Ketoconazole-Induced Apoptosis through P53-Dependent Pathway in Human Colorectal and Hepatocellular Carcinoma Cell Lines

• Published in: Toxicology and applied pharmacology 1998-11, Vol.153 (1), p.39-47
• Main Authors: Ho, Yuan-Soon, Tsai, Pei-Wen, Yu, Cheng-Fei, Liu, Hsu-Ling, Chen, Rong-Jane, Lin, Jen-Kun
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - physiopathology; Animals; Antineoplastic agents; apoptosis; Apoptosis - physiology; Bax; bcl-2-Associated X Protein; Biological and medical sciences; Blotting, Western; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - physiopathology; Cells, Cultured; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - physiopathology; Drug toxicity and drugs side effects treatment; General aspects; Humans; ketoconazole; Ketoconazole - pharmacology; Ketoconazole - therapeutic use; LaminA; Liver - drug effects; Liver - physiology; Liver Neoplasms - drug therapy; Liver Neoplasms - physiopathology; Medical sciences; PARP; Pharmacology. Drug treatments; Protein Kinase C - physiology; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Sprague-Dawley; Toxicity: digestive system; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - physiology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1998.8467

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 ofp53protein in a dose- and time-dependent manner. The level ofp53protein was elevated approximately three times as much in treated cells 24 h after KT (5 μM) exposure as in cells receiving mock treatment. We found that cells containing wild-typep53(COLO 205 and Hep G2) were more sensitive to KT exposure. Thebaxprotein was induced and thebcl-2protein was inhibited by KT in cells containing wild-typep53(Hep G2, COLO 205) but not in cells withoutp53(Hep 3B). The caspase-3 was activated 24 h after KT treatment. The Poly-(ADP ribose) polymerase (PARP) and thelaminA 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.