title: Induction of apoptosis by 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione through reactive oxygen species production, GADD153 expression, and caspases activation in human epidermoid carcinoma cells.
abstract: This study examined the growth inhibitory effects of the structurally related beta-diketones compounds in 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 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation 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 were detected, suggesting that HMDB induced irreparable DNA damage, which in turn triggered the process of apoptosis. Up-regulation of Bad and p21; down-regulation of Bcl-2, Bcl-XL, Bid, p53, and fatty acid synthase; and cleavage of Bax were found in HMDB-treated A431 cells. Glutathione and N-acetylcysteine (NAC) suppress HMDB-induced apoptosis. HMDB markedly enhanced growth arrest DNA 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 DNA damage and GADD153 gene activation, which in turn helps trigger apoptosis in A431 cells.
authors.affiliation: Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung 811, Taiwan. mhpan@mail.nkmu.edu.tw
authors.forename: Min-Hsiung
authors.initials: MH
authors.lastname: Pan
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Sin
authors.forename: Ching-Shu
authors.initials: CS
authors.lastname: Lai
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
authors.forename: Jen-Kun
authors.initials: JK
authors.lastname: Lin
authors.forename: Mingfu
authors.initials: M
authors.lastname: Wang
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D009369:Neoplasms / Q000201:enzymology*; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics*
chemical_list: C506624:1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione; D007659:Ketones; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D045304:Cytochromes c; D020169:Caspases; D011407:Propane