NDLI: Cluvenone induces apoptosis via a direct target in mitochondria: A possible mechanism to circumvent chemo-resistance?

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Cluvenone induces apoptosis via a direct target in mitochondria: A possible mechanism to circumvent chemo-resistance?

Content Provider	PubMed Central
Author	Gianni, Guizzunti Theodorakis, Emmanuel A. Yu, Alice L. Chiara, Zurzolo Batova, Ayse
Abstract	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.
Related Links	http://dx.doi.org/10.1007/s10637-011-9745-y
Ending Page	1848
Page Count	8
Starting Page	1841
File Format	PDF
ISSN	01676997
e-ISSN	15730646
Journal	Investigational new drugs
Issue Number	5
Volume Number	30
Language	English
Publisher Date	2012-10-01
Access Restriction	Open
Subject Keyword	Pharmacology (medical) Oncology Pharmacology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical) Oncology

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