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1
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Liu F, Cai H. Diabetes and calcific aortic valve disease: implications of glucose-lowering medication as potential therapy. Front Pharmacol 2025; 16:1583267. [PMID: 40356984 PMCID: PMC12066769 DOI: 10.3389/fphar.2025.1583267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
Calcific aortic valve disease (CAVD) is a progressive disease, of which the 2-year mortality is >50% for symptomatic disease. However, there are currently no pharmacotherapies to prevent the progression of CAVD unless transcatheter or surgical aortic valve replacement is performed. The prevalence of diabetes among CAVD has increased rapidly in recent decades, especially among those undergoing aortic valve replacement. Diabetes and its comorbidities, such as hypertension, hyperlipidemia, chronic kidney disease and ageing, participated jointly in the initiation and progression of CAVD, which increased the management complexity in patients with CAVD. Except from hyperglycemia, the molecular links between diabetes and CAVD included inflammation, oxidative stress and endothelial dysfunction. Traditional cardiovascular drugs like lipid-lowering agents and renin-angiotensin system blocking drugs have proven to be unsuccessful in retarding the progression of CAVD in clinical trials. In recent years, almost all kinds of glucose-lowering medications have been specifically assessed for decelerating the development of CAVD. Based on the efficacy for atherosclerotic cardiovascular disease and CAVD, this review summarized current knowledge about glucose-lowering medications as promising treatment options with the potential to retard CAVD.
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Affiliation(s)
| | - Haipeng Cai
- Department of Cardiology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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2
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Zhang X, Liu J, Bai C, Li Y, Fan Y. Exploring the potential role of ENPP2 in polycystic ovary syndrome and endometrial cancer through bioinformatic analysis. PeerJ 2024; 12:e18666. [PMID: 39717045 PMCID: PMC11665432 DOI: 10.7717/peerj.18666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 11/18/2024] [Indexed: 12/25/2024] Open
Abstract
Background Growing evidence indicates a significant correlation between polycystic ovary syndrome (PCOS) and endometrial carcinoma (EC); nevertheless, the fundamental molecular mechanisms involved continue to be unclear. Methods Initially, differential analysis, the least absolute shrinkage and selection operator (LASSO) regression, and support vector machine-recursive feature elimination (SVM-RFE) algorithms were employed to identify candidate genes associated with ferroptosis in PCOS. Subsequently, the TCGA-UCEC data were utilized to pinpoint the core gene. Then, the expression of ENPP2 in granulosa cells and endometrium of PCOS was validated using real-time PCR (RT-qPCR). Additionally, we investigated the role of ENPP2 in the progression from PCOS to EC through western blotting (WB), colony formation assay, cell scratch assay, transwell assay, and immunofluorescence (IF). Subsequently, ENPP2 gene set enrichment analysis (GSEA) analyses were conducted to identify common pathways involved in PCOS and EC, which were then verified by RT-qPCR. Finally, immune infiltration and the tumor microenvironment (TME) were explored to examine the involvement of ENPP2 in EC progression. Results The datasets TCGA-UCEC (pertaining to EC), GSE34526, GSE137684, and GSE6798 (related to PCOS) were procured and subjected to analysis. The gene ENPP2 has been recognized as the shared element connecting PCOS and EC. Next, we observed a significant downregulation of ENPP2 expression in the granulosa cells in PCOS compared to the normal patients, while an upregulation of ENPP2 expression was observed in the endometrium of hyperandrogenic PCOS patients relative to the normal. In vitro, the WB revealed that 5-dihydrotestosterone (DHT) upregulated ENPP2 expression in Ishikawa and HEC-1-A cells. Additionally, we found that ENPP2 promoted the proliferation, migration, and invasion of Ishikawa and HEC-1-A cells. Subsequently, we discovered that overexpressed ENPP2 may lead to an increase in CYP19A1 (aromatase) and AR mRNA level. IF demonstrated that ENPP2 increased the expression of AR, suggesting a regulatory role for ENPP2 in hormonal response within PCOS and EC. Our findings indicated a significant correlation between ENPP2 expression and the modulation of immune responses.
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Affiliation(s)
- Xumin Zhang
- The Fifth Clinical Medical College of Shanxi Medical University, TaiYuan, ShanXi, China
| | - Jianrong Liu
- The Fifth Clinical Medical College of Shanxi Medical University, TaiYuan, ShanXi, China
| | - Chunmei Bai
- The Fifth Clinical Medical College of Shanxi Medical University, TaiYuan, ShanXi, China
| | - Yang Li
- The Fifth Clinical Medical College of Shanxi Medical University, TaiYuan, ShanXi, China
| | - Yanxin Fan
- The Fifth Clinical Medical College of Shanxi Medical University, TaiYuan, ShanXi, China
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3
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Bhattacharyya S, Oon C, Diaz L, Sandborg H, Stempinski ES, Saoi M, Morgan TK, López CS, Cross JR, Sherman MH. Autotaxin-lysolipid signaling suppresses a CCL11-eosinophil axis to promote pancreatic cancer progression. NATURE CANCER 2024; 5:283-298. [PMID: 38195933 PMCID: PMC10899115 DOI: 10.1038/s43018-023-00703-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 12/06/2023] [Indexed: 01/11/2024]
Abstract
Lipids and their modifying enzymes regulate diverse features of the tumor microenvironment and cancer progression. The secreted enzyme autotaxin (ATX) hydrolyzes extracellular lysophosphatidylcholine to generate the multifunctional lipid mediator lysophosphatidic acid (LPA) and supports the growth of several tumor types, including pancreatic ductal adenocarcinoma (PDAC). Here we show that ATX suppresses the accumulation of eosinophils in the PDAC microenvironment. Genetic or pharmacologic ATX inhibition increased the number of intratumor eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop, wherein ATX-LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, in turn suppressing the expression of the potent eosinophil chemoattractant CCL11 (eotaxin-1). Eosinophils were identified in human PDAC specimens, and rare individuals with high intratumor eosinophil abundance had the longest overall survival. Together with recent findings, this study reveals the context-dependent, immune-modulatory potential of ATX-LPA signaling in cancer.
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Affiliation(s)
- Sohinee Bhattacharyya
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
- Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chet Oon
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
- Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Luis Diaz
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - Holly Sandborg
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
- Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Erin S Stempinski
- Multiscale Microscopy Core Facility, Oregon Health & Science University, Portland, OR, USA
| | - Michelle Saoi
- Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Terry K Morgan
- Department of Pathology, Oregon Health & Science University, Portland, OR, USA
| | - Claudia S López
- Multiscale Microscopy Core Facility, Oregon Health & Science University, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
| | - Justin R Cross
- Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mara H Sherman
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
- Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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4
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Calcific aortic valve disease: mechanisms, prevention and treatment. Nat Rev Cardiol 2023:10.1038/s41569-023-00845-7. [PMID: 36829083 DOI: 10.1038/s41569-023-00845-7] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/01/2023] [Indexed: 02/26/2023]
Abstract
Calcific aortic valve disease (CAVD) is the most common disorder affecting heart valves and is characterized by thickening, fibrosis and mineralization of the aortic valve leaflets. Analyses of surgically explanted aortic valve leaflets have shown that dystrophic mineralization and osteogenic transition of valve interstitial cells co-occur with neovascularization, microhaemorrhage and abnormal production of extracellular matrix. Age and congenital bicuspid aortic valve morphology are important and unalterable risk factors for CAVD, whereas additional risk is conferred by elevated blood pressure and plasma lipoprotein(a) levels and the presence of obesity and diabetes mellitus, which are modifiable factors. Genetic and molecular studies have identified that the NOTCH, WNT-β-catenin and myocardin signalling pathways are involved in the control and commitment of valvular cells to a fibrocalcific lineage. Complex interactions between valve endothelial and interstitial cells and immune cells promote the remodelling of aortic valve leaflets and the development of CAVD. Although no medical therapy is effective for reducing or preventing the progression of CAVD, studies have started to identify actionable targets.
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5
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Vít O, Petrák J. Autotaxin and Lysophosphatidic Acid Signalling: the Pleiotropic Regulatory Network in Cancer. Folia Biol (Praha) 2023; 69:149-162. [PMID: 38583176 DOI: 10.14712/fb2023069050149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Autotaxin, also known as ecto-nucleotide pyrophosphatase/phosphodiesterase family member 2, is a secreted glycoprotein that plays multiple roles in human physiology and cancer pathology. This protein, by converting lysophosphatidylcholine into lysophosphatidic acid, initiates a complex signalling cascade with significant biological implications. The article outlines the autotaxin gene and protein structure, expression regulation and physiological functions, but focuses mainly on the role of autotaxin in cancer development and progression. Autotaxin and lysophosphatidic acid signalling influence several aspects of cancer, including cell proliferation, migration, metastasis, therapy resistance, and interactions with the immune system. The potential of autotaxin as a diagnostic biomarker and promising drug target is also examined.
