Linked Life Data

15450938

Source:http://linkedlifedata.com/resource/pubmed/id/15450938

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2004-9-28
pubmed:abstractText
The purpose of this work is to develop agents for cancer differentiation therapy. We showed that five antiproliferative quinoline compounds in the National Cancer Institute database stimulated cell differentiation at growth inhibitory concentrations (3-14 microM) in MCF-7 human breast tumor cells in vitro. The differentiation-inducing quinolines caused lipid droplet accumulation, a phenotypic marker of differentiation, loss of Ki67 antigen expression, a cell cycle marker indicative of exit into G0, and reduced protein levels of the G1--S transcription factor, E2F1. The antimalarial quinolines, chloroquine, hydroxychloroquine and quinidine had similar effects in MCF-7 cells, but were 3-10 times less potent than the NSC compounds. NSC3852 and NSC86371 inhibited histone deacetylase (HDAC) activity in vitro and caused DNA damage and apoptosis in MCF-7 cells, consistent with their differentiation and antiproliferative activities. However, the HDAC assay results showed that for other compounds, direct HDAC enzyme inhibition was not required for differentiation activity. E2F1 protein was suppressed by all differentiation quinolines, but not by non-differentiating analogs, quinoline and primaquine. At equivalent antiproliferative concentrations, NSC69603 caused the greatest decrease in E2F1 protein (90%) followed by antimalarials quinidine and hydroxychloroquine. NSC69603 did not cause DNA damage. The other NSC compounds caused DNA damage and apoptosis and reduced E2F1 levels. The physicochemical properties of NSC3852, NSC69603, NSC86371, and NSC305819 predicted they are drug candidates suitable for development as experimental breast tumor cell differentiation agents. We conclude DNA damage and reductions in E2F1 protein are mechanistically important to the differentiation and antiproliferative activities of these quinoline drug candidates.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
68
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1729-38
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Differentiation-inducing quinolines as experimental breast cancer agents in the MCF-7 human breast cancer cell model.
pubmed:affiliation
Department of Biochemistry & Molecular Pharmacology, West Virginia University, Morgantown, WV 26506, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't