Linked Life Data

15695405

Source:http://linkedlifedata.com/resource/pubmed/id/15695405

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2005-2-7
pubmed:abstractText
Hypoxia-inducible factor 1 (HIF-1) is the central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. Inhibition of HIF-1 is expected to result in the attenuation of hypoxia-inducible genes, which are vital to many aspects of tumor biology, including adaptative responses for survival under anaerobic conditions. To identify small molecules inhibiting the HIF-1 pathway, we did a biological screen on a 10,000-membered natural product-like combinatorial library. The compounds of the library, which share a 2,2-dimethylbenzopyran structural motif, were tested for their ability to inhibit the hypoxic activation of an alkaline phosphatase reporter gene under the control of hypoxia-responsive elements in human glioma cells. This effort led to the discovery of 103D5R, a novel small-molecule inhibitor of HIF-1alpha. 103D5R markedly decreased HIF-1alpha protein levels induced by hypoxia or cobaltous ions in a dose- and time-dependent manner, whereas minimally affecting global cellular protein expression levels, including that of control proteins such as HIF-1beta, IkappaBalpha, and beta-actin. The inhibitory activity of 103D5R against HIF-1alpha was clearly shown under normoxia and hypoxia in cells derived from different cancer types, including glioma, prostate, and breast cancers. This inhibition prevented the activation of HIF-1 target genes under hypoxia such as vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). Investigations into the molecular mechanism showed that 103D5R strongly reduced HIF-1alpha protein synthesis, whereas HIF-1alpha mRNA levels and HIF-1alpha degradation were not affected. 103D5R inhibited the phosphorylation of Akt, Erk1/2, and stress-activated protein kinase/c-jun-NH(2)-kinase, without changing the total levels of these proteins. Further studies on the mechanism of action of 103D5R will likely provide new insights into its validity/applicability for the pharmacologic targeting of HIF-1alpha for therapeutic purposes.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
65
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
605-12
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15695405-Benzopyrans, pubmed-meshheading:15695405-Biological Factors, pubmed-meshheading:15695405-Breast Neoplasms, pubmed-meshheading:15695405-Cell Line, Tumor, pubmed-meshheading:15695405-Combinatorial Chemistry Techniques, pubmed-meshheading:15695405-DNA-Binding Proteins, pubmed-meshheading:15695405-Dose-Response Relationship, Drug, pubmed-meshheading:15695405-Glioblastoma, pubmed-meshheading:15695405-Humans, pubmed-meshheading:15695405-Hypoxia-Inducible Factor 1, pubmed-meshheading:15695405-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:15695405-Male, pubmed-meshheading:15695405-Nuclear Proteins, pubmed-meshheading:15695405-Prostatic Neoplasms, pubmed-meshheading:15695405-RNA, Messenger, pubmed-meshheading:15695405-Transcription, Genetic, pubmed-meshheading:15695405-Transcription Factors, pubmed-meshheading:15695405-Vascular Endothelial Growth Factor A
pubmed:year
2005
pubmed:articleTitle
Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway.
pubmed:affiliation
Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't