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Affiliation(s)
- Ondřej Vít
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
| | - Jiří Petrák
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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6
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Wang S, Chen J, Guo XZ. KAI1/CD82 gene and autotaxin-lysophosphatidic acid axis in gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:1388-1405. [PMID: 36160748 PMCID: PMC9412925 DOI: 10.4251/wjgo.v14.i8.1388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/06/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.
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Affiliation(s)
- Shuo Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Jiang Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Xiao-Zhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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7
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Roy A, Sarkar T, Datta S, Maiti A, Chakrabarti M, Mondal T, Mondal C, Banerjee A, Roy S, Mukherjee S, Muley P, Chakraborty S, Banerjee M, Kundu M, Roy KK. Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor. Chem Biol Drug Des 2021; 99:496-503. [PMID: 34951520 DOI: 10.1111/cbdd.14017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/10/2021] [Accepted: 12/21/2021] [Indexed: 01/06/2023]
Abstract
Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint = 15.6 μl/min/mg; T1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.
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Affiliation(s)
- Ashis Roy
- TCG Lifesciences Pvt. Ltd., Kolkata, India
| | | | | | - Arup Maiti
- TCG Lifesciences Pvt. Ltd., Kolkata, India
| | | | | | | | | | | | | | | | | | | | | | - Kuldeep K Roy
- Department of Pharmaceutical Sciences, School of Health Sciences, UPES, Dehradun, India
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Kitakaze K, Tsuboi K, Tsuda M, Takenouchi Y, Ishimaru H, Okamoto Y. Development of a selective fluorescence-based enzyme assay for glycerophosphodiesterase family members GDE4 and GDE7. J Lipid Res 2021; 62:100141. [PMID: 34673020 PMCID: PMC8591415 DOI: 10.1016/j.jlr.2021.100141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/08/2021] [Accepted: 10/12/2021] [Indexed: 01/02/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a lipid mediator that regulates various processes, including cell migration and cancer progression. Autotaxin (ATX) is a lysophospholipase D-type exoenzyme that produces extracellular LPA. In contrast, glycerophosphodiesterase (GDE) family members GDE4 and GDE7 are intracellular lysophospholipases D that form LPA, depending on Mg2+ and Ca2+, respectively. Since no fluorescent substrate for these GDEs has been reported, in the present study, we examined whether a fluorescent ATX substrate, FS-3, could be applied to study GDE activity. We found that the membrane fractions of human GDE4- and GDE7-overexpressing human embryonic kidney 293T cells hydrolyzed FS-3 in a manner almost exclusively dependent on Mg2+ and Ca2+, respectively. Using these assay systems, we found that several ATX inhibitors, including α-bromomethylene phosphonate analog of LPA and 3-carbacyclic phosphatidic acid, also potently inhibited GDE4 and GDE7 activities. In contrast, the ATX inhibitor S32826 hardly inhibited these activities. Furthermore, FS-3 was hydrolyzed in a Mg2+-dependent manner by the membrane fraction of human prostate cancer LNCaP cells that express GDE4 endogenously but not by those of GDE4-deficient LNCaP cells. Similar Ca2+-dependent GDE7 activity was observed in human breast cancer MCF-7 cells but not in GDE7-deficient MCF-7 cells. Finally, our assay system could selectively measure GDE4 and GDE7 activities in a mixture of the membrane fractions of GDE4- and GDE7-overexpressing human embryonic kidney 293T cells in the presence of S32826. These findings allow high-throughput assays of GDE4 and GDE7 activities, which could lead to the development of selective inhibitors and stimulators as well as a better understanding of the biological roles of these enzymes.
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Affiliation(s)
- Keisuke Kitakaze
- Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
| | - Kazuhito Tsuboi
- Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
| | - Maho Tsuda
- Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Yasuhiro Takenouchi
- Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Hironobu Ishimaru
- Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Yasuo Okamoto
- Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, Japan
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9
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Uranbileg B, Ito N, Kurano M, Kano K, Uchida K, Sumitani M, Aoki J, Yatomi Y. Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis. Sci Rep 2021; 11:3984. [PMID: 33597645 PMCID: PMC7889906 DOI: 10.1038/s41598-021-83569-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/04/2021] [Indexed: 12/13/2022] Open
Abstract
Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA1 receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.
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Affiliation(s)
- Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuko Ito
- Department of Anesthesiology and Pain Relief Center, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Kanji Uchida
- Department of Anesthesiology and Pain Relief Center, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Masahiko Sumitani
- Department of Pain and Palliative Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
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10
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Hirata T, Smith SV, Takahashi T, Miyata N, Roman RJ. Increased Levels of Renal Lysophosphatidic Acid in Rodent Models with Renal Disease. J Pharmacol Exp Ther 2021; 376:240-249. [PMID: 33277348 PMCID: PMC7841420 DOI: 10.1124/jpet.120.000353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/01/2020] [Indexed: 12/29/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that has been implicated in the pathophysiology of kidney disease. However, few studies have attempted to measure changes in the levels of various LPA species in the kidney after the development of renal disease. The present study measured the renal LPA levels during the development of kidney disease in rat models of hypertension, diabetes, and obstructive nephropathy using liquid chromatography/mass spectrometry/mass spectrometry. LPA levels (sum of 16:0, 18:0, 18:1, 18:2, and 20:4 LPA) were higher in the renal cortex of hypertensive Dahl salt-sensitive (Dahl S) rats fed a high-salt diet than those in normotensive rats fed a low-salt diet (296.6 ± 22.9 vs. 196.3 ± 8.5 nmol/g protein). LPA levels were elevated in the outer medulla of the kidney of streptozotocin-induced type 1 diabetic Dahl S rats compared with control rats (624.6 ± 129.5 vs. 318.8 ± 17.1 nmol/g protein). LPA levels were also higher in the renal cortex of 18-month-old, type 2 diabetic nephropathy (T2DN) rats with more severe renal injury than in 6-month-old T2DN rats (184.9 ± 20.9 vs. 116.9 ± 6.0 nmol/g protein). LPA levels also paralleled the progression of renal fibrosis in the renal cortex of Sprague-Dawley rats after unilateral ureteral obstruction (UUO). Administration of an LPA receptor antagonist, Ki16425, reduced the degree of renal fibrosis in UUO rats. These results suggest that the production of renal LPA increases during the development of renal injury and contributes to renal fibrosis. SIGNIFICANCE STATEMENT: The present study reveals that the lysophosphatidic acid (LPA) levels increase in the kidney in rat models of hypertension, diabetes, and obstructive nephropathy, and administration of an LPA receptor antagonist attenuates renal fibrosis. Therapeutic approaches that target the formation or actions of renal LPA might be renoprotective and have therapeutic potential.
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Affiliation(s)
- Takashi Hirata
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Stanley V Smith
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Teisuke Takahashi
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Noriyuki Miyata
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Richard J Roman
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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11
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Geraldo LHM, Spohr TCLDS, Amaral RFD, Fonseca ACCD, Garcia C, Mendes FDA, Freitas C, dosSantos MF, Lima FRS. Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies. Signal Transduct Target Ther 2021; 6:45. [PMID: 33526777 PMCID: PMC7851145 DOI: 10.1038/s41392-020-00367-5] [Citation(s) in RCA: 169] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.
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Affiliation(s)
- Luiz Henrique Medeiros Geraldo
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Université de Paris, PARCC, INSERM, F-75015, Paris, France
| | | | | | | | - Celina Garcia
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fabio de Almeida Mendes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Catarina Freitas
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcos Fabio dosSantos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Flavia Regina Souza Lima
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
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12
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Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors. Int J Mol Sci 2020; 21:ijms21197002. [PMID: 32977539 PMCID: PMC7582705 DOI: 10.3390/ijms21197002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/18/2020] [Accepted: 09/19/2020] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design.
