Linked Life Data

19949310

Source:http://linkedlifedata.com/resource/pubmed/id/19949310

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-4-13
pubmed:abstractText
The antiproliferative effects and apoptosis inducing abilities of four 18beta-glycyrrhetinic acid (GA) derivatives, methyl 2-cyano-3,11-dioxooleana-1,12-dien-30-oate (CDODO-Me-11), methyl 2-cyano-3,12-dioxooleana-1,12-dien-30-oate (CDODO-Me-12) and their non-esters were investigated in human leukemia cells. Methyl esterification and switching a keto group from position C(11) to C(12) significantly increased the antiproliferative effects. CDODO-Me-11 and CDODO-Me-12 were 10-fold more potent than their non-esters, respectively. CDODO-Me-12 was 10-fold more effective than CDODO-Me-11 in inducing apoptosis which was correlated with the activation of caspase-8 and caspase-9. Western blot analyses revealed that CDODO-Me-12 and CDODO-Me-11 downregulated the levels of anti-apoptosis proteins, c-FLIP, XIAP and Mcl-1, without altering the protein levels of Bcl-2 and the death receptors DR4 and DR5. Both agents decreased the levels of the mitochondrial membrane potential without altering the intracellular H(2)O(2) levels. Jurkat cells without expression of caspase-8 were not sensitive to CDODO-Me-12, but were somewhat responsive to CDODO-Me-11. K562 cells with higher intracellular reduced glutathione (GSH ) levels were less responsive to CDODO-Me-12 apoptosis induction than U937 cells even though both cell lines were equally sensitive to CDODO-Me-11 apoptosis induction. Both agents depleted intracellular GSH levels and exogenous GSH reversed apoptosis induction by either agent in HL-60 cells. N-acetylcysteine (NAC) significantly attenuated apoptosis induction by CDODO-Me-12, but only weakly, that by CDODO-Me-11. UV spectrophotometric analysis revealed that both agents interacted with GSH while only CDODO-Me-12 had high reactivity with NAC. These data suggest that both agents induce apoptosis requiring to bind to functional proteins with thiol groups and that GSH may play a protective role by forming inactive adducts with them.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1555-8576
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
96-108
pubmed:meshHeading
pubmed-meshheading:19949310-Antineoplastic Agents, Phytogenic, pubmed-meshheading:19949310-Apoptosis, pubmed-meshheading:19949310-CASP8 and FADD-Like Apoptosis Regulating Protein, pubmed-meshheading:19949310-Down-Regulation, pubmed-meshheading:19949310-Drug Screening Assays, Antitumor, pubmed-meshheading:19949310-Gene Expression Regulation, Leukemic, pubmed-meshheading:19949310-Glutathione, pubmed-meshheading:19949310-Glycyrrhetinic Acid, pubmed-meshheading:19949310-HL-60 Cells, pubmed-meshheading:19949310-Humans, pubmed-meshheading:19949310-Jurkat Cells, pubmed-meshheading:19949310-K562 Cells, pubmed-meshheading:19949310-Leukemia, Myeloid, Acute, pubmed-meshheading:19949310-Neoplasm Proteins, pubmed-meshheading:19949310-Oxidation-Reduction, pubmed-meshheading:19949310-Proto-Oncogene Proteins c-bcl-2, pubmed-meshheading:19949310-U937 Cells, pubmed-meshheading:19949310-X-Linked Inhibitor of Apoptosis Protein
pubmed:year
2010
pubmed:articleTitle
Downregulation of c-FLIP, XIAP and Mcl-1 protein as well as depletion of reduced glutathione contribute to the apoptosis induction of glycyrrhetinic acid derivatives in leukemia cells.
pubmed:affiliation
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't