-MS.ATK was a potent inhibitor of COX-1 and COX-2 with IC(50) values of 0.5 and 0.1 microM in MC3T3-E1 cells and of 1.7 and 2.6 microM using the pure enzymes. Inhibition was reversible, with slow- and tight-binding characteristics. The arachidonyl carbon chain was essential, as the saturated palmitoyl analogue had no effect.Attenuation of PG synthesis by ATK is taken to be the consequence of PLA(2) inhibition and the findings of many studies are interpreted on that basis. If there are, however, alternative routes for AA liberation (such as phospholipase C/diacyl glycerol lipase or phospholipase D), this interpretation can lead to false conclusions. As ATK is a widely used and important pharmacological tool in eicosanoid research, knowledge of its interactions with other major enzymes of the cascade is of considerable importance.

| S-EPMC2584923 | biostudies-other

Cytosolic phospholipase A2 alpha regulates TLR signaling and migration in metastatic 4T1 cells

Project description:We aimed at characterizing the response to reduced cPLA2α activity in metastatic versus non-metastatic cells. We employed an isogenic murine cell line pair displaying metastatic (4T1) and non-metastatic (67NR) phenotype to investigate the role of cPLA2α on migration. Further, we elucidate the effect of reduced cPLA2α activity on global gene expression in the metastatic cell line We found that cPLA2α inhibition may inhibit metastasis through an anti-migratory effect, possibly involving Toll-like receptor signaling and type I interferons

2019-09-26 | GSE138026 | GEO

A cytosolic phospholipase A2-initiated lipid mediator pathway induces autophagy in macrophages.

Project description:Autophagy delivers cytoplasmic constituents to autophagosomes and is involved in innate and adaptive immunity. Cytosolic phospholipase (cPLA(2))-initiated proinflammatory lipid mediator pathways play a critical role in host defense and inflammation. The crosstalk between the two pathways remains unclear. In this study, we report that cPLA(2) and its metabolite lipid mediators induced autophagy in the RAW246.7 macrophage cell line and in primary monocytes. IFN-γ-triggered autophagy involves activation of cPLA(2). Cysteinyl leukotrienes D(4) and E(4) and PGD(2) also induced these effects. The autophagy is independent of changes in mTOR or autophagic flux. cPLA(2) and lipid mediator-induced autophagy is ATG5 dependent. These data suggest that lipid mediators play a role in the regulation of autophagy, demonstrating a connection between the two seemingly separate innate immune responses, induction of autophagy and lipid mediator generation.

| S-EPMC3208068 | biostudies-literature

Cytosolic Phospholipase A2 Alpha Regulates TLR Signaling and Migration in Metastatic 4T1 Cells.

Project description:Metastatic disease is the leading cause of death in breast cancer patients. Disrupting the cancer cell's ability to migrate may be a strategy for hindering metastasis. Cytosolic phospholipase A2 ? (cPLA2?), along with downstream proinflammatory and promigratory metabolites, has been implicated in several aspects of tumorigenesis, as well as metastasis, in various types of cancer. In this study, we aim to characterize the response to reduced cPLA2? activity in metastatic versus non-metastatic cells. We employ an isogenic murine cell line pair displaying metastatic (4T1) and non-metastatic (67NR) phenotype to investigate the role of cPLA2? on migration. Furthermore, we elucidate the effect of reduced cPLA2? activity on global gene expression in the metastatic cell line. Enzyme inhibition is achieved by using a competitive pharmacological inhibitor, cPLA2? inhibitor X (CIX). Our data show that 4T1 expresses significantly higher cPLA2? levels as compared to 67NR, and the two cell lines show different sensitivity to the CIX treatment with regards to metabolism and proliferation. Inhibition of cPLA2? at nontoxic concentrations attenuates migration of highly metastatic 4T1 cells, but not non-metastatic 67NR cells. Gene expression analysis indicates that processes such as interferon type I (IFN-I) signaling and cell cycle regulation are key processes regulated by cPLA2a in metastatic 4T1 cells, supporting the findings from the biological assays. This study demonstrates that two isogenic cancer cell lines with different metastatic potential respond differently to reduced cPLA2? activity. In conclusion, we argue that cPLA2? is a potential therapeutic target in cancer and that enzyme inhibition may inhibit metastasis through an anti-migratory mechanism, possibly involving Toll-like receptor signaling and type I interferons.

| S-EPMC6801560 | biostudies-literature

Cytosolic phospholipase A2 gamma is involved in hepatitis C virus replication and assembly.