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13
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Guillot E, Le Bail JC, Paul P, Fourgous V, Briand P, Partiseti M, Cornet B, Janiak P, Philippo C. Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures. J Pharmacol Exp Ther 2020; 374:283-294. [PMID: 32409422 DOI: 10.1124/jpet.120.265454] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023] Open
Abstract
Lysophosphatidic acid (LPA) is the natural ligand for two phylogenetically distinct families of receptors (LPA1-3, LPA4-6) whose pathways control a variety of physiologic and pathophysiological responses. Identifying the benefit of balanced activation/repression of LPA receptors has always been a challenge because of the high lability of LPA and the limited availability of selective and/or stable agonists. In this study, we document the discovery of small benzofuran ethanolamine derivatives (called CpX and CpY) behaving as LPA1-3 agonists. Initially found as rabbit urethra contracting agents, their elusive receptors were identified from [35S]GTPγS-binding and β-arrestin2 recruitment investigations and then confirmed by [3H]CpX binding studies (urethra, hLPA1-2 membranes). Both compounds induced a calcium response in hLPA1-3 cells within a range of 0.4-1.5-log lower potency as compared with LPA. The contractions of rabbit urethra strips induced by these compounds perfectly matched binding affinities with values reaching the two-digit nanomolar level. The antagonist, KI16425, dose-dependently antagonized CpX-induced contractions in agreement with its affinity profile (LPA1≥LPA3>>LPA2). The most potent agonist, CpY, doubled intraurethral pressure in anesthetized female rats at 3 µg/kg i.v. Alternatively, CpX was shown to inhibit human preadipocyte differentiation, a process totally reversed by KI16425. Together with original molecular docking data, these findings clearly established these molecules as potent agonists of LPA1-3 and consolidated the pivotal role of LPA1 in urethra/prostate contraction as well as in fat cell development. The discovery of these unique and less labile LPA1-3 agonists would offer new avenues to investigate the roles of LPA receptors. SIGNIFICANCE STATEMENT: We report the identification of benzofuran ethanolamine derivatives behaving as potent selective nonlipid LPA1-3 agonists and shown to alter urethra muscle contraction or preadipocyte differentiation. Unique at this level of potency, selectivity, and especially stability, compared with lysophosphatidic acid, they represent more appropriate tools for investigating the physiological roles of lysophosphatidic acid receptors and starting point for optimization of drug candidates for therapeutic applications.
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Affiliation(s)
- Etienne Guillot
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
| | - Jean-Christophe Le Bail
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
| | - Pascal Paul
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
| | - Valérie Fourgous
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
| | - Pascale Briand
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
| | - Michel Partiseti
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
| | - Bruno Cornet
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
| | - Philip Janiak
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
| | - Christophe Philippo
- Diabetes and Cardiovascular Unit, Sanofi R&D, Chilly-Mazarin, France (E.G., J.C.L.B., P.B., P.J.); Global Research Portfolio and Project Management, Sanofi R&D, Chilly-Mazarin, France (C.P.); Translational Science Unit, Sanofi R&D, Chilly-Mazarin, France (P.P., V.F.); In-silico design, Chilly-Mazarin, France (B.C.); and Integrated Drug Discovery, Sanofi R&D, Vitry-Sur-Seine, France (M.P.)
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Cuozzo JW, Clark MA, Keefe AD, Kohlmann A, Mulvihill M, Ni H, Renzetti LM, Resnicow DI, Ruebsam F, Sigel EA, Thomson HA, Wang C, Xie Z, Zhang Y. Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry. J Med Chem 2020; 63:7840-7856. [PMID: 32584034 DOI: 10.1021/acs.jmedchem.0c00688] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound 1 inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.
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Affiliation(s)
- John W Cuozzo
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Matthew A Clark
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Anthony D Keefe
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Anna Kohlmann
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Mark Mulvihill
- X-Rx, Inc., 430 East 29th Street, Suite 1060, New York, New York 10016, United States
| | - Haihong Ni
- BioDuro, LLC, Building E, No. 29 Life Science Park Road, Changping District, Beijing 102206, China
| | - Louis M Renzetti
- X-Rx, Inc., 430 East 29th Street, Suite 1060, New York, New York 10016, United States
| | - Daniel I Resnicow
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Frank Ruebsam
- BioDuro, LLC, Building E, No. 29 Life Science Park Road, Changping District, Beijing 102206, China
| | - Eric A Sigel
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Heather A Thomson
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Ce Wang
- BioDuro, LLC, Building E, No. 29 Life Science Park Road, Changping District, Beijing 102206, China
| | - Zhifeng Xie
- BioDuro, LLC, Building E, No. 29 Life Science Park Road, Changping District, Beijing 102206, China
| | - Ying Zhang
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
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15
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Iwaki Y, Ohhata A, Nakatani S, Hisaichi K, Okabe Y, Hiramatsu A, Watanabe T, Yamamoto S, Nishiyama T, Kobayashi J, Hirooka Y, Moriguchi H, Maeda T, Katoh M, Komichi Y, Ota H, Matsumura N, Okada M, Sugiyama T, Saga H, Imagawa A. ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model. ACS Med Chem Lett 2020; 11:1335-1341. [PMID: 32551021 DOI: 10.1021/acsmedchemlett.0c00200] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/14/2020] [Indexed: 12/21/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.
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16
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Peyruchaud O, Saier L, Leblanc R. Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface. Cancers (Basel) 2019; 12:cancers12010105. [PMID: 31906151 PMCID: PMC7016970 DOI: 10.3390/cancers12010105] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/19/2019] [Accepted: 12/29/2019] [Indexed: 12/18/2022] Open
Abstract
Autotaxin (ATX) is an exoenzyme which, due to its unique lysophospholipase D activity, is responsible for the synthesis of lysophosphatidic acid (LPA). ATX activity is responsible for the concentration of LPA in the blood. ATX expression is increased in various types of cancers, including breast cancer, where it promotes metastasis. The expression of ATX is also remarkably increased under inflammatory conditions, particularly in the osteoarticular compartment, where it controls bone erosion. Biological actions of ATX are mediated by LPA. However, the phosphate head group of LPA is highly sensitive to degradation by the action of lipid phosphate phosphatases, resulting in LPA inactivation. This suggests that for efficient action, LPA requires protection, which is potentially achieved through docking to a carrier protein. Interestingly, recent reports suggest that ATX might act as a docking molecule for LPA and also support the concept that binding of ATX to the cell surface through its interaction with adhesive molecules (integrins, heparan sulfate proteoglycans) could facilitate a rapid route of delivering active LPA to its cell surface receptors. This new mechanism offers a new vision of how ATX/LPA works in cancer metastasis and inflammatory bone diseases, paving the way for new therapeutic developments.
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Affiliation(s)
- Olivier Peyruchaud
- INSERM, Unit 1033, Université Claude Bernard Lyon 1, 69372 Lyon, France;
- Correspondence: ; Tel.: +3-34-78-77-86-72
| | - Lou Saier
- INSERM, Unit 1033, Université Claude Bernard Lyon 1, 69372 Lyon, France;
| | - Raphaël Leblanc
- Centre de Recherche en Cancérologie de Marseille, Institut Poli-Calmettes, INSERM, Unit 1068, University Aix/Marseille, 13009 Marseille, France;
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17
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Pleotropic Roles of Autotaxin in the Nervous System Present Opportunities for the Development of Novel Therapeutics for Neurological Diseases. Mol Neurobiol 2019; 57:372-392. [PMID: 31364025 DOI: 10.1007/s12035-019-01719-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/23/2019] [Indexed: 12/23/2022]
Abstract
Autotaxin (ATX) is a soluble extracellular enzyme that is abundant in mammalian plasma and cerebrospinal fluid (CSF). It has two known enzymatic activities, acting as both a phosphodiesterase and a phospholipase. The majority of its biological effects have been associated with its ability to liberate lysophosphatidic acid (LPA) from its substrate, lysophosphatidylcholine (LPC). LPA has diverse pleiotropic effects in the central nervous system (CNS) and other tissues via the activation of a family of six cognate G protein-coupled receptors. These LPA receptors (LPARs) are expressed in some combination in all known cell types in the CNS where they mediate such fundamental cellular processes as proliferation, differentiation, migration, chronic inflammation, and cytoskeletal organization. As a result, dysregulation of LPA content may contribute to many CNS and PNS disorders such as chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer's disease, metabolic syndrome-induced brain damage, traumatic brain injury, hepatic encephalopathy-induced cerebral edema, macular edema, major depressive disorder, stress-induced psychiatric disorder, alcohol-induced brain damage, HIV-induced brain injury, pruritus, and peripheral nerve injury. ATX activity is now known to be the primary biological source of this bioactive signaling lipid, and as such, represents a potentially high-value drug target. There is currently one ATX inhibitor entering phase III clinical trials, with several additional preclinical compounds under investigation. This review discusses the physiological and pathological significance of the ATX-LPA-LPA receptor signaling axis and summarizes the evidence for targeting this pathway for the treatment of CNS diseases.
