Linked Life Data

16211219

Source:http://linkedlifedata.com/resource/pubmed/id/16211219

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2005-10-7
pubmed:abstractText
The effects of the nuclear factor (NF)-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), combined with tumor necrosis factor (TNF)-alpha were evaluated in PK-8 pancreatic cancer cells. NF-kappaB was activated by TNF-alpha; however, the administration of DHMEQ abrogated its transcriptional activity. The addition of DHMEQ to TNF-alpha markedly induced apoptosis in PK-8 cells with down-regulation of anti-apoptotic c-FLIP and survivin. Combined treatment significantly suppressed cell viability in vitro, and the anti-tumor effect of DHMEQ was also significant in vivo. We investigated the apoptosis signaling pathway involved in these cell killing effects. Truncated Bid was produced by activated caspase-8, and the subsequent depolarization of the mitochondrial membrane potential (Delta Psi m) peaked at 6 h. Then, the activity of caspase-3 was up-regulated 8-fold. Z-VAD-fmk (a pan-caspase inhibitor) perfectly inhibited the up-regulation of caspase-3 but failed to reverse the cell viability. The above findings indicated that the growth inhibitory effect of combined treatment largely depended on mitochondria-associated caspase-independent apoptosis. The intracellular behavior of apoptosis-inducing factor (AIF) following depolarization of Delta Psi m suggested that AIF executed such a caspase-independent apoptosis. Interestingly, caspase-dependent apoptosis appeared within 6 h, whereas the caspase-independent apoptosis lagged. Thus, the addition of DHMEQ to TNF-alpha was capable of inducing caspase-independent apoptosis in pancreatic cancer cells. Once caspase-independent apoptosis was induced, the apoptosis demonstrated powerful cytotoxicity. Therefore, DHMEQ in combination with TNF-alpha may be a promising treatment for pancreatic cancer.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1019-6439
pubmed:author
pubmed:issnType
Print
pubmed:volume
27
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1247-55
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-kappaB inhibitor.
pubmed:affiliation
Department of Surgery, Tokyo Metropolitan Komagome Hospital, Bunkyo-ku, Tokyo 113-8677, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't