Linked Life Data

16930563

Source:http://linkedlifedata.com/resource/pubmed/id/16930563

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2006-10-23
pubmed:abstractText
We previously synthesized several K-vitamin derivatives, which are potent growth inhibitors of human tumor cells, including Hep3B human hepatoma cells. Among these, Cpd 5 was the most potent. However, being a quinone derivative, Cpd 5 has the potential for generating toxic reactive oxygen species (ROS). We therefore synthesized a fluorinated derivative of Cpd 5, F-Cpd 5. The calculated reduction potential of F-Cpd 5 was much higher than that for Cpd 5 and it was not predicted to generate ROS. This was supported by our observation that F-Cpd 5 generated significantly lower ROS than Cpd 5. F-Cpd 5 was three times more potent than Cpd 5 in inhibiting Hep3B cell growth. Interestingly, under identical culture conditions, F-Cpd 5 inhibited mitogen-induced DNA synthesis in normal rat hepatocytes 12-fold less potently than Hep3B cells. F-Cpd 5 was found to induce caspase-3 cleavage and nuclear DNA laddering, evidences for apoptosis. It preferentially inhibited the activities of the cell cycle controlling phosphatases Cdc25A and Cdc25B, by binding to their catalytic cysteines. Consequently, inhibitory tyrosine phosphorylation of the Cdc25 substrate kinases Cdk2 and Cdk4 were induced. F-Cpd 5 also induced phosphorylation of the MAPK proteins ERK1/2, JNK1/2 and p38 in Hep3B cells and the MAPK inhibitors (U0126, JNKI-II, and SB 203580) antagonized its growth inhibition. F-Cpd 5 inhibited the action of cytosolic ERK phosphatase activity, which likely caused the ERK phosphorylation. F-Cpd 5 thus differentially inhibited growth of normal and tumor cells by preferentially inhibiting the actions of Cdc25A and Cdc25B phosphatases and inducing MAPK phosphorylation.
pubmed:grant
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
15
pubmed:volume
72
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1217-27
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16930563-Animals, pubmed-meshheading:16930563-Antineoplastic Agents, pubmed-meshheading:16930563-Apoptosis, pubmed-meshheading:16930563-Binding, Competitive, pubmed-meshheading:16930563-Cell Line, Tumor, pubmed-meshheading:16930563-Cell Proliferation, pubmed-meshheading:16930563-DNA, pubmed-meshheading:16930563-Enzyme Activation, pubmed-meshheading:16930563-Hepatocytes, pubmed-meshheading:16930563-Humans, pubmed-meshheading:16930563-Male, pubmed-meshheading:16930563-Mitogen-Activated Protein Kinase Kinases, pubmed-meshheading:16930563-Naphthoquinones, pubmed-meshheading:16930563-Phosphorylation, pubmed-meshheading:16930563-Rats, pubmed-meshheading:16930563-Rats, Inbred F344, pubmed-meshheading:16930563-Reactive Oxygen Species, pubmed-meshheading:16930563-Vitamin K, pubmed-meshheading:16930563-cdc25 Phosphatases
pubmed:year
2006
pubmed:articleTitle
Fluorinated Cpd 5, a pure arylating K-vitamin derivative, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating MAPK.
pubmed:affiliation
Liver Cancer Center, Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh PA, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural