Linked Life Data

16322259

Source:http://linkedlifedata.com/resource/pubmed/id/16322259

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2005-12-2
pubmed:abstractText
The heterodimeric hypoxia-inducible factor-1 (HIF-1) is involved in key steps of tumor progression and therapy resistance and thus represents an attractive antitumor target. Because heat shock protein 90 (HSP90) plays an important role in HIF-1alpha protein stabilization and because HSP90 inhibitors are currently being tested in clinical phase I trials for anticancer treatment, we investigated their role as anti-HIF-1alpha agents. Surprisingly, low-dose (5-30 nmol/L) treatment of HeLa cells with three different HSP90 inhibitors (17-AAG, 17-DMAG, and geldanamycin) increased HIF-1-dependent reporter gene activity, whereas higher doses (1-3 micromol/L) resulted in a reduction of hypoxia-induced HIF-1 activity. In line with these data, low-dose treatment with HSP90 inhibitors increased and high-dose treatment reduced hypoxic HIF-1alpha protein levels, respectively. HIF-1alpha protein stabilized by HSP90 inhibitors localized to the nucleus. As a result of HSP90-modulated HIF-1 activity, the levels of the tumor-relevant HIF-1 downstream targets carbonic anhydrase IX, prolyl-4-hydroxylase domain protein 3, and vascular endothelial growth factor were increased or decreased after low-dose or high-dose treatment, respectively. Bimodal effects of 17-AAG on vessel formation were also seen in the chick chorioallantoic membrane angiogenesis assay. In summary, these results suggest that dosage will be a critical factor in the treatment of tumor patients with HSP90 inhibitors.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/17-(allylamino)-17-demethoxygeldanam..., http://linkedlifedata.com/resource/pubmed/chemical/17-(dimethylaminoethylamino)-17-deme..., http://linkedlifedata.com/resource/pubmed/chemical/Antibiotics, Antineoplastic, http://linkedlifedata.com/resource/pubmed/chemical/Benzoquinones, http://linkedlifedata.com/resource/pubmed/chemical/HIF1A protein, human, http://linkedlifedata.com/resource/pubmed/chemical/HSP90 Heat-Shock Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1, alpha..., http://linkedlifedata.com/resource/pubmed/chemical/Lactams, Macrocyclic, http://linkedlifedata.com/resource/pubmed/chemical/Quinones, http://linkedlifedata.com/resource/pubmed/chemical/Rifabutin, http://linkedlifedata.com/resource/pubmed/chemical/geldanamycin
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
65
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
11094-100
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Induction of the hypoxia-inducible factor system by low levels of heat shock protein 90 inhibitors.
pubmed:affiliation
Cell Physiology Group, Medical Faculty, Martin Luther University Halle, Halle, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't