Document Detail


Cytotoxic activity of 3,3',4,4',5,5'-hexahydroxystilbene against breast cancer cells is mediated by induction of p53 and downregulation of mitochondrial superoxide dismutase.
MedLine Citation:
PMID:  18434081     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The phytochemical resveratrol, which is found in grapes and red wine, has been reported to have a variety of biological properties. It was shown in our previous research that introduction of additional hydroxyl groups into the stilbene structure increases the biological activity of resveratrol. In this study, the activity of 3,3',4,4',5,5'-hexahydroxystilbene (M8) was investigated in ZR-75-1, MDA-MB-231 and T47D human breast cancer cells. For evaluation of cytotoxic activity of M8, clonogenic and cell proliferation assays were used. The IC50 values obtained in the clonogenic assay were 0.846 microM for T47D, 8.53 microM for ZR-75-1 cells and 25.5 microM for MDA-MB-231, while IC50 values obtained in the cell proliferation assay were significantly higher: 90.1 microM, 98.4 microM, 127.8 microM for T47D, ZR-75-1 and MDA-MB-231 cells, respectively. Compound M8 caused the activation of caspase-8 in MDA-MB-231 cells (marker of extrinsic apoptotic pathway), while activities of caspase-9 (marker of intrinsic apoptotic pathway) and caspase-3 were increased in all 3 tested cell lines. Activation of caspase-9 and caspase-3 was connected with loss of mitochondrial potential and increase of p53, which could have an impact on downregulation of mitochondrial superoxide dismutase (MnSOD) seen in our experiments. MnSOD is a key enzyme providing antioxidative defense in mitochondria - the cellular center of reactive oxygen species' generation. Downregulation of MnSOD can therefore cause a significant decrease of antioxidant defense in cancer cells. An increase of oxidative stress conditions was suggested by loss of reduced glutathione in tested cells. Since cancer cells are usually under permanent oxidative stress, additional increased ROS generation as a result of the interaction of M8 with the mitochondrial respiratory chain and a decrease in oxidative defense can therefore be a promising method for selective elimination of cancer cells.
Authors:
Marek Murias; Michal W Luczak; Anna Niepsuj; Violetta Krajka-Kuzniak; Malgorzata Zielinska-Przyjemska; Pawel P Jagodzinski; Walter Jäger; Thomas Szekeres; Jadwiga Jodynis-Liebert
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-03-15
Journal Detail:
Title:  Toxicology in vitro : an international journal published in association with BIBRA     Volume:  22     ISSN:  0887-2333     ISO Abbreviation:  Toxicol In Vitro     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-06-16     Completed Date:  2008-08-29     Revised Date:  2009-04-10    
Medline Journal Info:
Nlm Unique ID:  8712158     Medline TA:  Toxicol In Vitro     Country:  England    
Other Details:
Languages:  eng     Pagination:  1361-70     Citation Subset:  IM    
Affiliation:
Department of Toxicology, Poznan University of Medical Sciences, ul Dojazd 30, 60-631 Poznan, Poland. marek.murias@ump.edu.pl
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / toxicity*
Breast Neoplasms / drug therapy*,  metabolism,  pathology
Caspases / biosynthesis,  drug effects
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Clone Cells
Dose-Response Relationship, Drug
Down-Regulation / drug effects
Enzyme Activation
Female
Humans
Membrane Potential, Mitochondrial / drug effects
Mitochondria / drug effects*,  enzymology
Pyrogallol / analogs & derivatives*,  toxicity
Stilbenes / toxicity*
Superoxide Dismutase / drug effects*,  metabolism
Tumor Suppressor Protein p53 / biosynthesis*
Chemical
Reg. No./Substance:
0/3,3',4,4',5,5'-hexahydroxystilbene; 0/Antineoplastic Agents; 0/Stilbenes; 0/Tumor Suppressor Protein p53; 87-66-1/Pyrogallol; EC 1.15.1.1/Superoxide Dismutase; EC 3.4.22.-/Caspases

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