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18
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Sakamoto K, Noguchi Y, Ueshima K, Ohtake A, Sato S, Imazumi K, Takeda M, Masuda N. Modulation of urinary frequency via type 1 lysophosphatidic acid receptors: Effect of the novel antagonist ASP6432 in conscious rats. Eur J Pharmacol 2019; 853:11-17. [PMID: 30853531 DOI: 10.1016/j.ejphar.2019.03.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/25/2019] [Accepted: 03/06/2019] [Indexed: 01/04/2023]
Abstract
Bladder dysfunctions associated with benign prostatic hyperplasia are not sufficiently alleviated by current pharmacotherapies. Lysophosphatidic acid (LPA) is a phospholipid with diverse biological effects. LPA modulates prostate and urethral contraction via the type 1 LPA (LPA1) receptor, suggesting the potential of the LPA1 receptor as a therapeutic target. However, the role of LPA and the LPA1 receptor in bladder function has not been studied in vivo. We investigated the effects of LPA and the novel LPA1 receptor antagonist ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}- 1,3-thiazole-4-carbonyl)- 3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide) on the micturition reflex in conscious rats using cystometry. Intravenous infusion of LPA decreased the micturition interval and threshold pressure with no apparent changes in baseline pressure or maximum intravesical pressure. ASP6432 inhibited the LPA-induced decrease in MI. In contrast, ASP6432 had no effect on the LPA-induced decrease in threshold pressure. Similarly, ASP6432 had no effect on either baseline pressure or maximum intravesical pressure. We also evaluated the effect of ASP6432 on the urinary frequency induced by the nitric oxide synthase inhibitor L-Nω-nitro arginine methyl ester (L-NAME). Intravenous L-NAME administration decreased the micturition interval. ASP6432 dose-dependently reversed the L-NAME-induced decrease in micturition interval. Our findings demonstrate for the first time that LPA causes bladder overactivity in rats. ASP6432 inhibited the LPA- and L-NAME-induced decrease in micturition interval, suggesting a significant role for the LPA1 receptor in regulating the functional capacity of the bladder. Our results also suggest the potential of ASP6432 as a novel therapy for the treatment of bladder dysfunction associated with lower urinary tract diseases.
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Affiliation(s)
| | | | - Koji Ueshima
- Drug Discovery Research, Astellas Pharma Inc., Japan
| | | | - Shuichi Sato
- Drug Discovery Research, Astellas Pharma Inc., Japan
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19
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Auciello FR, Bulusu V, Oon C, Tait-Mulder J, Berry M, Bhattacharyya S, Tumanov S, Allen-Petersen BL, Link J, Kendsersky ND, Vringer E, Schug M, Novo D, Hwang RF, Evans RM, Nixon C, Dorrell C, Morton JP, Norman JC, Sears RC, Kamphorst JJ, Sherman MH. A Stromal Lysolipid-Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression. Cancer Discov 2019; 9:617-627. [PMID: 30837243 PMCID: PMC6497553 DOI: 10.1158/2159-8290.cd-18-1212] [Citation(s) in RCA: 238] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 02/03/2019] [Accepted: 02/28/2019] [Indexed: 01/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features transdifferentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin-LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. SIGNIFICANCE: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration.See related commentary by Biffi and Tuveson, p. 578.This article is highlighted in the In This Issue feature, p. 565.
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Affiliation(s)
- Francesca R Auciello
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Vinay Bulusu
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Chet Oon
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Jacqueline Tait-Mulder
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Mark Berry
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Sohinee Bhattacharyya
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Sergey Tumanov
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Jason Link
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon
| | - Nicholas D Kendsersky
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon
| | - Esmee Vringer
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Michelle Schug
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - David Novo
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Rosa F Hwang
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ronald M Evans
- The Salk Institute for Biological Studies, Gene Expression Laboratory, Howard Hughes Medical Institute, La Jolla, California
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Craig Dorrell
- Oregon Health & Science University Brenden-Colson Center for Pancreatic Care, Portland, Oregon
| | | | - Jim C Norman
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Rosalie C Sears
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon
| | - Jurre J Kamphorst
- Cancer Research UK Beatson Institute, Glasgow, UK.
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Mara H Sherman
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon.
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20
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Sakamoto K, Noguchi Y, Imazumi K, Ueshima K, Ohtake A, Takeda M, Masuda N. ASP6432, a type 1 lysophosphatidic acid receptor antagonist, reduces urethral function during urine voiding and improves voiding dysfunction. Eur J Pharmacol 2019; 847:83-90. [DOI: 10.1016/j.ejphar.2019.01.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 01/11/2019] [Accepted: 01/14/2019] [Indexed: 01/23/2023]
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21
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Kise R, Okasato R, Kano K, Inoue A, Kawahara A, Aoki J. Identification and biochemical characterization of a second zebrafish autotaxin gene. J Biochem 2019; 165:269-275. [PMID: 30629186 DOI: 10.1093/jb/mvy114] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 12/18/2018] [Indexed: 01/01/2023] Open
Abstract
Autotaxin (ATX) is a secreted enzyme that produces a bioactive lysophospholipid, lysophosphatidic acid (LPA). ATX plays a role in vascular and neural development in embryos but its mechanisms remain unclear. At the beginning of this study, only one zebrafish atx gene (atxa) was known and had been investigated. In this study, we generated ATX knockout (KO) fish by TALEN targeting atxa. Unexpectedly, atxa KO fish showed neither vascular defects nor reduction of ATX activity, implying the existence of one or more other ATXs in the genome. By a BLAST search using ATXa protein fragments as a query, we found a genomic sequence that closely resembled atxa exons 13, 14 and 15. Consequently, we cloned a cDNA encoding a second zebrafish autotaxin (ATXb), and found that it was transcribed in various tissues. The atxb gene encoded a protein of 832 amino acids (compared to 850 amino acids in ATXa) with 60% amino acid identity to ATXa and clustered with ATXs from other species. A recombinant ATXb protein showed lysophospholipase D (lysoPLD) activities with substrate specificities similar to those of ATXa and mammalian ATXs. These results indicate that ATXb is a second zebrafish ATX, which possibly shares redundant roles with ATXa in embryonic development.
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Affiliation(s)
- Ryoji Kise
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Japan
| | - Ryohei Okasato
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Japan
| | - Kuniyuki Kano
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Japan.,AMED-LEAP, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Tokyo, Japan
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Japan.,AMED-LEAP, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Tokyo, Japan
| | - Atsuo Kawahara
- Graduate School of Medical Science, Center for Medical Education and Sciences, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi, Japan
| | - Junken Aoki
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Japan.,AMED-LEAP, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Tokyo, Japan
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22
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Molecular mechanism of lysophosphatidic acid-induced hypertensive response. Sci Rep 2019; 9:2662. [PMID: 30804442 PMCID: PMC6389983 DOI: 10.1038/s41598-019-39041-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 01/04/2019] [Indexed: 12/28/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a blood-derived bioactive lipid with numerous biological activities exerted mainly through six defined G protein-coupled receptors (LPA1-LPA6). LPA was first identified as a vasoactive compound because it induced transient hypertension when injected intravenously in rodents. Here, we examined the molecular mechanism underlying the LPA-induced hypertensive response. The LPA-induced hypertensive response was significantly attenuated by pretreatment with a Rho kinase inhibitor, which blocks Gα12/13 signaling. Consistent with this, the response was weakened in KO mice of LPA4, a Gα12/13-coupling LPA receptor. KO mice of another Gα12/13-coupling LPA receptor, LPA6, also showed an attenuated LPA-induced hypertensive response. However, LPA6 KO mice also displayed attenuated pressor responses to an adrenergic agent and abnormal blood vessel formation. Using several LPA analogs with varied affinity for each LPA receptor, we found a good correlation between the hypertensive and LPA4 agonistic activities. Incubated mouse plasma, which contained abundant LPA, also induced a hypertensive response. Interestingly the response was completely abolished when the plasma was incubated in the presence of an ATX inhibitor. Together, these results indicate that circulating LPA produced by ATX contributes to the elevation of blood pressure through multiple LPA receptors, mainly LPA4.
