Linked Life Data

15657351

Source:http://linkedlifedata.com/resource/pubmed/id/15657351

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2005-1-19
pubmed:abstractText
The molecular mechanisms underlying the acquisition of resistance to the antiestrogen Faslodex are poorly understood, although enhanced expression and activity of nuclear factor kappaB (NFkappaB) have been implicated as a critical element of this phenotype. The purpose of this study was to elucidate the mechanism by which NFkappaB up-regulation contributes to Faslodex resistance and to determine whether pharmacologic inhibition of NFkappaB by the small molecule parthenolide could restore Faslodex-mediated suppression of cell growth. Basal expression of multiple NFkappaB-related molecules in MCF7-derived LCC1 (antiestrogen-sensitive) and LCC9 (antiestrogen-resistant) breast cancer cells was determined, and cells were treated with Faslodex or parthenolide. The effect of these drugs either singly or in combination was assessed by cell proliferation, estrogen receptor (ER)-dependent transcriptional activation, cell cycle analysis, and apoptosis assays. Expression of the p65 NFkappaB subunit and the upstream NFkappaB regulator IkappaB kinase gamma/NFkappaB essential modulator were increased in the resistant MCF7/LCC9 cells (P=0.001 and 0.04, respectively). Whereas MCF7/LCC9 cells were unresponsive to Faslodex alone, parthenolide effectively inhibited MCF7/LCC9 cell proliferation and the combination of Faslodex and parthenolide resulted in a 4-fold synergistic reduction in cell growth (P=0.03). This corresponded to a restoration of Faslodex-induced apoptosis (P=0.001), with no observable changes in ER-dependent transcription or cell cycle phase distribution. Because parthenolide has shown safety in Phase I clinical trials, these findings have direct clinical relevance and provide support for the design of clinical studies combining antiestrogens and parthenolide in ER-positive breast cancer.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1535-7163
pubmed:author
pubmed:issnType
Print
pubmed:volume
4
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
33-41
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
The nuclear factor kappa B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells.
pubmed:affiliation
Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Room W405A Research Building, 3970 Reservoir Road Northwest, Washington, DC 20057, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.