Document Detail


Antileukemic activity of lysophosphatidic acid acyltransferase-beta inhibitor CT32228 in chronic myelogenous leukemia sensitive and resistant to imatinib.
MedLine Citation:
PMID:  17085669     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Lysophosphatidic acid acyltransferase (LPAAT)-beta catalyzes the conversion of lysophosphatidic acid to phosphatidic acid, an essential component of several signaling pathways, including the Ras/mitogen-activated protein kinase pathway. Inhibition of LPAAT-beta induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-beta as a potential drug target in neoplasia. EXPERIMENTAL DESIGN: In this study, we investigated the effects of CT32228, a specific LPAAT-beta inhibitor, on BCR-ABL-transformed cell lines and primary cells from patients with chronic myelogenous leukemia. RESULTS: CT32228 had antiproliferative activity against BCR-ABL-positive cell lines in the nanomolar dose range, evidenced by cell cycle arrest in G2-M and induction of apoptosis. Treatment of K562 cells with CT32228 led to inhibition of extracellular signal-regulated kinase 1/2 phosphorylation, consistent with inhibition of mitogen-activated protein kinase signaling. Importantly, CT32228 was highly active in cell lines resistant to the Bcr-Abl kinase inhibitor imatinib. Combination of CT32228 with imatinib produced additive inhibition of proliferation in cell lines with residual sensitivity toward imatinib. In short-term cultures in the absence of growth factors, CT32228 preferentially inhibited the growth of granulocyte-macrophage colony-forming units from chronic myelogenous leukemia patients compared with healthy controls. CONCLUSION: These data establish LPAAT-beta as a potential drug target for the treatment of BCR-ABL-positive leukemias.
Authors:
Paul La Rosée; Taiping Jia; Shadmer Demehri; Nicolai Härtel; Peter de Vries; Lynn Bonham; David Hollenback; Jack W Singer; Junia V Melo; Brian J Druker; Michael W Deininger
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  12     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-06     Completed Date:  2007-01-09     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6540-6     Citation Subset:  IM    
Affiliation:
Division of Hematology and Medical Oncology, Oregon Health and Sciences University, Portland, Oregon.
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MeSH Terms
Descriptor/Qualifier:
Acyltransferases / pharmacology*
Antineoplastic Agents / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm*
Drug Synergism
Enzyme Inhibitors / pharmacology*
Extracellular Signal-Regulated MAP Kinases / drug effects
Hematopoietic Stem Cells / drug effects
Humans
Hydrocarbons, Halogenated / pharmacology*
Immunoblotting
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Phosphorylation / drug effects
Piperazines / pharmacology*
Pyrimidines / pharmacology*
Triazines / pharmacology*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CT-32228; 0/Enzyme Inhibitors; 0/Hydrocarbons, Halogenated; 0/Piperazines; 0/Pyrimidines; 0/Triazines; 152459-95-5/imatinib; EC 2.3.-/Acyltransferases; EC 2.3.1.52/2-acylglycerophosphate acyltransferase; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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