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23
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Matralis AN, Afantitis A, Aidinis V. Development and therapeutic potential of autotaxin small molecule inhibitors: From bench to advanced clinical trials. Med Res Rev 2018; 39:976-1013. [PMID: 30462853 DOI: 10.1002/med.21551] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/21/2018] [Accepted: 10/19/2018] [Indexed: 12/11/2022]
Abstract
Several years after its isolation from melanoma cells, an increasing body of experimental evidence has established the involvement of Autotaxin (ATX) in the pathogenesis of several diseases. ATX, an extracellular enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) into the bioactive lipid lysophosphatidic acid (LPA), is overexpressed in a variety of human metastatic cancers and is strongly implicated in chronic inflammation and liver toxicity, fibrotic diseases, and thrombosis. Accordingly, the ATX-LPA signaling pathway is considered a tractable target for therapeutic intervention substantiated by the multitude of research campaigns that have been successful in identifying ATX inhibitors by both academia and industry. Furthermore, from a therapeutic standpoint, the entry and the so far promising results of the first ATX inhibitor in advanced clinical trials against idiopathic pulmonary fibrosis (IPF) lends support to the viability of this approach, bringing it to the forefront of drug discovery efforts. The present review article aims to provide a comprehensive overview of the most important series of ATX inhibitors developed so far. Special weight is lent to the design, structure activity relationship and mode of binding studies carried out, leading to the identification of advanced leads. The most significant in vitro and in vivo pharmacological results of these advanced leads are also summarized. Lastly, the development of the first ATX inhibitor entered in clinical trials accompanied by its phase 1 and 2a clinical trial data is disclosed.
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Affiliation(s)
- Alexios N Matralis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece
| | - Antreas Afantitis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece.,NovaMechanics Ltd Cheminformatics Company, Nicosia, Cyprus
| | - Vassilis Aidinis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece
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24
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Ninou I, Kaffe E, Müller S, Budd DC, Stevenson CS, Ullmer C, Aidinis V. Pharmacologic targeting of the ATX/LPA axis attenuates bleomycin-induced pulmonary fibrosis. Pulm Pharmacol Ther 2018; 52:32-40. [DOI: 10.1016/j.pupt.2018.08.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 08/16/2018] [Indexed: 02/08/2023]
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25
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Sakamoto K, Noguchi Y, Ueshima K, Yamakuni H, Ohtake A, Sato S, Ishizu K, Hosogai N, Kawaminami E, Takeda M, Masuda N. Effect of ASP6432, a Novel Type 1 Lysophosphatidic Acid Receptor Antagonist, on Urethral Function and Prostate Cell Proliferation. J Pharmacol Exp Ther 2018; 366:390-396. [PMID: 29884626 DOI: 10.1124/jpet.118.247908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 05/30/2018] [Indexed: 03/08/2025] Open
Abstract
Current pharmacotherapies for lower urinary tract symptoms associated with benign prostate hyperplasia (LUTS/BPH) are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid with various biologic functions. However, its exact role in the lower urinary tract and its target receptor subtype have not been fully elucidated. We investigated the role of LPA and the type 1 LPA receptor (LPA1) in urethral/prostatic contractile function and prostate cell proliferation by pharmacologically characterizing ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}-1,3-thiazole-4-carbonyl)-3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide), a novel LPA1 antagonist. ASP6432 exhibited potent and selective antagonistic activity against LPA1 in cells expressing LPA receptor subtypes. In isolated rat tissue strips and anesthetized rats, ASP6432 concentration-/dose-dependently inhibited LPA-induced urethra and prostate contractions. In addition, in anesthetized rats, ASP6432 maximally decreased the urethral perfusion pressure (UPP) in the absence of exogenous LPA stimulation by 43% from baseline, whereas tamsulosin, an α1-adrenoceptor antagonist, reduced UPP by 22%. Further, in human prostate stromal cells, ASP6432 significantly and concentration-dependently suppressed LPA-induced bromodeoxyuridine incorporation. These results demonstrate a pivotal role for LPA and LPA1 in the regulation of urethral tonus and prostate cell proliferation. The potent urethral relaxation and inhibition of prostatic stromal cell growth indicate the potential of ASP6432 as a novel therapeutic agent for LUTS/BPH.
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Affiliation(s)
- Kazuyuki Sakamoto
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Yukiko Noguchi
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Koji Ueshima
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Hisashi Yamakuni
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Akiyoshi Ohtake
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Shuichi Sato
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Kenichiro Ishizu
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Naomi Hosogai
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Eiji Kawaminami
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Masahiro Takeda
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
| | - Noriyuki Masuda
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan (K.S., Y.N., K.U., A.O., S.S., K.I., N.H., E.K., M.T., N.M.), Astellas Research Technologies Co., Ltd., Tsukuba, Ibaraki, Japan (H.Y.) and School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan (K.S.)
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26
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Terakado M, Suzuki H, Hashimura K, Tanaka M, Ueda H, Hirai K, Asada M, Ikura M, Matsunaga N, Saga H, Shinozaki K, Karakawa N, Takada Y, Minami M, Egashira H, Sugiura Y, Yamada M, Nakade S, Takaoka Y. Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia. ACS Med Chem Lett 2017; 8:1281-1286. [PMID: 29259748 DOI: 10.1021/acsmedchemlett.7b00383] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 11/20/2017] [Indexed: 01/08/2023] Open
Abstract
Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.
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Affiliation(s)
- Masahiko Terakado
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Hidehiro Suzuki
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Kazuya Hashimura
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Motoyuki Tanaka
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Hideyuki Ueda
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Keisuke Hirai
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Masaki Asada
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Masahiro Ikura
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Naoki Matsunaga
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Hiroshi Saga
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Koji Shinozaki
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Naoko Karakawa
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Yuka Takada
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Masashi Minami
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Hiromu Egashira
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Yoshihiro Sugiura
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Masanori Yamada
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Shinji Nakade
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Yoshikazu Takaoka
- Medicinal
Chemistry Research Laboratories, §Exploratory Research Laboratories, and #Discovery Research
Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
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27
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Nikolaou A, Kokotou MG, Limnios D, Psarra A, Kokotos G. Autotaxin inhibitors: a patent review (2012-2016). Expert Opin Ther Pat 2017; 27:815-829. [DOI: 10.1080/13543776.2017.1323331] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Aikaterini Nikolaou
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Maroula G. Kokotou
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitris Limnios
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Psarra
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - George Kokotos
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
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28
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Banerjee S, Norman DD, Lee SC, Parrill AL, Pham TCT, Baker DL, Tigyi GG, Miller DD. Highly Potent Non-Carboxylic Acid Autotaxin Inhibitors Reduce Melanoma Metastasis and Chemotherapeutic Resistance of Breast Cancer Stem Cells. J Med Chem 2017; 60:1309-1324. [PMID: 28112925 PMCID: PMC7938327 DOI: 10.1021/acs.jmedchem.6b01270] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC50 ∼ 32 nM; 3b, IC50 ∼ 9 nM; and 14, IC50 ∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro. Two of the most potent compounds, 3b and 3f (IC50 ∼ 84 nM), lack inhibitory action on ENPP6 and ENPP7 but possess weak antagonist action specific to the LPA1 G protein-coupled receptor. In particular, compound 3b potently reduced in vitro chemotherapeutic resistance of 4T1 breast cancer stem-like cells to paclitaxel and significantly reduced B16 melanoma metastasis in vivo.
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Affiliation(s)
- Souvik Banerjee
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Derek D. Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Abby L. Parrill
- Department of Chemistry, The University of Memphis, Memphis, Tennessee 38152, United States
- Computational Research on Materials Institute, The University of Memphis, Memphis, Tennessee 38152, United States
| | - Truc Chi T. Pham
- Department of Chemistry, The University of Memphis, Memphis, Tennessee 38152, United States
| | - Daniel L. Baker
- Department of Chemistry, The University of Memphis, Memphis, Tennessee 38152, United States
| | - Gabor G. Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Duane D. Miller
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
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29
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Bretschneider T, Luippold AH, Romig H, Bischoff D, Klinder K, Nicklin P, Rist W. Ultrafast and Predictive Mass Spectrometry-Based Autotaxin Assays for Label-Free Potency Screening. SLAS DISCOVERY 2017; 22:425-432. [PMID: 28328321 DOI: 10.1177/2472555217690484] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Autotaxin (ATX) is a promising drug target for the treatment of several diseases, such as cancer and fibrosis. ATX hydrolyzes lysophosphatidyl choline (LPC) into bioactive lysophosphatidic acid (LPA). The potency of ATX inhibitors can be readily determined by using fluorescence-based LPC derivatives. While such assays are ultra-high throughput, they are prone to false positives compared to assays based on natural LPC. Here we report the development of ultrafast mass spectrometry-based ATX assays enabling the measurement of data points within 13 s, which is 10 times faster than classic liquid chromatography-mass spectrometry. To this end, we set up a novel in vitro and whole-blood assay. We demonstrate that the potencies determined with these assays are in good agreement with the in vivo efficacy and that the whole-blood assay has the best predictive power. This high-throughput label-free approach paired with the translatable data quality is highly attractive for appropriate guidance of medicinal chemists for constructing strong structure-activity relationships.
