Document Detail


Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells.
MedLine Citation:
PMID:  19458629     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and is a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has the potential to eradicate AML progenitor cells.
Authors:
B Z Carter; D H Mak; R Woessner; S Gross; W D Schober; Z Estrov; H Kantarjian; M Andreeff
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-05-21
Journal Detail:
Title:  Leukemia     Volume:  23     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-10-14     Completed Date:  2009-11-05     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1755-62     Citation Subset:  IM    
Affiliation:
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Blotting, Western
Caspase 8 / genetics,  metabolism
Cell Cycle / drug effects*
Cell Line, Tumor
Colony-Forming Units Assay
Female
Humans
Kinesin / antagonists & inhibitors*,  metabolism
Mice
Mice, SCID
Mitochondria / drug effects*,  metabolism
Mutation / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Thiadiazoles / pharmacology*
Tumor Suppressor Protein p53 / antagonists & inhibitors,  metabolism
X-Linked Inhibitor of Apoptosis Protein / metabolism
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
CA16672/CA/NCI NIH HHS; P01 CA049639/CA/NCI NIH HHS; P01 CA055164/CA/NCI NIH HHS; P01 CA49639/CA/NCI NIH HHS; P01 CA55164/CA/NCI NIH HHS; P30 CA016672/CA/NCI NIH HHS; P50 CA100632/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/ARRY 520; 0/Antineoplastic Agents; 0/KIF11 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/Thiadiazoles; 0/Tumor Suppressor Protein p53; 0/X-Linked Inhibitor of Apoptosis Protein; EC 3.4.22.-/Caspase 8; EC 3.6.1.-/Kinesin
Comments/Corrections

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