Ketoconazole-induced apoptosis through p53-dependent pathway in human colorectal and hepatocellular carcinoma cell lines

In this study, we first demonstrated that the widely used oral antifungal d rug, ketoconazole (KT), can induce apoptosis in various type of human cance r cells and in a primary culture of rat liver cells. We further investigate d the molecular mechanisms of KT-induced apoptosis. It was found that KT in duced nuclear accumulation of p53 protein in a dose- and time-dependent man ner. The level of p53 protein was elevated approximately three times as muc h in treated cells 24 h after KT (5 mu M) exposure as in cells receiving mo ck treatment. We found that cells containing wild-type p53 (COLO 205 and He p G2) were more sensitive to KT exposure. The bax protein was induced and t he 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 act ivated 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 th at none of the PKC gene family was involved in KT-induced apoptosis. (C) 19 98 Academic Press.