title: Ketoconazole-induced apoptosis through P53-dependent pathway in human colorectal and hepatocellular carcinoma cell lines.
abstract: In this study, we first demonstrated that the widely used oral antifungal drug, ketoconazole (KT), can induce apoptosis in various type of human cancer cells and in a primary culture of rat liver cells. We further investigated the molecular mechanisms of KT-induced apoptosis. It was found that KT induced nuclear accumulation of p53 protein in a dose- and time-dependent manner. The level of p53 protein was elevated approximately three times as much in treated cells 24 h after KT (5 microM) exposure as in cells receiving mock treatment. We found that cells containing wild-type p53 (COLO 205 and Hep G2) were more sensitive to KT exposure. The bax protein was induced and the bcl-2 protein was inhibited by KT in cells containing wild-type p53 (Hep G2, COLO 205) but not in cells without p53 (Hep 3B). The caspase-3 was activated 24 h after KT treatment. The Poly-(ADP ribose) polymerase (PARP) and the lamin A degradation was induced by KT, which promoted nuclear membrane disassembly and eventually caused apoptosis. Our results also indicated that none of the PKC gene family was involved in KT-induced apoptosis.
authors.affiliation: School of Medical Technology, Taipei Medical College, Taiwan, Republic of China.
authors.forename: Y S
authors.initials: YS
authors.lastname: Ho
authors.forename: P W
authors.initials: PW
authors.lastname: Tsai
authors.forename: C F
authors.initials: CF
authors.lastname: Yu
authors.forename: H L
authors.initials: HL
authors.lastname: Liu
authors.forename: R J
authors.initials: RJ
authors.lastname: Chen
authors.forename: J K
authors.initials: JK
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000503:physiopathology; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D011493:Protein Kinase C / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D011493:Protein Kinase C; D007654:Ketoconazole