2-Aryl(pyrrolidin-4-yl)acetic acids are potent agonists of sphingosine-1-phosphate (S1P) receptors

2006 ◽  
Vol 16 (13) ◽  
pp. 3564-3568 ◽  
Author(s):  
Lin Yan ◽  
Richard Budhu ◽  
Pei Huo ◽  
Christopher L. Lynch ◽  
Jeffrey J. Hale ◽  
...  
Keyword(s):  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Acetic Acids

scholarly journals Modulating Sphingosine-1-Phosphate receptors to improve chemotherapy delivery to Ewing sarcoma

2019 ◽  
Author(s):  
Enrica Marmonti ◽  
Hannah Savage ◽  
Aiqian Zhang ◽  
Claudia Alvarez ◽  
Miriam Morrell ◽  
...  
Keyword(s):  
G Protein ◽  
Ewing Sarcoma ◽  
Tyrosine Kinases ◽  
Tumor Vasculature ◽  
Cell Junction ◽  
Tumor Vessels ◽  
S1p Receptors ◽  
Vessel Permeability ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

ABSTRACTTumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper-permeability promotes chemotherapy delivery primarily to a tumor’s periphery. Here we identify a method for enhancing chemotherapy delivery and efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein-coupled Sphinosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper-permeability can be reversed. In this study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE-013 caused more organized, mature, and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved chemotherapy delivery to the tumor and anti-tumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.NOVELTY AND IMPACTThis study demonstrates that Sphingosine-1-Phosphate (S1P) receptors are potential novel targets for tumor vasculature remodeling and adjuvant therapy for the treatment of Ewing Sarcoma. Unlike receptor tyrosine kinases that have already been extensively evaluated for use as vascular normalizing agents in oncology, S1P receptors are G protein-coupled receptors, which have not been well studied in tumor endothelium. Pharmacologic activators and inhibitors of S1P receptors are currently in clinical trials for treatment of auto-immune and cardiovascular diseases, indicating potential for clinical translation of this work.

Sphingosine 1-phosphate (S1P) induces shape change in rat C6 glioma cells through the S1P2receptor: development of an agonist for S1P receptors

2007 ◽  
Vol 59 (7) ◽  
pp. 1035-1041 ◽  
Author(s):  
Kyeok Kim ◽  
Yu-Lee Kim ◽  
Santosh J. Sacket ◽  
Hyo-Lim Kim ◽  
Mijin Han ◽  
...  
Keyword(s):  
Shape Change ◽  
Glioma Cells ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Rat C6 Glioma

scholarly journals FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment

2020 ◽  
Vol 27 (18) ◽  
pp. 2979-2993 ◽  
Author(s):  
Zifeng Wang ◽  
Masahito Kawabori ◽  
Kiyohiro Houkin
Keyword(s):  
Clinical Trials ◽  
Blood Stream ◽  
Oral Drug ◽  
Cerebral Stroke ◽  
Laboratory Findings ◽  
Stroke Treatment ◽  
Positive Effects ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Clinical Experiments

FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional “antagonist” and “agonist” mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.

Sphingosine 1-Phosphate (S1P) Is a Chemotactic Factor for CD34+ Progenitors and CD34+ Cell Lines Expressing the S1P1 Receptor: Possible Contribution to Progenitor Cell Trafficking.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2681-2681 ◽  
Author(s):  
Gabriele Seitz ◽  
Andreas M. Boehmler ◽  
Tina Wiesner ◽  
Lothar Kanz ◽  
Robert Möhle
Keyword(s):  
Progenitor Cells ◽  
Cell Lines ◽  
Chemotactic Factor ◽  
Jurkat Cells ◽  
Optimum Dose ◽  
Boyden Chamber ◽  
Cell Trafficking ◽  
Hematopoietic Stem ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate

Abstract Trafficking of hematopoietic stem and progenitor cells (HPC) is controlled by G protein coupled receptors (GPRs), particularly by the chemokine receptor CXCR4. However, homing of HPC does not exclusively depend on CXCR4 and its ligand SDF-1. In addition to chemokine receptors, also GPRs for non-peptide lipid mediators may be involved in HPC migration. In the present study, we demonstrate that sphingosine 1-phosphate (S1P) is chemotactic for human CD34+ HPC (optimum dose 5 μM), as measured in a modified Boyden chamber system. In CD34+ cell lines, the chemotactic response was even stronger and occurred at lower S1P concentrations (e.g., optimum dose 100 nM for Jurkat cells, 2-fold stronger migration compared to HPC). By RT-PCR, we measured mRNA expression of the 5 different S1P receptors (S1P1,2,3,4,5). All CD34+ hematopoietic cell lines analyzed (KG1, KG1a, Jurkat) expressed S1P1, a S1P receptor with known chemotactic activity, while CD34- cell lines (HL-60, THP-1) were negative for S1P1. In HL-60 cells, chemotaxis in response to S1P was even reduced compared to spontaneous migration, which might be due to the expression of S1P receptors other than S1P1 with known inhibitory effects, particularly S1P2. In mobilized peripheral blood CD34+ progenitor cells from different donors, S1P1 was consistently expressed in both CD34+CD38+ and more primitive CD34+CD38- HPC, while expression of S1P2,3,4,5 was variable. S1P induced also other typical responses of GPR-mediated signaling in CD34+ cell lines and HPC, such as polymerization of filamentous actin, as measured by flow cytometry after labeling of the cells with FITC-phalloidin. We conclude that S1P is a chemotactic factor for CD34+ HPC and CD34+ cell lines due to expression of the GPR S1P1. As megakaryocytes and platelets represent an abundant source of S1P in the bone marrow, our results suggest that S1P and its receptor S1P1 may contribute to trafficking and spatial distribution of HPC in the hematopoietic microenvironment.

