Induction of Apoptosis by 1-(2-Hydroxy-5-methylphenly)-3-phenyl-1,3-propanedione through Reactive Oxygen Species Production, GADD153 Expression, and Caspases Activation in Human Epidermoid Carcinoma C

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• 作者：Min-Hsiung Pan ; Yi-Hong Sin ; Ching-Shu Lai ; Ying-Jan Wang ; Jen-Kun Lin ; Mingfu Wang ; and Chi-Tang Ho
• 刊名：Journal of Agricultural and Food Chemistry
• 出版年：2005
• 出版时间：November 16, 2005
• 年：2005
• 卷：53
• 期：23
• 页码：9039 - 9049
• 全文大小：828K
• 年卷期：v.53,no.23(November 16, 2005)
• ISSN：1520-5118

文摘

This study examined the growth inhibitory effects of the structurally related -diketones compoundsin human cancer cells. Here, we report that 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione(HMDB) induces growth inhibition of human cancer cells and induction of apoptosis in A431 cellsthrough modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROSgeneration occurs in the early stages of HMDB-induced apoptosis, preceding cytochrome c release,caspase activation, and DNA fragmentation. The changes occurred after single breaks in DNA weredetected, suggesting that HMDB induced irreparable DNA damage, which in turn triggered the processof apoptosis. Up-regulation of Bad and p21; down-regulation of Bcl-2, Bcl-X_L, Bid, p53, and fatty acidsynthase; and cleavage of Bax were found in HMDB-treated A431 cells. Glutathione and N-acetylcysteine (NAC) suppress HMDB-induced apoptosis. HMDB markedly enhanced growth arrestDNA damage inducible gene 153 (GADD153) mRNA and protein in a time- and concentration-dependent manner. NAC prevented up-regulation of GADD153 mRNA expression caused by HMDB.These findings suggest that HMDB creates an oxidative cellular environment that induces DNAdamage and GADD153 gene activation, which in turn helps trigger apoptosis in A431 cells.Keywords: HMDB; apoptosis; cytochrome c; caspase-9; caspase-3; poly(ADP-ribose) polymerase;antioxidant; GADD153; reactive oxygen species