Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current Perspectives.
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ABSTRACT:
SUBMITTER: Zulfikar S
PROVIDER: S-EPMC7367740 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current Perspectives.
Zulfikar Sabrina S Mulholland Sarah S Adamali Huzaifa H Barratt Shaney L SL
Clinical pharmacology : advances and applications 20200713
Idiopathic pulmonary fibrosis is a progressive fibrosing interstitial lung disease for which there is no known cure. Currently available therapeutic options have been shown at best to slow the progression of the disease and thus there remains an urgent unmet need to identify new therapies. In this article, we will discuss the mechanisms of action, pre-clinical and clinical trial data surrounding inhibitors of the autotaxin-lysophosphatidic acid axis, which show promise as emerging novel therapie ...[more]
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Project description:Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic acid (2ccPA), induces various biological activities in vitro and in vivo. Although cPA is similar to lysophosphatidic acid (LPA) in structure and synthetic pathway, some of cPA biological functions apparently differ from those reported for LPA. We previously investigated the pharmacokinetic profile of 2ccPA, which was found to be rapidly degraded, especially in acidic conditions, yielding an unidentified compound. Thus, not only cPA but also its degradation compound may contribute to the biological activity of cPA, at least for 2ccPA. In this study, we determined the structure and examined the biological activities of 2-carba-lysophosphatidic acid (2carbaLPA) as a 2ccPA degradation compound, which is a type of β-LPA analogue. Similar to LPA and cPA, 2carbaLPA induced the phosphorylation of the extracellular signal-regulated kinase and showed potent agonism for all known LPA receptors (LPA1-6) in the transforming growth factor-α (TGFα) shedding assay, in particular for LPA3 and LPA4. 2carbaLPA inhibited the lysophospholipase D activity of autotaxin (ATX) in vitro similar to other cPA analogues, such as 2ccPA, 3-carba-cPA, and 3-carba-LPA (α-LPA analogue). Our study shows that 2carbaLPA is a novel β-LPA analogue with high potential for the activation of some LPA receptors and ATX inhibition.
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Project description:Primary open-angle glaucoma is the second leading cause of blindness in the United States and is commonly associated with elevated intraocular pressure (IOP) resulting from diminished aqueous humor (AH) drainage through the trabecular pathway. Developing effective therapies for increased IOP in glaucoma patients requires identification and characterization of molecular mechanisms that regulate IOP and AH outflow. This study describes the identification and role of autotaxin (ATX), a secretory protein and a major source for extracellular lysophosphatidic acid (LPA), in regulation of IOP in a rabbit model. Quantitative proteomics analysis identified ATX as an abundant protein in both human AH derived from non-glaucoma subjects and in AH from different animal species. The lysophospholipase D (LysoPLD) activity of ATX was found to be significantly elevated (by ?1.8 fold; n=20) in AH derived from human primary open angle glaucoma patients as compared to AH derived from age-matched cataract control patients. Immunoblotting analysis of conditioned media derived from primary cultures of human trabecular meshwork (HTM) cells has confirmed secretion of ATX and the ability of cyclic mechanical stretch of TM cells to increase the levels of secreted ATX. Topical application of a small molecular chemical inhibitor of ATX (S32826), which inhibited AH LysoPLD activity in vitro (by >90%), led to a dose-dependent and significant decrease of IOP in Dutch-Belted rabbits. Single intracameral injection of S32826 (?2 µM) led to significant reduction of IOP in rabbits, with the ocular hypotensive response lasting for more than 48 hrs. Suppression of ATX expression in HTM cells using small-interfering RNA (siRNA) caused a decrease in actin stress fibers and myosin light chain phosphorylation. Collectively, these observations indicate that the ATX-LPA axis represents a potential therapeutic target for lowering IOP in glaucoma patients.
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Project description:Lysophosphatidylcholine (LPC) is a bioactive lipid that has been shown to attenuate endothelium-dependent vasorelaxation contributing to endothelial dysfunction; however, the underlying mechanisms are not well understood. In this study, we investigated the molecular mechanisms involved in the development of LPC-evoked impairment of endothelium-dependent vasorelaxation. In aortic rings isolated from wild-type (WT) mice, a 20-min exposure to LPC significantly reduced the acetylcholine chloride (ACh)-induced vasorelaxation indicating the impairment of normal endothelial function. Interestingly, pharmacological inhibition of autotaxin (ATX) by GLPG1690 partially reversed the endothelial dysfunction, suggesting that lysophosphatidic acid (LPA) derived from LPC may be involved in the effect. Therefore, the effect of LPC was also tested in aortic rings isolated from different LPA receptor knock-out (KO) mice. LPC evoked a marked reduction in ACh-dependent vasorelaxation in Lpar1, Lpar2, and Lpar4 KO, but its effect was significantly attenuated in Lpar5 KO vessels. Furthermore, addition of superoxide dismutase reduced the LPC-induced endothelial dysfunction in WT but not in the Lpar5 KO mice. In addition, LPC increased H2O2 release from WT vessels, which was significantly reduced in Lpar5 KO vessels. Our findings indicate that the ATX-LPA-LPA5 receptor axis is involved in the development of LPC-induced impairment of endothelium-dependent vasorelaxation via LPA5 receptor-mediated reactive oxygen species production. Taken together, in this study, we identified a new pathway contributing to the development of LPC-induced endothelial dysfunction.
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Project description:Ocular hypertension due to impaired aqueous humor (AH) drainage through the trabecular meshwork (TM) is a major risk factor for glaucoma, a leading cause of irreversible blindness. However, the etiology of ocular hypertension remains unclear. Although autotaxin, a secreted lysophospholipase D and its catalytic product lysophosphatidic acid (LPA) have been shown to modulate AH drainage through TM, we do not have a complete understanding of their role and regulation in glaucoma patients, TM and AH outflow. This study reports a significant increase in the levels of autotaxin, lysophosphatidylcholine (LPC), LPA and connective tissue growth factor (CTGF) in the AH of Caucasian and African American open angle glaucoma patients relative to age-matched non-glaucoma patients. Treatment of human TM cells with dexamethasone, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) increased the levels of autotaxin protein, a response that was mitigated by inhibitors of glucocorticoid receptor, NF-kB and SMAD3. Dexamethasone, TNF-α, IL-1β and LPC treatment of TM cells also led to an increase in the levels of CTGF, fibronectin and collagen type 1 in an autotaxin dependent manner. Additionally, in perfused enucleated mouse eyes, autotaxin and LPC were noted to decrease, while inhibition of autotaxin was increased aqueous outflow through the TM. Taken together, these results provide additional evidence for dysregulation of the autotaxin-LPA axis in the AH of glaucoma patients, reveal molecular insights into the regulation of autotaxin expression in TM cells and the consequences of autotaxin inhibitors in suppressing the fibrogenic response and resistance to AH outflow through the TM.
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Project description:Background The loss of endothelial integrity increases the risk of intracerebral hemorrhage during ischemic stroke. Adjunct therapeutic targets for reperfusion in ischemic stroke are in need to prevent blood-brain barrier disruption. Recently, we have shown that endothelial permeability is mediated by lysophosphatidic acid (LPA), but the role of autotaxin, which produces LPA, remains unclear in stroke. We investigate whether autotaxin/LPA axis regulates blood-brain barrier integrity after cerebral ischemia. Methods and Results Ischemic stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by 24-hour reperfusion. The therapeutic efficacy of autotaxin/LPA receptor blockade was evaluated using triphenyl tetrazolium chloride staining, Evans blue permeability, infrared imaging, mass spectrometry, and XF24 analyzer to evaluate blood-brain barrier integrity, autotaxin activity, and mitochondrial bioenergetics. In our mouse model of ischemic stroke, the mRNA levels of autotaxin were elevated 1.7-fold following the cerebral ischemia and reperfusion (I/R) group compared with the sham. The enzymatic activity of autotaxin was augmented by 4-fold in the I/R group compared with the sham. Plasma and brain tissues in I/R group showed elevated LPA levels. The I/R group also demonstrated mitochondrial dysfunction, as evidenced by decreased (P<0.01) basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity. Treatment with autotaxin inhibitors (HA130 or PF8380) or autotaxin/LPA receptor inhibitor (BrP-LPA) rescued endothelial permeability and mitochondrial dysfunction in I/R group. Conclusions Autotaxin-LPA signaling blockade attenuates blood-brain barrier disruption and mitochondrial function following I/R, suggesting targeting this axis could be a new therapeutic approach toward treating ischemic stroke.
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Project description:Autotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from lysophosphatidylcholine. LPA is an important signaling phospholipid that can bind to six G protein-coupled receptors (LPA1-6). The ATX-LPA signaling axis is a critical component in many physiological and pathophysiological conditions. Here, we describe a potent inhibition of Δ9-trans-tetrahydrocannabinol (THC), the main psychoactive compound of medicinal cannabis and related cannabinoids, on the catalysis of two isoforms of ATX with nanomolar apparent EC50 values. Furthermore, we decipher the binding interface of ATX to THC, and its derivative 9(R)-Δ6a,10a-THC (6a10aTHC), by X-ray crystallography. Cellular experiments confirm this inhibitory effect, revealing a significant reduction of internalized LPA1 in the presence of THC with simultaneous ATX and lysophosphatidylcholine stimulation. Our results establish a functional interaction of THC with autotaxin-LPA signaling and highlight novel aspects of medicinal cannabis therapy.
