Linked Life Data

17943175

Source:http://linkedlifedata.com/resource/pubmed/id/17943175

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2008-1-16
pubmed:abstractText
Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor play an important role in the pathogenesis of acute myeloid leukemia (AML) and represent an attractive therapeutic target. ABT-869 has demonstrated potent effects in AML cells with FLT3-ITDs. Here, we provide further evidence that ABT-869 treatment significantly downregulates cyclins D and E but increases the expression of p21 and p27. ABT-869 induces apoptosis through downregulation of Bcl-xL and upregulation of BAK, BID and BAD. We also evaluate the combinations of ABT-869 and chemotherapy. ABT-869 demonstrates significant sequence-dependent synergism with cytarabine and doxorubicin in cell lines and primary leukemia samples. The optimal combination was validated in MV4-11 xenografts. Low-density array analysis revealed the synergistic interaction involved in downregulation of cell cycle and mitogen-activated protein kinase pathway genes. CCND1 and c-Mos were the most significantly inhibited targets on both transcriptional and translational levels. Treatment with short hairpin RNAs targeting either CCND1 or c-Mos further sensitized MV4-11 cells to ABT-869. These findings suggest that specific pathway genes were further targeted by adding chemotherapy and support the rationale of combination therapy. Thus, a clinical trial using sequence-dependent combination therapy with ABT-869 in AML is warranted.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1476-5551
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
138-46
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:17943175-Acute Disease, pubmed-meshheading:17943175-Animals, pubmed-meshheading:17943175-Antineoplastic Combined Chemotherapy Protocols, pubmed-meshheading:17943175-Apoptosis, pubmed-meshheading:17943175-Cell Cycle Proteins, pubmed-meshheading:17943175-Cytarabine, pubmed-meshheading:17943175-Down-Regulation, pubmed-meshheading:17943175-Doxorubicin, pubmed-meshheading:17943175-Drug Synergism, pubmed-meshheading:17943175-Drug Therapy, Combination, pubmed-meshheading:17943175-Gene Expression Profiling, pubmed-meshheading:17943175-Humans, pubmed-meshheading:17943175-Indazoles, pubmed-meshheading:17943175-Leukemia, Myeloid, pubmed-meshheading:17943175-Mice, pubmed-meshheading:17943175-Mice, SCID, pubmed-meshheading:17943175-Mitogen-Activated Protein Kinases, pubmed-meshheading:17943175-Phenylurea Compounds, pubmed-meshheading:17943175-Proto-Oncogene Proteins c-mos, pubmed-meshheading:17943175-RNA, Small Interfering, pubmed-meshheading:17943175-Receptor Protein-Tyrosine Kinases, pubmed-meshheading:17943175-Signal Transduction, pubmed-meshheading:17943175-Transplantation, Heterologous
pubmed:year
2008
pubmed:articleTitle
Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway.
pubmed:affiliation
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't