Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond
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TLDR
The ways in which S1P might be therapeutically targeted are discussed — for example, via the development of chemical inhibitors that target the generation, transport and degradation of S 1P and via thedevelopment of specific S1p receptor agonists.Abstract:
The bioactive lipid sphingosine-1-phosphate (S1P) is involved in multiple cellular signalling systems and has a pivotal role in the control of immune cell trafficking. As such, S1P has been implicated in disorders such as cancer and inflammatory diseases. This Review discusses the ways in which S1P might be therapeutically targeted — for example, via the development of chemical inhibitors that target the generation, transport and degradation of S1P and via the development of specific S1P receptor agonists. We also highlight recent conflicting results observed in preclinical studies targeting S1P and discuss ongoing clinical trials in this field.read more
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References
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Journal ArticleDOI
Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate
Yugesh Kharel,Thomas P. Mathews,Amanda M. Gellett,Jose L. Tomsig,Perry C. Kennedy,Morgan L. Moyer,Timothy L. Macdonald,Kevin R. Lynch +7 more
TL;DR: It is demonstrated that a set of submicromolar amidine-based SphK1 inhibitors effectively lower S1P levels in cell-based assays, but it is unable to correlate Sphk1 inhibition with changes in cell survival.
Journal ArticleDOI
Structure and function of sphingosine-1-phosphate lyase, a key enzyme of sphingolipid metabolism.
TL;DR: The structurally and functionally characterized yeast SPL (Dpl1p) and its first prokaryotic homolog, from Symbiobacterium thermophilum, and reveal which residues are involved in activity and substrate binding and pave the way to studies aimed at controlling the activity of this pivotal enzyme.
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S1P is associated with protection in human and experimental cerebral malaria.
Constance A. M. Finney,Constance A. M. Finney,Cheryl A. Hawkes,Dylan C Kain,Aggrey Dhabangi,Charles Musoke,Christine Cserti-Gazdewich,Tamas Oravecz,W. Conrad Liles,W. Conrad Liles,W. Conrad Liles,Kevin C. Kain,Kevin C. Kain,Kevin C. Kain +13 more
TL;DR: Dysregulation of the S1P pathway in the pathogenesis of human and murine CM is implicate and a novel therapeutic strategy to improve clinical outcome in severe malaria is suggested.
Journal ArticleDOI
Truth and consequences of sphingosine-1-phosphate lyase
Ana E. Aguilar,Julie D. Saba +1 more
TL;DR: It seems likely that targeting SPL to modulate S1P signaling could be useful in a variety of clinical contexts, and the recent crystallization of a prokaryotic SPL has provided insight into the function and potential regulation and drug targeting of this enzyme.
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The sphingosine-1-phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice
Gema Tarrasón,Mariona Aulí,Sanam Mustafa,Vladislav A. Dolgachev,Maria Teresa Domènech,Neus Prats,María Domínguez,Rosa López,Nuria Aguilar,Marta Calbet,Mercè Pont,Graeme Milligan,Steven L. Kunkel,Nuria Godessart +13 more
TL;DR: The results support the hypothesis that lymphopenia evoked by S1P1 agonists is due to functional antagonism of S 1P1 in lymphocytes, and it is shown that both the S1p1 antagonist and a S1 P1 agonist cause lymph Openia in vivo in spite of their different effects on receptor expression in vitro.