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Project description:Glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Its prognosis is one of the worst among all cancer types, and it is considered a fatal malignancy, incurable with conventional therapeutic strategies. As the bioactive multifunctional lipid mediator lysophosphatidic acid (LPA) is well recognized to be involved in the tumorigenesis of cancers by acting on G-protein-coupled receptors, LPA receptor (LPAR) antagonists and LPA synthesis inhibitors have been proposed as promising drugs for cancer treatment. Six LPARs, named LPA1-6, are currently recognized. Among them, LPA1 is the dominant LPAR in the CNS and is highly expressed in GBM in combination with the overexpression of autotaxin (ATX), the enzyme (a phosphodiesterase, which is a potent cell motility-stimulating factor) that produces LPA.Invasion is a defining hallmark of GBM. LPA is significantly related to cell adhesion, cell motility, and invasion through the Rho family GTPases Rho and Rac. LPA1 is responsible for LPA-driven cell motility, which is attenuated by LPA4. GBM is among the most vascular human tumors. Although anti-angiogenic therapy (through the inhibition of vascular endothelial growth factor (VEGF)) was established, sufficient results have not been obtained because of the increased invasiveness triggered by anti-angiogenesis. As both ATX and LPA play a significant role in angiogenesis, similar to VEGF, inhibition of the ATX/LPA axis may be beneficial as a two-pronged therapy that includes anti-angiogenic and anti-invasion therapy. Conventional approaches to GBM are predominantly directed at cell proliferation. Recurrent tumors regrow from cells that have invaded brain tissues and are less proliferative, and are thus quite resistant to conventional drugs and radiation, which preferentially kill rapidly proliferating cells. A novel approach that targets this invasive subpopulation of GBM cells may improve the prognosis of GBM. Patients with GBM that contacts the subventricular zone (SVZ) have decreased survival. A putative source of GBM cells is the SVZ, the largest area of neurogenesis in the adult human brain. GBM stem cells in the SVZ that are positive for the neural stem cell surface antigen CD133 are highly tumorigenic and enriched in recurrent GBM. LPA1 expression appears to be increased in these cells. Here, the author reviews research on the ATX/LPAR axis, focusing on GBM and an ATX/LPAR-targeted approach.
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Project description:Muscular dystrophies (MDs) are a diverse group of severe disorders characterized by increased skeletal muscle feebleness. In many cases, respiratory and cardiac muscles are also compromised. Skeletal muscle inflammation and fibrosis are hallmarks of several skeletal muscle diseases, including MDs. Until now, several keys signaling pathways and factors that regulate inflammation and fibrosis have been identified. However, no curative treatments are available. Therefore, it is necessary to find new therapeutic targets to fight these diseases and improve muscle performance. Lysophosphatidic acid (LPA) is an active glycerophospholipid mainly synthesized by the secreted enzyme autotaxin (ATX), which activates six different G protein-coupled receptors named LPA1 to LPA6 (LPARs). In conjunction, they are part of the ATX/LPA/LPARs axis, involved in the inflammatory and fibrotic response in several organs-tissues. This review recapitulates the most relevant aspects of inflammation and fibrosis in MDs. It analyzes experimental evidence of the effects of the ATX/LPA/LPARs axis on inflammatory and fibrotic responses. Finally, we speculate about its potential role as a new therapeutic pharmacological target to treat these diseases.
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Project description:Previous studies provide high evidence that autotaxin (ATX)-lysophosphatidic acid (LPA) signaling through LPA receptors (LPAR) plays an important role in breast cancer initiation, progression, and invasion. However, its specific role in different breast cancer cell lines remains to be fully elucidated to offer improvements in targeted therapies. Within this study, we analyzed in vitro the effect of LPA 18:1 and the LPAR1, LPAR3 (and LPAR2) inhibitor Ki16425 on cellular functions of different human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, BT-474, SKBR-3) and the human breast epithelial cell line MCF-10A, as well as Interleukin 8 (IL-8), Interleukin 6 (IL-6) and tumor necrosis factor (TNF)-alpha cytokine secretion after LPA-incubation. ATX-LPA signaling showed a dose-dependent stimulatory effect especially on cellular functions of triple-negative and luminal A breast cancer cell lines. Ki16425 inhibited the LPA-induced stimulation of triple-negative breast cancer and luminal A cell lines in variable intensity depending on the functional assay, indicating the interplay of different LPAR in those assays. IL-8, IL-6 and TNF-alpha secretion was induced by LPA in MDA-MB-468 cells. This study provides further evidence about the role of the ATX-LPA axis in different breast cancer cell lines and might contribute to identify subtypes suitable for a future targeted therapy of the ATX-LPA axis.
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