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Affiliation(s)
- Tom Bretschneider
- 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | | | - Helmut Romig
- 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Daniel Bischoff
- 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Klaus Klinder
- 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Paul Nicklin
- 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Wolfgang Rist
- 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
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30
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Aikawa S, Kano K, Inoue A, Aoki J. Proliferation of mouse endometrial stromal cells in culture is highly sensitive to lysophosphatidic acid signaling. Biochem Biophys Res Commun 2017; 484:202-208. [PMID: 28073697 DOI: 10.1016/j.bbrc.2016.12.154] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 12/22/2016] [Indexed: 01/01/2023]
Abstract
Endometrial stromal cells (ESCs) proliferate rapidly both in vivo and in vitro. Here we show that proliferation of ESCs in vitro is strongly dependent on lysophosphatidic acid (LPA) signaling. LPA is produced by autotaxin (ATX) and induces various kinds of cellular processes including migration, proliferation and inhibition of cell death possibly through six G protein-coupled receptors (LPA1-6). We found that ESCs proliferated rapidly in vitro in an autocrine manner and that the proliferation was prominently suppressed by either an ATX inhibitor (ONO-8430506) or an LPA1/3 antagonist (Ki16425). Among the cells lines tested, mouse ESCs were the most sensitive to these inhibitors. Proliferation of ESCs isolated from either LPA1- or LPA3-deficient mice was comparable to proliferation of ESCs isolated from control mice. An LPA receptor antagonist (AM095), which was revealed to be a dual LPA1/LPA3 antagonist, also suppressed the proliferation of ESCs. The present results show that LPA signaling has a critical role in the proliferation of ESCs, and that this role is possibly mediated redundantly by LPA1 and LPA3.
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Affiliation(s)
- Shizu Aikawa
- Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, 980-8578, Japan
| | - Kuniyuki Kano
- Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, 980-8578, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, 100-0004, Japan
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, 980-8578, Japan; Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Saitama, 332-0012, Japan
| | - Junken Aoki
- Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, 980-8578, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, 100-0004, Japan.
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31
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Nsaibia MJ, Mahmut A, Boulanger MC, Arsenault BJ, Bouchareb R, Simard S, Witztum JL, Clavel MA, Pibarot P, Bossé Y, Tsimikas S, Mathieu P. Autotaxin interacts with lipoprotein(a) and oxidized phospholipids in predicting the risk of calcific aortic valve stenosis in patients with coronary artery disease. J Intern Med 2016; 280:509-517. [PMID: 27237700 DOI: 10.1111/joim.12519] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Studies have shown that lipoprotein(a) [Lp(a)], an important carrier of oxidized phospholipids, is causally related to calcific aortic valve stenosis (CAVS). Recently, we found that Lp(a) mediates the development of CAVS through autotaxin (ATX). OBJECTIVE To determine the predictive value of circulating ATX mass and activity for CAVS. METHODS We performed a case-control study in 300 patients with coronary artery disease (CAD). Patients with CAVS plus CAD (cases, n = 150) were age- and gender-matched (1 : 1) to patients with CAD without aortic valve disease (controls, n = 150). ATX mass and enzymatic activity and levels of Lp(a) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) were determined in fasting plasma samples. RESULTS Compared to patients with CAD alone, ATX mass (P < 0.0001), ATX activity (P = 0.05), Lp(a) (P = 0.003) and OxPL-apoB (P < 0.0001) levels were elevated in those with CAVS. After adjustment, we found that ATX mass (OR 1.06, 95% CI 1.03-1.10 per 10 ng mL-1 , P = 0.001) and ATX activity (OR 1.57, 95% CI 1.14-2.17 per 10 RFU min-1 , P = 0.005) were independently associated with CAVS. ATX activity interacted with Lp(a) (P = 0.004) and OxPL-apoB (P = 0.001) on CAVS risk. After adjustment, compared to patients with low ATX activity (dichotomized at the median value) and low Lp(a) (<50 mg dL-1 ) or OxPL-apoB (<2.02 nmol L-1 , median) levels (referent), patients with both higher ATX activity (≥84 RFU min-1 ) and Lp(a) (≥50 mg dL-1 ) (OR 3.46, 95% CI 1.40-8.58, P = 0.007) or OxPL-apoB (≥2.02 nmol L-1 , median) (OR 5.48, 95% CI 2.45-12.27, P < 0.0001) had an elevated risk of CAVS. CONCLUSION Autotaxin is a novel and independent predictor of CAVS in patients with CAD.
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Affiliation(s)
- M J Nsaibia
- Laboratory of Cardiovascular Pathobiology Quebec Heart and Lung Institute/Research Center, Department of Surgery, Quebec, Canada
| | - A Mahmut
- Laboratory of Cardiovascular Pathobiology Quebec Heart and Lung Institute/Research Center, Department of Surgery, Quebec, Canada
| | - M-C Boulanger
- Laboratory of Cardiovascular Pathobiology Quebec Heart and Lung Institute/Research Center, Department of Surgery, Quebec, Canada
| | - B J Arsenault
- Department of Medicine, Laval University, Quebec, Canada
| | - R Bouchareb
- Laboratory of Cardiovascular Pathobiology Quebec Heart and Lung Institute/Research Center, Department of Surgery, Quebec, Canada
| | - S Simard
- Statistical Consulting Service Unit at the Quebec Heart and Lung Institute/Research Center, Laval University, Quebec, Canada
| | - J L Witztum
- University of California San Diego, La Jolla, CA, USA
| | - M-A Clavel
- Department of Medicine, Laval University, Quebec, Canada
| | - P Pibarot
- Department of Medicine, Laval University, Quebec, Canada
| | - Y Bossé
- Department of Molecular Medicine, Laval University, Quebec, Canada
| | - S Tsimikas
- University of California San Diego, La Jolla, CA, USA
| | - P Mathieu
- Laboratory of Cardiovascular Pathobiology Quebec Heart and Lung Institute/Research Center, Department of Surgery, Quebec, Canada.
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Terakado M, Suzuki H, Hashimura K, Tanaka M, Ueda H, Kohno H, Fujimoto T, Saga H, Nakade S, Habashita H, Takaoka Y, Seko T. Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead. ACS Med Chem Lett 2016; 7:913-918. [PMID: 27774128 DOI: 10.1021/acsmedchemlett.6b00225] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 08/19/2016] [Indexed: 12/31/2022] Open
Abstract
Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1 antagonists and their in vivo efficacy.
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Affiliation(s)
- Masahiko Terakado
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Hidehiro Suzuki
- Exploratory Research
Laboratories, ONO Pharmaceutical Co., Ltd., 17-2 Wadai, Tsukuba, Ibaraki 300-4247, Japan
| | - Kazuya Hashimura
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Motoyuki Tanaka
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Hideyuki Ueda
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Hiroshi Kohno
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Taku Fujimoto
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Hiroshi Saga
- Exploratory Research
Laboratories, ONO Pharmaceutical Co., Ltd., 17-2 Wadai, Tsukuba, Ibaraki 300-4247, Japan
| | - Shinji Nakade
- Exploratory Research
Laboratories, ONO Pharmaceutical Co., Ltd., 17-2 Wadai, Tsukuba, Ibaraki 300-4247, Japan
| | - Hiromu Habashita
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Yoshikazu Takaoka
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
| | - Takuya Seko
- Medicinal
Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai,
Shimamoto, Mishima, Osaka 618-8585, Japan
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Structural basis for specific inhibition of Autotaxin by a DNA aptamer. Nat Struct Mol Biol 2016; 23:395-401. [PMID: 27043297 DOI: 10.1038/nsmb.3200] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 03/10/2016] [Indexed: 12/14/2022]
Abstract
ATX is a plasma lysophospholipase D that hydrolyzes lysophosphatidylcholine (LPC) and produces lysophosphatidic acid. To date, no ATX-inhibition-mediated treatment strategies for human diseases have been established. Here, we report anti-ATX DNA aptamers that inhibit ATX with high specificity and efficacy. We solved the crystal structure of ATX in complex with the anti-ATX aptamer RB011, at 2.0-Å resolution. RB011 binds in the vicinity of the active site through base-specific interactions, thus preventing the access of the choline moiety of LPC substrates. Using the structural information, we developed the modified anti-ATX DNA aptamer RB014, which exhibited in vivo efficacy in a bleomycin-induced pulmonary fibrosis mouse model. Our findings reveal the structural basis for the specific inhibition of ATX by the anti-ATX aptamer and highlight the therapeutic potential of anti-ATX aptamers for the treatment of human diseases, such as pulmonary fibrosis.
