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

• Published in: Toxicology in vitro Vol. 22; no. 5; pp. 1361 - 1370
• Main Authors: Murias, Marek, Luczak, Michal W., Niepsuj, Anna, Krajka-Kuzniak, Violetta, Zielinska-Przyjemska, Malgorzata, Jagodzinski, Pawel P., Jäger, Walter, Szekeres, Thomas, Jodynis-Liebert, Jadwiga
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2008
• Subjects: 3,3′,4,4′,5,5′- trans-tetrahydroxystilbene; Antineoplastic Agents - toxicity; Breast cancer cell lines; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Caspase-3; Caspase-8; Caspase-9; Caspases - biosynthesis; Caspases - drug effects; Catalase; 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; MDA-MB-231; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondrial apoptotic pathway; p53; Pyrogallol - analogs & derivatives; Pyrogallol - toxicity; Resveratrol; Stilbenes - toxicity; Superoxide dismutase; Superoxide Dismutase - drug effects; Superoxide Dismutase - metabolism; T47D; Tumor Suppressor Protein p53 - biosynthesis; Vitaceae; ZR-75-1; 3,3′,4,4′,5,5′- trans-tetrahydroxystilbene; DMSO; ZR-75-1; SOD; Superoxide dismutase; T47D; Breast cancer cell lines; Caspase-3; Mitochondrial apoptotic pathway; HHRA; p53; DDTC; Caspase-8; DMEM; Catalase; FBS; CAT; MnSOD; ROS; Resveratrol; Caspase-9; GSH; MDA-MB-231; JC-1
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2008.03.002

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 IC 50 values obtained in the clonogenic assay were 0.846 μM for T47D, 8.53 μM for ZR-75-1 cells and 25.5 μM for MDA-MB-231, while IC 50 values obtained in the cell proliferation assay were significantly higher: 90.1 μM, 98.4 μM, 127.8 μM 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.