Document Detail


Cluvenone induces apoptosis via a direct target in mitochondria: a possible mechanism to circumvent chemo-resistance?
MedLine Citation:
PMID:  21898184     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The synthetic caged Garcinia xanthone, cluvenone, has potent and selective cytotoxicity against numerous cancer cell lines including those that are multi-drug resistant. The direct target of this structurally and functionally unique agent is unknown and that of the parent natural product, gambogic acid (GA), presently in clinical trials, is not yet entirely clear. For the first time, using fluorescently labeled GA (GA-Bodipy), we determined that GA-Bodipy localized in mitochondria and was effectively displaced by cluvenone in competition experiments indicating that the direct target of cluvenone resided in mitochondria and was shared by GA. In agreement with these findings, treatment of HeLa cells with cluvenone or GA resulted in disruption of mitochondrial morphology within 4 h. Furthermore, experiments using the potential sensitive JC-1 dye demonstrated that cells treated with 1 μM cluvenone for 1 h had significant loss of MMP compared to control cells. Examination of Cyt c levels in leukemia cells treated with 1 μM cluvenone resulted in a 4-fold increase in levels of both cytosolic and mitochondrial Cyt c. In agreement with Cyt c release, caspase 9 activity was increased 2.6-fold after treatment of cells for 5 h with 1 μM cluvenone. Remarkably, the caspase-9 inhibitor, Z-LEHD-FMK, blocked cluvenone-induced apoptosis in a dose-dependent manner with apoptosis being completely blocked by 10 μM of the inhibitor. In conclusion, cluvenone, an agent with potent cytotoxicity against multi-drug resistant tumor cells, has direct targets in mitochondria thus setting precedence for drug discovery efforts against these targets in the treatment of refractory cancers.
Authors:
Gianni Guizzunti; Emmanuel A Theodorakis; Alice L Yu; Chiara Zurzolo; Ayse Batova
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-07
Journal Detail:
Title:  Investigational new drugs     Volume:  30     ISSN:  1573-0646     ISO Abbreviation:  Invest New Drugs     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-04     Completed Date:  2013-04-03     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1841-8     Citation Subset:  IM    
Affiliation:
Department of Cell Biology and Infection, Membrane Traffic and Pathogenesis Unit, Pasteur Institute, Paris, France.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Caspase 9 / metabolism
Cell Line, Tumor
Cytochromes c / metabolism
Drug Resistance, Neoplasm
HeLa Cells
Humans
Leukemia / drug therapy,  metabolism
Mitochondria / drug effects*
Xanthones / pharmacology*
Grant Support
ID/Acronym/Agency:
CA 133002/CA/NCI NIH HHS; R01 CA133002/CA/NCI NIH HHS; R01 CA133002-03/CA/NCI NIH HHS; R01 CA133002-04/CA/NCI NIH HHS; R01 CA133002-05/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Xanthones; 0/cluvenone; 2752-65-0/gambogic acid; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspase 9
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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