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Nishioka T, Arima N, Kano K, Hama K, Itai E, Yukiura H, Kise R, Inoue A, Kim SH, Solnica-Krezel L, Moolenaar WH, Chun J, Aoki J. ATX-LPA1 axis contributes to proliferation of chondrocytes by regulating fibronectin assembly leading to proper cartilage formation. Sci Rep 2016; 6:23433. [PMID: 27005960 PMCID: PMC4804234 DOI: 10.1038/srep23433] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 03/07/2016] [Indexed: 12/20/2022] Open
Abstract
The lipid mediator lysophosphatidic acid (LPA) signals via six distinct G protein-coupled receptors to mediate both unique and overlapping biological effects, including cell migration, proliferation and survival. LPA is produced extracellularly by autotaxin (ATX), a secreted lysophospholipase D, from lysophosphatidylcholine. ATX-LPA receptor signaling is essential for normal development and implicated in various (patho)physiological processes, but underlying mechanisms remain incompletely understood. Through gene targeting approaches in zebrafish and mice, we show here that loss of ATX-LPA1 signaling leads to disorganization of chondrocytes, causing severe defects in cartilage formation. Mechanistically, ATX-LPA1 signaling acts by promoting S-phase entry and cell proliferation of chondrocytes both in vitro and in vivo, at least in part through β1-integrin translocation leading to fibronectin assembly and further extracellular matrix deposition; this in turn promotes chondrocyte-matrix adhesion and cell proliferation. Thus, the ATX-LPA1 axis is a key regulator of cartilage formation.
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Affiliation(s)
- Tatsuji Nishioka
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan
| | - Naoaki Arima
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan
| | - Kuniyuki Kano
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan
| | - Kotaro Hama
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan
| | - Eriko Itai
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan
| | - Hiroshi Yukiura
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan
| | - Ryoji Kise
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.,Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi City, Saitama 332-0012, Japan
| | - Seok-Hyung Kim
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Lilianna Solnica-Krezel
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Wouter H Moolenaar
- Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Jerold Chun
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA-92037, USA
| | - Junken Aoki
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.,Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, Tokyo 100-0004 Japan
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Promising Effects of a Novel EP2 and EP3 Receptor Dual Agonist, ONO-8055, on Neurogenic Underactive Bladder in a Rat Lumbar Canal Stenosis Model. J Urol 2016; 196:609-16. [PMID: 26880410 DOI: 10.1016/j.juro.2016.02.064] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2016] [Indexed: 12/29/2022]
Abstract
PURPOSE We investigated whether the novel EP (prostaglandin E2) receptor agonist ONO-8055 would improve the lower urinary tract dysfunction of neurogenic underactive bladder in a rat lumbar spinal canal stenosis model. MATERIALS AND METHODS First, we studied the agonistic effect of ONO-8055 on EP receptors in EP receptor expressing CHO (Chinese hamster ovary) cells using the increase in the intracellular calcium level and intracellular cAMP (cyclic adenosine monophosphate) production as indicators of receptor activation. The effects of ONO-8055 on bladder and urethral strips from normal rats were then investigated. Finally, the effects of ONO-8055 on bladder and urethral function in rats with lumbar spinal canal stenosis were evaluated by awake cystometry and intraurethral perfusion pressure, respectively. The effects of tamsulosin and distigmine on urethral pressure were also evaluated. RESULTS ONO-8055 is a highly potent and selective agonist for EP2 and EP3 receptors on CHO cells. While this compound contracted bladder strips, it relaxed urethral strips. Awake cystometry showed that ONO-8055 significantly decreased bladder capacity, post-void residual urine and voiding pressure. Compared with vehicle, tamsulosin and ONO-8055 significantly decreased urethral pressure. CONCLUSIONS ONO-8055 decreased post-void residual urine, probably by decreasing bladder capacity. The decrease in voiding pressure probably resulted from the lowered urethral pressure due to relaxation of the urethra. Thus, the novel EP2 and EP3 receptor dual agonist ONO-8055 has the potential to improve neurogenic underactive bladder.
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Federico L, Jeong KJ, Vellano CP, Mills GB. Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression. J Lipid Res 2016; 57:25-35. [PMID: 25977291 PMCID: PMC4689343 DOI: 10.1194/jlr.r060020] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 05/07/2015] [Indexed: 12/18/2022] Open
Abstract
The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, inflammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers.
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Affiliation(s)
- Lorenzo Federico
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Kang Jin Jeong
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Christopher P Vellano
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Gordon B Mills
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
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37
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Skindersoe ME, Krogfelt KA, Blom A, Jiang G, Prestwich GD, Mansell JP. Dual Action of Lysophosphatidate-Functionalised Titanium: Interactions with Human (MG63) Osteoblasts and Methicillin Resistant Staphylococcus aureus. PLoS One 2015; 10:e0143509. [PMID: 26605796 PMCID: PMC4659682 DOI: 10.1371/journal.pone.0143509] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 11/05/2015] [Indexed: 11/18/2022] Open
Abstract
Titanium (Ti) is a widely used material for surgical implants; total joint replacements (TJRs), screws and plates for fixing bones and dental implants are forged from Ti. Whilst Ti integrates well into host tissue approximately 10% of TJRs will fail in the lifetime of the patient through a process known as aseptic loosening. These failures necessitate revision arthroplasties which are more complicated and costly than the initial procedure. Finding ways of enhancing early (osseo)integration of TJRs is therefore highly desirable and continues to represent a research priority in current biomaterial design. One way of realising improvements in implant quality is to coat the Ti surface with small biological agents known to support human osteoblast formation and maturation at Ti surfaces. Lysophosphatidic acid (LPA) and certain LPA analogues offer potential solutions as Ti coatings in reducing aseptic loosening. Herein we present evidence for the successful bio-functionalisation of Ti using LPA. This modified Ti surface heightened the maturation of human osteoblasts, as supported by increased expression of alkaline phosphatase. These functionalised surfaces also deterred the attachment and growth of Staphylococcus aureus, a bacterium often associated with implant failures through sepsis. Collectively we provide evidence for the fabrication of a dual-action Ti surface finish, a highly desirable feature towards the development of next-generation implantable devices.
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Affiliation(s)
- Mette Elena Skindersoe
- Department of Systems Biology, Technical University of Denmark, Kgs. Lyngby, Denmark
- Department for Infection and Microbiology Control, Statens Serum Institut, Copenhagen S, Denmark
| | - Karen A. Krogfelt
- Department for Infection and Microbiology Control, Statens Serum Institut, Copenhagen S, Denmark
| | - Ashley Blom
- Musculoskeletal Research Unit, University of Bristol, Southmead Hospital, Bristol, BS10 5NB, United Kingdom
| | - Guowei Jiang
- Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108, United States of America
| | - Glenn D. Prestwich
- Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108, United States of America
| | - Jason Peter Mansell
- Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Frenchay Campus, Bristol, BS16 1QY, United Kingdom
- * E-mail:
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38
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Katsifa A, Kaffe E, Nikolaidou-Katsaridou N, Economides AN, Newbigging S, McKerlie C, Aidinis V. The Bulk of Autotaxin Activity Is Dispensable for Adult Mouse Life. PLoS One 2015; 10:e0143083. [PMID: 26569406 PMCID: PMC4646642 DOI: 10.1371/journal.pone.0143083] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/31/2015] [Indexed: 12/12/2022] Open
Abstract
Autotaxin (ATX, Enpp2) is a secreted lysophospholipase D catalysing the production of lysophosphatidic acid, a pleiotropic growth factor-like lysophospholipid. Increased ATX expression has been detected in a number of chronic inflammatory diseases and different types of cancer, while genetic interventions have proven a role for ATX in disease pathogenesis. Therefore, ATX has emerged as a potential drug target and a large number of ATX inhibitors have been developed exhibiting promising therapeutic potential. However, the embryonic lethality of ATX null mice and the ubiquitous expression of ATX and LPA receptors in adult life question the suitability of ATX as a drug target. Here we show that inducible, ubiquitous genetic deletion of ATX in adult mice, as well as long-term potent pharmacologic inhibition, are well tolerated, alleviating potential toxicity concerns of ATX therapeutic targeting.
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Affiliation(s)
- Aggeliki Katsifa
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Eleanna Kaffe
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | | | - Aris N. Economides
- Genome Engineering Technologies Group and Skeletal Diseases TFA Group, Regeneron Pharmaceuticals Inc., Tarrytown, New York, United States of America
| | - Susan Newbigging
- Physiology and Experimental Medicine Research Program, the Hospital for Sick Children, Center for Phenogenomics, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Colin McKerlie
- Physiology and Experimental Medicine Research Program, the Hospital for Sick Children, Center for Phenogenomics, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Vassilis Aidinis
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
- * E-mail:
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Benesch MGK, Tang X, Venkatraman G, Bekele RT, Brindley DN. Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo. J Biomed Res 2015; 30:272-84. [PMID: 27533936 PMCID: PMC4946318 DOI: 10.7555/jbr.30.20150058] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Revised: 05/12/2015] [Accepted: 05/20/2015] [Indexed: 12/21/2022] Open
Abstract
Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.