Project description:Similar to other positive-sense, single-stranded RNA viruses, hepatitis C virus (HCV) replicates its genome in a remodeled intracellular membranous structure known as the membranous web (MW). To date, the process of MW formation remains unclear. It is generally acknowledged that HCV nonstructural protein 4B (NS4B) can induce MW formation through interaction with the cytosolic endoplasmic reticulum (ER) membrane. Many host proteins, such as phosphatidylinositol 4-kinase III? (PI4KIII?), have been identified as critical factors required for this process. We now report a new factor, the cytosolic phospholipase A2 gamma (PLA2G4C), which contributes to MW formation, HCV replication, and assembly. The PLA2G4C gene was identified as a host gene with upregulated expression upon HCV infection. Knockdown of PLA2G4C in HCV-infected cells or HCV replicon-containing cells by small interfering RNA (siRNA) significantly suppressed HCV replication and assembly. In addition, the chemical inhibitor methyl arachidonyl fluorophosphonate (MAFP), which specifically inhibits PLA2, reduced HCV replication and assembly. Electron microscopy demonstrated that MW structure formation was defective after PLA2G4C knockdown in HCV replicon-containing cells. Further analysis by immunostaining and immunoprecipitation assays indicated that PLA2G4C colocalized with the HCV proteins NS4B and NS5A in cells infected with JFH-1 and interacted with NS4B. In addition, PLA2G4C was able to transport the HCV nonstructural proteins from replication sites to lipid droplets, the site for HCV assembly. These data suggest that PLA2G4C plays an important role in the HCV life cycle and might represent a potential target for anti-HCV therapy.

| S-EPMC3497680 | biostudies-literature

Dietary pyruvate targets cytosolic phospholipase A2 to mitigate inflammation and obesity in mice.

Project description:Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity but it also sheds light on the mechanism of its action. Pyruvate's prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.

| S-EPMC11365557 | biostudies-literature

Critical Involvement of Calcium-Dependent Cytosolic Phospholipase A2? in Aortic Valve Interstitial Cell Calcification.

Project description:The involvement of calcium-dependent cytosolic phospholipase A2? (cPLA2?) in aortic valve calcification is not exhaustively elucidated. Here, cPLA2? 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 cPLA2?-immunoreactive cells, with parallel ultrastructural examination of AVIC calcific degeneration. These evaluations also involved pro-calcific AVIC cultures treated with cPLA2? inhibitor dexamethasone. cPLA2? 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, cPLA2? 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, cPLA2? 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 cPLA2? amounts were paralleled by drastic decreases in mineralization degrees, as revealed ultrastructurally. In conclusion, cPLA2? 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.

| S-EPMC7503521 | biostudies-literature

Cytosolic phospholipase A2? increases proliferation and de-differentiation of human renal tubular epithelial cells.

Project description:The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2?) enzyme controls the release of arachidonic acid from membrane bound phospholipids and is the rate-limiting step in production of eicosanoids. A variety of different kidney injuries activate cPLA2?, therefore we hypothesized that cPLA2? activity would regulate pathologic processes in HK-2 cells, a human renal tubular epithelial cell line, by regulating cell phenotype and proliferation. In two lentiviral cPLA2?-silenced knockdowns, we observed decreased proliferation and increased apoptosis compared to control HK-2 cells. cPLA2?-silenced cells also demonstrated an altered morphology, had increased expression E-cadherin, and decreased expression of Ncadherin. Increased levels of E-cadherin were associated with increased promoter activity and decreased levels of SNAIL1, SNAIL2, and ZEB1, transcriptional repressors of E-cadherin expression. Addition of exogenous arachidonic acid, but not PGE2, reversed the phenotypic changes in cPLA2?-silenced cells. These data suggest that cPLA2? may play a key role in renal repair after injury through a PGE2-independent mechanism.

| S-EPMC5099119 | biostudies-literature

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