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Ketoconazole-induced apoptosis through P53-dependent pathway in human colorectal and hepatocellular carcinoma cell
1School of Medical Technology, Taipei Medical College, Taiwan, Republic of China.
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.
Insights
The antifungal drug ketoconazole (KT) triggers apoptosis, programmed cell death, in human cancer and rat liver cells. It activates p53 protein and related pathways, offering potential for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Ketoconazole (KT) is a widely used oral antifungal medication.
- Apoptosis is a critical process in regulating cell death.
- Understanding drug-induced apoptosis mechanisms is vital for therapeutic development.
Purpose of the Study:
- To investigate the potential of ketoconazole (KT) to induce apoptosis in cancer and liver cells.
- To elucidate the molecular mechanisms underlying KT-induced apoptosis.
Main Methods:
- Treatment of human cancer cell lines (COLO 205, Hep G2, Hep 3B) and primary rat liver cells with ketoconazole.
- Analysis of p53 protein levels, bax and bcl-2 protein expression, caspase-3 activation, and degradation of PARP and lamin A.
- Assessment of sensitivity in cells with wild-type versus mutated p53.
Main Results:
- Ketoconazole (KT) induced apoptosis in various human cancer cells and rat liver cells.
- KT treatment led to dose- and time-dependent nuclear accumulation of p53 protein.
- Apoptosis induction was more pronounced in cells with wild-type p53, involving bax induction, bcl-2 inhibition, caspase-3 activation, and PARP/lamin A degradation.
- The PKC gene family was not implicated in KT-induced apoptosis.
Conclusions:
- Ketoconazole (KT) effectively induces apoptosis in cancer and liver cells through p53-dependent pathways.
- KT activates key apoptotic markers including caspase-3 and promotes degradation of PARP and lamin A.
- These findings suggest ketoconazole's potential as an anticancer agent, warranting further investigation.