PMID- 21848514
OWN - NLM
STAT- MEDLINE
DCOM- 20120116
LR  - 20211020
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 440
IP  - 3
DP  - 2011 Dec 15
TI  - Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating 
      sphingosine 1-phosphate.
PG  - 345-53
LID - 10.1042/BJ20110817 [doi]
AB  - S1P (sphingosine 1-phosphate) is a signalling molecule involved in a host of 
      cellular and physiological functions, most notably cell survival and migration. 
      S1P, which signals via a set of five G-protein-coupled receptors (S1P1-S1P5), is 
      formed by the action of two SphKs (sphingosine kinases) from Sph (sphingosine). 
      Interfering RNA strategies and SphK1 (sphingosine kinase type 1)-null (Sphk1-/-) 
      mouse studies implicate SphK1 in multiple signalling cascades, yet there is a 
      paucity of potent and selective SphK1 inhibitors necessary to evaluate the 
      effects of rapid onset inhibition of this enzyme. We have identified a set of 
      submicromolar amidine-based SphK1 inhibitors and report using a pair of these 
      compounds to probe the cellular and physiological functions of SphK1. In so 
      doing, we demonstrate that our inhibitors effectively lower S1P levels in 
      cell-based assays, but we have been unable to correlate SphK1 inhibition with 
      changes in cell survival. However, SphK1 inhibition did diminish EGF (epidermal 
      growth factor)-driven increases in S1P levels and Akt (also known as protein 
      kinase B)/ERK (extracellular-signal-regulated kinase) phosphorylation. Finally, 
      administration of the SphK1 inhibitor to wild-type, but not Sphk1-/-, mice 
      resulted in a rapid decrease in blood S1P levels indicating that circulating S1P 
      is rapidly turned over.
FAU - Kharel, Yugesh
AU  - Kharel Y
AD  - Department of Pharmacology, University of Virginia, 1340 Jefferson Park Avenue, 
      Charlottesville, VA 22908, USA.
FAU - Mathews, Thomas P
AU  - Mathews TP
FAU - Gellett, Amanda M
AU  - Gellett AM
FAU - Tomsig, Jose L
AU  - Tomsig JL
FAU - Kennedy, Perry C
AU  - Kennedy PC
FAU - Moyer, Morgan L
AU  - Moyer ML
FAU - Macdonald, Timothy L
AU  - Macdonald TL
FAU - Lynch, Kevin R
AU  - Lynch KR
LA  - eng
GR  - P30 CA044579/CA/NCI NIH HHS/United States
GR  - R01 GM067958/GM/NIGMS NIH HHS/United States
GR  - T32 GM008715/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Amidines)
RN  - 0 (Lysophospholipids)
RN  - 0 (Pyrrolidines)
RN  - 0 (Sphingolipids)
RN  - 26993-30-6 (sphingosine 1-phosphate)
RN  - EC 2.4.2.30 (PARP1 protein, human)
RN  - EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Amidines/pharmacokinetics/*pharmacology
MH  - Animals
MH  - Caspase 3/metabolism
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - Lysophospholipids/blood/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/*antagonists & inhibitors
MH  - Poly (ADP-Ribose) Polymerase-1
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyrrolidines/pharmacokinetics/*pharmacology
MH  - Rats
MH  - Sphingolipids/metabolism
MH  - Sphingosine/*analogs & derivatives/blood/metabolism
MH  - Stereoisomerism
PMC - PMC3443603
MID - NIHMS402480
COIS- Conflict of Interest Statement: Y.K., T.P.M., T.L.M. and K.R.L. are inventors on 
      a patent application claiming amidine-based sphingosine kinase inhibitors 
      including 1a and 1b. This application has been licensed by the University of 
      Virginia to a commercial entity in which both T.L.M. and K.R.L. have equity 
      positions.
EDAT- 2011/08/19 06:00
MHDA- 2012/01/17 06:00
PMCR- 2012/12/15
CRDT- 2011/08/19 06:00
PHST- 2011/08/19 06:00 [entrez]
PHST- 2011/08/19 06:00 [pubmed]
PHST- 2012/01/17 06:00 [medline]
PHST- 2012/12/15 00:00 [pmc-release]
AID - BJ20110817 [pii]
AID - 10.1042/BJ20110817 [doi]
PST - ppublish
SO  - Biochem J. 2011 Dec 15;440(3):345-53. doi: 10.1042/BJ20110817.