(R)-FTY720 methyl ether is a specific sphingosine kinase 2 inhibitor: Effect on sphingosine kinase 2 expression in HEK 293 cells and actin rearrangement and survival of MCF-7 breast cancer cells

Lim, Keng Gat; Sun, Chaode; Bittman, Robert; Pyne, Nigel J.; Pyne, Susan

doi:10.1016/j.cellsig.2011.05.010

Cited by 93 publications

(114 citation statements)

References 22 publications

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“…This represents another plausible explanation for a constantly high intracellular Fingolimod concentration in respective sub-compartments. Lim et al (2011) determined a K m value for SphK2 to phosphorylate FTY720 of about 5-10 μm. Therefore, it seems quite reasonable to assume that these high concentrations of FTY720-P are also reached in humans receiving Fingolimod for the treatment of MS.…”

Section: Discussionmentioning

confidence: 99%

Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

Schröder

Arlt

Schmidt

et al. 2015

Biological Chemistry

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FTY720 (Fingolimod; Gilenya ® ) is an immunemodulatory prodrug which, after intracellular phosphorylation by sphingosine kinase 2 (SphK2) and export, mimics effects of the endogenous lipid mediator sphingosine-1-phosphate. Fingolimod has been introduced to treat relapsing-remitting multiple sclerosis. However, little has been published about the immune cell membrane penetration and subcellular distribution of FTY720 and FTY720-P. Thus, we applied a newly established LC-MS/MS method to analyze the subcellular distribution of FTY720 and FTY720-P in subcellular compartments of spleen cells of wild type, SphK1-and SphK2-deficient mice. These studies demonstrated that, when normalized to the original cell volume and calculated on molar basis, FTY720 and FTY720-P dramatically accumulated several hundredfold within immune cells reaching micromolar concentrations. The amount and distribution of FTY720 was differentially affected by SphK1-and SphK2-deficiency. On the background of recently described relevant intracellular FTY720 effects in the nanomolar range and the prolonged application in multiple sclerosis, this data showing a substantial intracellular accumulation of FTY720, has to be considered for benefit/risk ratio estimates.

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Section: Discussionmentioning

confidence: 99%

Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

Schröder

Arlt

Schmidt

et al. 2015

Biological Chemistry

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“…FTY720 was synthesized with subsequent HPLC purification (47), and identity/purity was confirmed by nuclear magnetic resonance and mass spectrometry. (S)-FTY720-OMe, OSU-2S, and (S)-FTY720-regioisomer were synthesized as described previously (48,49).…”

Section: Primary Cellsmentioning

confidence: 99%

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

et al. 2013

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“…RB-005) (Baek et al, 2013). ABC294640 (French et al, 2010) and (R)-FTY720 methylether (ROMe) (Lim et al, 2011b) are SK2-selective inhibitors with K i values ~ 10 M. With the very recent resolution of the crystal structure of SK1 (Wang et al, 2103), it may now be possible to understand the mechanisms of action of these compounds and their selectivity for SK1. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 6 Allosteric inhibitors Allosteric inhibitors and activators might bind to unique allosteric sites in SK1 or alternatively, might induce cooperative effects with bound substrate.…”

Section: Current Advances In the Identification Of Sk1 And Sk2 Inhibimentioning

confidence: 99%

The role of sphingosine 1-phosphate in inflammation and cancer

Pyne

Ohotski

Bittman

et al. 2014

Advances in Biological Regulation

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This version is available at https://strathprints.strath.ac.uk/49243/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. The lipid sphingosine 1-phosphate (S1P) is a key regulator of cell growth, survival, invasion, lymphocyte trafficking, vascular integrity and cytokine production, and plays a central role in inflammatory disease and cancer. S1P is formed by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SK1 and SK2) that differ in their biochemical properties, sub-cellular localization, and function (Pyne and Pyne, 2011). S1P is cleaved by S1P lyase to produce trans-2-hexadecenal and phosphoethanolamine. S1P can also be dephosphorylated by S1P phosphatases to recycle into sphingolipids (Pyne and Pyne, 2011). S1P is an agonist of S1P-specific G-protein coupled receptors, termed S1P 1-5 , and also binds to intracellular protein targets, such as histone deacetylase 1 and 2 (HDAC1/2, which regulate gene expression) (for review see

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(R)-FTY720 methyl ether is a specific sphingosine kinase 2 inhibitor: Effect on sphingosine kinase 2 expression in HEK 293 cells and actin rearrangement and survival of MCF-7 breast cancer cells

Cited by 93 publications

References 22 publications

Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

The role of sphingosine 1-phosphate in inflammation and cancer

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