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

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.

SUBMITTER: Dai Y

PROVIDER: S-EPMC2481545 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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

Dai Yun Y Chen Shuang S Venditti Charis A CA Pei Xin-Yan XY Nguyen Tri K TK Dent Paul P Grant Steven S

Blood 20080527 3

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 ...[more]

PMID: 18505786

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Project description:We investigated the ability of HDAC inhibitors (HDACi) to target CML stem cells. Treatment with HDACi combined with IM effectively induced apoptosis in quiescent CML progenitors resistant to elimination by IM alone, and eliminated CML stem cells capable of engrafting immunodeficient mice. In vivo administration of HDACi with IM markedly diminished LSC in a transgenic mouse model of CML. The interaction of IM and HDACi inhibited genes regulating hematopoietic stem cell maintenance and survival. HDACi treatment represents a novel and effective strategy to target LSC in CML patients receiving tyrosine kinase inhibitors. CML CD34+CD38- cells were selected using flow cytometry sorting and treated with IM, LBH and the combination of IM and LBH or cultured without exposure to drugs (controls) for 24 hours (n=3 each). Total RNA from 5000 cells was extracted using the RNeasy kit (Qiagen), amplified and labeled using GeneChip Two-Cycle Target Labeling and Control Reagents (Affymetrix, Santa Clara, CA). 15 Âµg cRNA from each sample was hybridized to Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. Microarray data analyses were performed using R (version 2.9) with genomic analysis packages from Bioconductor (version 2.4). Expression data were normalized using the robust multiarray average (RMA) algorithm, with background adjustment, quantile normalization and median polish summarization. Probesets with low expression levels or low variability across samples were filtered. For genes with multiple probesets, the gene level expression was set to be the median of the probesets. Linear regression was used to model the gene expression with the consideration of 2x2 factorial design and matched samples. Differentially expressed genes were identified by calculating empirical Bayes moderated t-statistic, and p-values were adjusted by FDR using the âLIMMAâ package. Gene Set Enrichment Analyses (GSEA) was performed using GSEA software version 2.04 [http://www.broadinstitute.org/gsea/] to detect enrichment of predetermined gene sets using t-scores and gene sets in C2 (curated gene sets) category from the Molecular Signature Database (MsigDB). Gene sets representing common functional categories were categorized and grouped. We also analyzed enrichment of gene sets with common transcription factor binding sites (586 sets) from MsigDB.

Dataset Information

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

Publications

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

Similar Datasets

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