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Affiliation(s)
- Matthew G K Benesch
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada
| | - Xiaoyun Tang
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada
| | - Ganesh Venkatraman
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada
| | - Raie T Bekele
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada
| | - David N Brindley
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada.
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40
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Yue HW, Jing QC, Liu PP, Liu J, Li WJ, Zhao J. Sphingosylphosphorylcholine in cancer progress. Int J Clin Exp Med 2015; 8:11913-11921. [PMID: 26550104 PMCID: PMC4612789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 05/28/2015] [Indexed: 06/05/2023]
Abstract
Sphingosylphosphorylcholine (SPC) is a naturally occurring bioactive sphingolipid in blood plasma, metabolizing from the hydrolysis of the membrane sphingolipid. It has been shown to exert multifunctional role in cell physiological regulation either as an intracellular second messenger or as an extracellular agent through G protein coupled receptors (GPCRs). Because of elevated levels of SPC in malicious ascites of patients with cancer, the role of SPC in tumor progression has prompted wide interest. The factor was reported to affect the proliferation and/or migration of many cancer cells, including pancreatic cancer cells, epithelial ovarian carcinoma cells, rat C6 glioma cells, neuroblastoma cells, melanoma cells, and human leukemia cells. This review covers current knowledge of the role of SPC in tumor.
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Affiliation(s)
- Hong-Wei Yue
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong UniversityJinan 250100, China
| | - Qing-Chuan Jing
- Institute of Poultry Science, Shandong Academy of Agricultural SciencesJinan 250023, China
| | - Ping-Ping Liu
- Department of Cardiology, Affiliated Hospital of Binzhou Medical UniversityYantai 264000, China
| | - Jing Liu
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong UniversityJinan 250100, China
| | - Wen-Jing Li
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong UniversityJinan 250100, China
| | - Jing Zhao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong UniversityJinan 250100, China
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Benesch MGK, Ko YM, Tang X, Dewald J, Lopez-Campistrous A, Zhao YY, Lai R, Curtis JM, Brindley DN, McMullen TPW. Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer. Endocr Relat Cancer 2015; 22:593-607. [PMID: 26037280 DOI: 10.1530/erc-15-0045] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/02/2015] [Indexed: 12/15/2022]
Abstract
Autotaxin is a secreted enzyme that converts extracellular lysophosphatidylcholine to lysophosphatidate (LPA). In cancers, LPA increases tumour growth, metastasis and chemoresistance by activating six G-protein coupled receptors. We examined >200 human thyroid biopsies. Autotaxin expression in metastatic deposits and primary carcinomas was four- to tenfold higher than in benign neoplasms or normal thyroid tissue. Autotaxin immunohistochemical staining was also increased in benign neoplasms with leukocytic infiltrations. Malignant tumours were distinguished from benign tumours by high tumour autotaxin, LPA levels and inflammatory mediators including IL1β, IL6, IL8, GMCSF, TNFα, CCL2, CXCL10 and platelet-derived growth factor (PDGF)-AA. We determined the mechanistic explanation for these results and revealed a vicious regulatory cycle in which LPA increased the secretion of 16 inflammatory modulators in papillary thyroid cancer cultures. Conversely, treating cancer cells with ten inflammatory cytokines and chemokines or PDGF-AA and PDGF-BB increased autotaxin secretion. We confirmed that this autotaxin/inflammatory cycle occurs in two SCID mouse models of papillary thyroid cancer by blocking LPA signalling using the autotaxin inhibitor ONO-8430506. This decreased the levels of 16 inflammatory mediators in the tumours and was accompanied by a 50-60% decrease in tumour volume. This resulted from a decreased mitotic index for the cancer cells and decreased levels of vascular endothelial growth factor and angiogenesis in the tumours. Our results demonstrate that the autotaxin/inflammatory cycle is a focal point for driving malignant thyroid tumour progression and possibly treatment resistance. Inhibiting autotaxin activity provides an effective and novel strategy for decreasing the inflammatory phenotype in thyroid carcinomas, which should complement other treatment modalities.
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Affiliation(s)
- Matthew G K Benesch
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - Yi M Ko
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - Xiaoyun Tang
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - Jay Dewald
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - Ana Lopez-Campistrous
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - Yuan Y Zhao
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - Raymond Lai
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - Jonathan M Curtis
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - David N Brindley
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
| | - Todd P W McMullen
- Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3
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Abstract
A snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development.
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Benesch MGK, Zhao YY, Curtis JM, McMullen TPW, Brindley DN. Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate. J Lipid Res 2015; 56:1134-44. [PMID: 25896349 DOI: 10.1194/jlr.m057661] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Indexed: 12/14/2022] Open
Abstract
Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and inflammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. However, this feedback regulation can be overcome by the inflammatory cytokines, TNF-α or interleukin 1β. This enables high LPA and ATX levels to coexist in inflammatory conditions. The results are discussed in terms of ATX regulation in wound healing and cancer.
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Affiliation(s)
- Matthew G K Benesch
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Yuan Y Zhao
- Departments of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Jonathan M Curtis
- Departments of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | | | - David N Brindley
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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Barbayianni E, Kaffe E, Aidinis V, Kokotos G. Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic inflammation and cancer. Prog Lipid Res 2015; 58:76-96. [DOI: 10.1016/j.plipres.2015.02.001] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 01/20/2015] [Accepted: 02/12/2015] [Indexed: 02/07/2023]
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Venkatraman G, Benesch MGK, Tang X, Dewald J, McMullen TPW, Brindley DN. Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: implications for cancer treatment. FASEB J 2014; 29:772-85. [PMID: 25398768 DOI: 10.1096/fj.14-262659] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The present work elucidates novel mechanisms for lysophosphatidate (LPA)-induced chemoresistance using human breast, lung, liver, and thyroid cancer cells. LPA (0.5-10 μM) increased Nrf2 transcription factor stability and nuclear localization by ≤5-fold. This involved lysophosphatidate type 1 (LPA1) receptors as identified with 1 μM wls-31 (LPA1/2 receptor agonist) and blocking this effect with 20 μM Ki16425 (LPA1-3 antagonist, Ki = 0.34 μM). Knockdown of LPA1 by 50% to 60% with siRNA decreased Nrf2 stability and expressing LPA1, but not LPA2/3, in human HepG2 cells increased Nrf2 stabilization. LPA-induced Nrf2 expression increased transcription of multidrug-resistant transporters and antioxidant genes by 2- to 4-fold through the antioxidant response element. This protected cells from doxorubicin-induced death. This pathway was verified in vivo by orthotopic injection of 20,000 mouse 4T1 breast cancer cells into syngeneic mice. Blocking LPA production with 10 mg/kg per d ONO-8430506 (competitive autotaxin inhibitor, IC90 = 100 nM) decreased expression of Nrf2, multidrug-resistant transporters, and antioxidant genes in breast tumors by ≤90%. Combining 4 mg/kg doxorubicin every third day with ONO-8430506 synergistically decreased tumor growth and metastasis to lungs and liver by >70%, whereas doxorubicin alone had no significant effect. This study provides the first evidence that LPA increases antioxidant gene and multidrug-resistant transporter expression. Blocking this aspect of LPA signaling provides a novel strategy for improving chemotherapy.
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Affiliation(s)
- Ganesh Venkatraman
- *Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and Department of Surgery, University of Alberta, WC Mackenzie Health Science Centre, Edmonton, Alberta, Canada
| | - Matthew G K Benesch
- *Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and Department of Surgery, University of Alberta, WC Mackenzie Health Science Centre, Edmonton, Alberta, Canada
| | - Xiaoyun Tang
- *Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and Department of Surgery, University of Alberta, WC Mackenzie Health Science Centre, Edmonton, Alberta, Canada
| | - Jay Dewald
- *Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and Department of Surgery, University of Alberta, WC Mackenzie Health Science Centre, Edmonton, Alberta, Canada
| | - Todd P W McMullen
- *Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and Department of Surgery, University of Alberta, WC Mackenzie Health Science Centre, Edmonton, Alberta, Canada
| | - David N Brindley
- *Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and Department of Surgery, University of Alberta, WC Mackenzie Health Science Centre, Edmonton, Alberta, Canada
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