Linked Life Data

15878867

Source:http://linkedlifedata.com/resource/pubmed/id/15878867

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
27
pubmed:dateCreated
2005-7-4
pubmed:abstractText
We have studied the potential effect against human malignant mesotheliomas (MM) of alpha-tocopheryl succinate (alpha-TOS), a redox-silent vitamin E analog with strong pro-apoptotic and anti-cancer activity. alpha-TOS at sub-apoptotic levels inhibited proliferation of MM cell lines, while being nontoxic to nonmalignant mesothelial cells. Because MM cells are typified by a highly metastatic phenotype, we investigated the effect of alpha-TOS on genes playing a major role in MM progression. Of these, alpha-TOS down regulated fibroblast growth factor (FGF)-1 and, in particular, FGF-2 on the transcriptional level in MM cells, and this was not observed in their nonmalignant counterparts. FGF-2 short interfering RNA suppressed proliferation of MM cells. Down-regulation of FGF-2 was likely because of inhibition of the egr-1 transcription activity that was decreased in MM cells via oxidative stress induced by alpha-TOS, as evidenced by EPR spectroscopy, whereas nonmalignant cells did not show this response. Treatment of MM cells with egr-1 short interfering RNA suppressed proliferation, which was overridden by exogenously added recombinant FGF-1 and, in particular, FGF-2. An analog of coenzyme Q targeted to mitochondria and superoxide dismutase overrode inhibition of MM cell proliferation by alpha-TOS as well as alpha-TOS-induced inhibition of egr-1-dependent transactivation. Finally, alpha-TOS significantly suppressed experimental MM in immunocompromised mice. Our data suggest that alpha-TOS suppresses MM cell proliferation by disrupting the FGF-FGF receptor autocrine signaling loop by generating oxidative stress and point to the agent as a selective drug against thus far fatal mesotheliomas.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
25369-76
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop: mechanism and the role of oxidative stress.
pubmed:affiliation
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, 4216 Queensland, Australia.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't