Sphingosine 1-Phosphate (S1P) Induces Migration and ERK/MAP-Kinase-Dependent Proliferation in Chronic Lymphocytic Leukemia (B-CLL) Due to Expression of the G Protein-Coupled Receptors S1P1/4.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4996-4996
Author(s):  
Gabriele Seitz ◽  
Sedat Yildirim ◽  
Andreas M. Boehmler ◽  
Lothar Kanz ◽  
Robert Möhle
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
G Protein ◽  
Cell Lines ◽  
Peripheral Blood ◽  
G Protein Coupled Receptors ◽  
Lymphocytic Leukemia ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Abstract Egress of lymphocytes from lymphoid organs into the circulation has been shown to depend on the presence of the lipid mediator sphingosine 1-phosphate (S1P) in the peripheral blood, and expression of corresponding S1P receptors (i.e., S1P1), that belong to the family of 7-transmembrane G protein-coupled receptors (GPCR). As circulating lymphocytic lymphoma cells are a hallmark of chronic lymphocytic leukemia, we analyzed expression of different S1P receptors and the effects of S1P on B-CLL cells. By qualitative and quantitative (TaqMan) RT-PCR, significant mRNA expression of S1P1 and S1P4 was found in CLL cell lines (EHEB, MEC-1) and in most samples (S1P1 in 88%, S1P4 in 100%) of primary CD19+ cells isolated from the peripheral blood of untreated B-CLL patients. mRNA of other S1P receptors (S1P2, S1P3, S1P5) was less consistently detected. Normal, nonmalignant B cells were strongly positive for S1P1, while other S1P receptors were weakly expressed or negative. S1P induced typical effects of chemotactic GPCR, such as actin polymerization (analyzed by flow cytometry) and chemotaxis (measured in a modified Boyden chamber assay) in CLL cell lines and primary B-CLL cells. After serum deprivation in vitro, S1P induced phosphorylation of ERK/MAP-kinase as analyzed by Western blot, demonstrating that S1P receptors expressed in CLL were able to activate signaling pathways of GPCR not only related to cell migration and chemotaxis, but also to cell proliferation. Of note, the S1P1 ligand FTY720, which induces receptor internalization after prolonged exposure and acts as an antagonist, resulted in apoptosis in CLL cell lines and primary CLL cells in vitro, as measured by MTT-test and staining with Annexin-FITC, respectively. We conclude that sphingosine 1-phosphate, which is present in the peripheral blood in considerable amounts, contributes to the trafficking of B-CLL cells expressing the GPCRs S1P1/4, and to their prolonged survival.

Sphingosine 1-phosphate signalling in cancer

2012 ◽  
Vol 40 (1) ◽  
pp. 94-100 ◽  
Author(s):  
Nigel J. Pyne ◽  
Francesca Tonelli ◽  
Keng Gat Lim ◽  
Jaclyn S. Long ◽  
Joanne Edwards ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Sphingosine Kinase ◽  
Receptor Expression ◽  
Sphingosine Kinase 1 ◽  
Histone Deacetylase 1 ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

There is an increasing body of evidence demonstrating a critical role for the bioactive lipid S1P (sphingosine 1-phosphate) in cancer. S1P is synthesized and metabolized by a number of enzymes, including sphingosine kinase, S1P lyase and S1P phosphatases. S1P binds to cell-surface G-protein-coupled receptors (S1P1–S1P5) to elicit cell responses and can also regulate, by direct binding, a number of intracellular targets such as HDAC (histone deacetylase) 1/2 to induce epigenetic regulation. S1P is involved in cancer progression including cell transformation/oncogenesis, cell survival/apoptosis, cell migration/metastasis and tumour microenvironment neovascularization. In the present paper, we describe our research findings regarding the correlation of sphingosine kinase 1 and S1P receptor expression in tumours with clinical outcome and we define some of the molecular mechanisms underlying the involvement of sphingosine kinase 1 and S1P receptors in the formation of a cancer cell migratory phenotype. The role of sphingosine kinase 1 in the acquisition of chemotherapeutic resistance and the interaction of S1P receptors with oncogenes such as HER2 is also reviewed. We also discuss novel aspects of the use of small-molecule inhibitors of sphingosine kinase 1 in terms of allosterism, ubiquitin–proteasomal degradation of sphingosine kinase 1 and anticancer activity. Finally, we describe how S1P receptor-modulating agents abrogate S1P receptor–receptor tyrosine kinase interactions, with potential to inhibit growth-factor-dependent cancer progression.

scholarly journals Sphingosine 1-Phosphate (S1P) Receptors 1 and 2 Coordinately Induce Mesenchymal Cell Migration through S1P Activation of Complementary Kinase Pathways

2013 ◽  
Vol 288 (8) ◽  
pp. 5398-5406 ◽  
Author(s):  
Patrick Quint ◽  
Ming Ruan ◽  
Larry Pederson ◽  
Moustapha Kassem ◽  
Jennifer J. Westendorf ◽  
...  
Keyword(s):  
Cell Migration ◽  
Mesenchymal Cell ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate
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