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PMID: 18505786 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate.

Blood ·Vol. 112 ·No. 3 ·2008-08-01 ·Pages 793-804

Dai Y, Chen S, Venditti CA, Pei XY, Nguyen TK, Dent P, Grant S

Abstract

Interactions between the dual Bcr/Abl and aurora kinase inhibitor MK-0457 and the histone deacetylase inhibitor vorinostat were examined in Bcr/Abl(+) leukemia cells, including those resistant to imatinib mesylate (IM), particularly those with the T315I mutation. Coadministration of vorinostat dramatically increased MK-0457 lethality in K562 and LAMA84 cells. Notably, the MK-0457/vorinostat regimen was highly active against primary CD34(+) chronic myelogenous leukemia (CML) cells and Ba/F3 cells bearing various Bcr/Abl mutations (ie, T315I, E255K, and M351T), as well as IM-resistant K562 cells exhibiting Bcr/Abl-independent, Lyn-dependent resistance. These events were associated with inactivation and down-regulation of wild-type (wt) and mutated Bcr/Abl (particularly T315I). Moreover, treatment with MK-0457 resulted in accumulation of cells with 4N or more DNA content, whereas coadministration of vorinostat markedly enhanced aurora kinase inhibition by MK-0457, and preferentially killed polyploid cells. Furthermore, vorinostat also interacted with a selective inhibitor of aurora kinase A and B to potentiate apoptosis without modifying Bcr/Abl activity. Finally, vorinostat markedly induced Bim expression, while blockade of Bim induction by siRNA dramatically diminished the capacity of this agent to potentiate MK-0457 lethality. Together, these findings indicate that vorinostat strikingly increases MK-0457 activity against IM-sensitive and -resistant CML cells through inactivation of Bcr/Abl and aurora kinases, as well as by induction of Bim.

MeSH Terms
Animals Antineoplastic Combined Chemotherapy Protocols/pharmacology Apoptosis Regulatory Proteins/antagonists & inhibitors Aurora Kinase A Aurora Kinases Bcl-2-Like Protein 11 Benzamides Cell Line, Tumor Drug Resistance, Neoplasm Drug Synergism Fusion Proteins, bcr-abl/antagonists & inhibitors Humans Hydroxamic Acids/pharmacology Imatinib Mesylate Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy Membrane Proteins/antagonists & inhibitors Piperazines/pharmacology Protein Serine-Threonine Kinases/antagonists & inhibitors Proto-Oncogene Proteins/antagonists & inhibitors Pyrimidines Vorinostat
Chemicals
Apoptosis Regulatory Proteins BCL2L11 protein, human Bcl-2-Like Protein 11 Benzamides Hydroxamic Acids Membrane Proteins Piperazines Proto-Oncogene Proteins Pyrimidines Vorinostat VX680 Imatinib Mesylate Fusion Proteins, bcr-abl AURKA protein, human Aurora Kinase A Aurora Kinases Protein Serine-Threonine Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Dai Yun
Department of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA 23298, USA.
Chen Shuang
Venditti Charis A
Pei Xin-Yan
Nguyen Tri K
Dent Paul
Grant Steven
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2007-10-116376
Published
2008-08-01
Epub
2008-00-27
Pages
793-804
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2481545
Subset
IM
Grants
NCI NIH HHS · CA63753 · United States
NCI NIH HHS · R01 CA100866 · United States
NCI NIH HHS · R01 CA063753 · United States
NCI NIH HHS · R01 CA093738 · United States
NCI NIH HHS · CA 100866 · United States
NCI NIH HHS · CA 93738 · United States
External Links
PubMed source DOI: 10.1182/blood-2007-10-116376 PMC Full Text View journal details
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