Butin (7,3',4'-trihydroxydihydroflavone) reduces oxidative stress-induced cell death via inhibition of the mitochondria-dependent apoptotic pathway

• Published in: International journal of molecular sciences Vol. 12; no. 6; pp. 3871 - 3887
• Main Authors: Zhang, Rui, Lee, In Kyung, Piao, Mei Jing, Kim, Ki Cheon, Kim, Areum Daseul, Kim, Hye Sun, Chae, Sungwook, Kim, Hee Sun, Hyun, Jin Won
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.06.2011; Molecular Diversity Preservation International (MDPI)
• Subjects: 8-Hydroxy-2'-Deoxyguanosine; Aging; Animals; Antioxidants; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Benzopyrans - chemistry; Benzopyrans - pharmacology; butin; Cancer; Cell death; Cell Line; Cricetinae; Cricetulus; Cytochrome; Cytochromes c - metabolism; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - chemistry; Deoxyguanosine - metabolism; Diabetes; DNA Damage - drug effects; Electronic mail systems; Enzymes; Flavonoids; Hydrogen Peroxide - toxicity; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; MAP Kinase Kinase Kinase 4 - antagonists & inhibitors; MAP Kinase Kinase Kinase 4 - metabolism; Medical research; Medicine; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; mitochondria-dependent apoptotic pathway; Oxidative stress; Oxidative Stress - drug effects; Physiology; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - metabolism; butin; mitochondria-dependent apoptotic pathway; oxidative stress
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms12063871

Recently, we demonstrated that butin (7,3',4'-trihydroxydihydroflavone) protected cells against hydrogen peroxide (H(2)O(2))-induced apoptosis by: (1) scavenging reactive oxygen species (ROS), activating antioxidant enzymes such superoxide dismutase and catalase; (2) decreasing oxidative stress-induced 8-hydroxy-2'-deoxyguanosine levels via activation of oxoguanine glycosylase 1, and (3), reducing oxidative stress-induced mitochondrial dysfunction. The objective of this study was to determine the cytoprotective effects of butin on oxidative stress-induced mitochondria-dependent apoptosis, and possible mechanisms involved. Butin significantly reduced H(2)O(2)-induced loss of mitochondrial membrane potential as determined by confocal image analysis and flow cytometry, alterations in Bcl-2 family proteins such as decrease in Bcl-2 expression and increase in Bax and phospho Bcl-2 expression, release of cytochrome c from mitochondria into the cytosol and activation of caspases 9 and 3. Furthermore, the anti-apoptotic effect of butin was exerted via inhibition of mitogen-activated protein kinase kinase-4, c-Jun NH(2)-terminal kinase (JNK) and activator protein-1 cascades induced by H(2)O(2) treatment. Finally, butin exhibited protective effects against H(2)O(2)-induced apoptosis, as demonstrated by decreased apoptotic bodies, sub-G(1) hypodiploid cells and DNA fragmentation. Taken together, the protective effects of butin against H(2)O(2)-induced apoptosis were exerted via blockade of membrane potential depolarization, inhibition of the JNK pathway and mitochondria-involved caspase-dependent apoptotic pathway.