Evidence map›Paper›PMID 25563902›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2015

The apoptotic mechanism of action of the sphingosine kinase 1 selective inhibitor SKI-178 in human acute myeloid leukemia cell lines.

Taryn E Dick, Jeremy A Hengst, Todd E Fox, Ashley L Colledge, Vijay P Kale, Shen-Shu Sung, Arun Sharma, Shantu Amin, Thomas P Loughran, Mark Kester and 2 more

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Article in The Journal of pharmacology and experimental therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

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30 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

12 authors.

Taryn E DickDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Jeremy A HengstDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Todd E FoxDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Ashley L ColledgeDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Vijay P KaleDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Shen-Shu SungDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Arun SharmaDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Shantu AminDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Thomas P LoughranDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Mark KesterDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Hong-Gang WangDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia.
Jong K YunDepartment of Pharmacology (T.E.D., J.A.H., A.L.C., V.P.K., S.-S.S., A.S., S.A., H.-G.W., J.K.Y.) and The Jake Gittlen Laboratories for Cancer Research (T.E.D., J.A.H., A.L.C., V.P.K., J.K.Y.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology (T.E.F., M.K.), and University of Virginia Cancer Center (T.P.L.), University of Virginia, Charlottesville, Virginia jky1@psu.edu.

Funding

Women's Oncology Program - WONP30CA044579 · NCI · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI Jay William FOX · 1987 to 2026
$72.1M
Tissue Repository and Animal Models CoreP01CA171983 · NCI · UNIVERSITY OF VIRGINIA · PI FISHER-WELLMAN, KELSEY H · 2013 to 2024
$19.9M
NCI NIH HHS P01 CA171983NCI NIH HHS P01-CA171983NCI NIH HHS P30 CA044579
6 · The paper itself

Abstract

We previously developed SKI-178 (N'-[(1E)-1-(3,4-dimethoxyphenyl)ethylidene]-3-(4-methoxxyphenyl)-1H-pyrazole-5-carbohydrazide) as a novel sphingosine kinase-1 (SphK1) selective inhibitor and, herein, sought to determine the mechanism-of-action of SKI-178-induced cell death. Using human acute myeloid leukemia (AML) cell lines as a model, we present evidence that SKI-178 induces prolonged mitosis followed by apoptotic cell death through the intrinsic apoptotic cascade. Further examination of the mechanism of action of SKI-178 implicated c-Jun NH2-terminal kinase (JNK) and cyclin-dependent protein kinase 1 (CDK1) as critical factors required for SKI-178-induced apoptosis. In cell cycle synchronized human AML cell lines, we demonstrate that entry into mitosis is required for apoptotic induction by SKI-178 and that CDK1, not JNK, is required for SKI-178-induced apoptosis. We further demonstrate that the sustained activation of CDK1 during prolonged mitosis, mediated by SKI-178, leads to the simultaneous phosphorylation of the prosurvival Bcl-2 family members, Bcl-2 and Bcl-xl, as well as the phosphorylation and subsequent degradation of Mcl-1. Moreover, multidrug resistance mediated by multidrug-resistant protein1 and/or prosurvival Bcl-2 family member overexpression did not affect the sensitivity of AML cells to SKI-178. Taken together, these findings highlight the therapeutic potential of SKI-178 targeting SphK1 as a novel therapeutic agent for the treatment of AML, including multidrug-resistant/recurrent AML subtypes.

Indexed as

ApoptosisCell Line, TumorDose-Response Relationship, DrugHL-60 CellsHumansHydrazinesLeukemia, Myeloid, AcutePhosphotransferases (Alcohol Group Acceptor)PyrazolesSphingosine KinaseU937 CellsHydrazinesN'-((1E)-1-(3,4-dimethoxyphenyl)ethylidene)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazidePhosphotransferases (Alcohol Group Acceptor)PyrazolesSphingosine Kinase

Identifiers

PMID25563902
PMCPMC4352591

What OpenQuestion holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.