Linked Life Data

17595328

Source:http://linkedlifedata.com/resource/pubmed/id/17595328

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2007-8-24
pubmed:abstractText
The effects of the multikinase inhibitor sorafenib (BAY 43-9006), an agent shown previously to induce apoptosis in human leukemia cells through inhibition of myeloid cell leukemia-1 (Mcl-1) translation, have been examined in Bcr/Abl(+) leukemia cells resistant to imatinib mesylate (IM). When administered at pharmacologically relevant concentrations (10-15 microM), sorafenib potently induced apoptosis in imatinib mesylate-resistant cells expressing high levels of Bcr/Abl, cells exhibiting a Bcr/Abl-independent, Lyn-dependent form of resistance, and CD34(+) cells obtained from imatinib-resistant patients. In addition, Ba/F3 cells expressing mutations rendering them resistant to IM (e.g., E255K, M351T) or to IM, dasatinib, and nilotinib (T315I) remained fully sensitive to sorafenib. Induction of apoptosis by sorafenib was associated with rapid and pronounced down-regulation of Mcl-1 and diminished signal transducer and activator of transcription (STAT) 5 phosphorylation and reporter activity but only very modest and delayed inactivation of the Bcr/Abl downstream target Crkl. Moreover, transfection with a constitutively active STAT5 construct partially but significantly protected cells from sorafenib lethality. Ba/F3 cells expressing Bcr/Abl mutations were as sensitive to sorafenib-induced Mcl-1 down-regulation and dephosphorylation of STAT5 and eukaryotic initiation factor 4E as wild-type cells. Finally, stable knockdown of Bcl-2-interacting mediator of cell death (Bim) with short hairpin RNA in K562 cells significantly diminished sorafenib lethality, arguing strongly for a functional role of this proapoptotic Bcl-2 family member in the lethality of this agent. Together, these findings suggest that sorafenib effectively induces apoptosis in highly imatinib-resistant chronic myelogenous leukemia cells, most likely by inhibiting or down-regulating targets (i.e., STAT5 and Mcl-1) downstream or independent of Bcr/Abl.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
72
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
788-95
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:17595328-Antineoplastic Agents, pubmed-meshheading:17595328-Apoptosis, pubmed-meshheading:17595328-Benzenesulfonates, pubmed-meshheading:17595328-Dose-Response Relationship, Drug, pubmed-meshheading:17595328-Down-Regulation, pubmed-meshheading:17595328-Drug Resistance, Neoplasm, pubmed-meshheading:17595328-Fusion Proteins, bcr-abl, pubmed-meshheading:17595328-Gene Expression Regulation, Neoplastic, pubmed-meshheading:17595328-Humans, pubmed-meshheading:17595328-K562 Cells, pubmed-meshheading:17595328-Leukemia, Myelogenous, Chronic, BCR-ABL Positive, pubmed-meshheading:17595328-Piperazines, pubmed-meshheading:17595328-Protein Kinase Inhibitors, pubmed-meshheading:17595328-Pyridines, pubmed-meshheading:17595328-Pyrimidines, pubmed-meshheading:17595328-STAT5 Transcription Factor
pubmed:year
2007
pubmed:articleTitle
The multikinase inhibitor sorafenib induces apoptosis in highly imatinib mesylate-resistant bcr/abl+ human leukemia cells in association with signal transducer and activator of transcription 5 inhibition and myeloid cell leukemia-1 down-regulation.
pubmed:affiliation
Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural