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Ketoconazole induces G0/G1 arrest in human colorectal and hepatocellular carcinoma cell lines
1Graduate Institute of Medical Sciences, Taipei Medical College, Taiwan.
Abstract:
Ketoconazole is an oral-antifungal agent that has been used worldwide in the treatment of some hormone-dependent human cancer. In this study, we demonstrated that ketoconazole (20 microM) induced various types of human cancer cell growth arrest in the G0/G1 phase. Our results revealed that ketoconazole-induced growth arrest was more profound in COLO 205 and Hep G2 (with wild-type p53) than in HT 29 (p53 His(273) mutant) and Hep 3B (with deleted p53) cells. The protein levels of p53, p21/Cip1, and p27/Kip1 were significantly elevated by ketoconazole (10 microM) treatment in COLO 205 but not in HT 29 cells. The ketoconazole-induced G0/G1 phase arrest in COLO 205 cells was attenuated by p53-specific antisense oligodeoxynucleotides (20 microM) treatment. These results suggested that the p53-associated signaling pathway is involved in the regulation of ketoconazole-induced cancer cell growth arrest. By Western blot analysis, we demonstrated that cyclin D3 and CDK4 protein but not other G0/G1 phase regulatory protein levels were decreased by ketoconazole-treatment in both COLO 205 and HT 29 cells. Our study provides the basis of molecular mechanisms for ketoconazole in growth inhibition of human cancer cells and such results may have significant applications for cancer chemotherapy.
Insights
Ketoconazole, an antifungal drug, halts human cancer cell growth by arresting them in the G0/G1 phase. This effect is linked to the p53 signaling pathway, suggesting potential in cancer chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ketoconazole is an antifungal agent with established use in treating hormone-dependent human cancers.
- Cancer cell growth regulation is a critical area for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying ketoconazole's anti-cancer effects.
- To determine the role of the p53 signaling pathway in ketoconazole-induced cancer cell growth arrest.
Main Methods:
- Human cancer cell lines (COLO 205, Hep G2, HT 29, Hep 3B) were treated with ketoconazole.
- Cell cycle progression was analyzed using flow cytometry.
- Protein levels of key cell cycle regulators (p53, p21/Cip1, p27/Kip1, cyclin D3, CDK4) were assessed by Western blot.
- p53 function was modulated using specific antisense oligodeoxynucleotides.
Main Results:
- Ketoconazole induced G0/G1 phase cell cycle arrest in various human cancer cell lines.
- The growth arrest was more pronounced in cells with wild-type p53 (COLO 205, Hep G2) compared to those with mutant or deleted p53 (HT 29, Hep 3B).
- Ketoconazole treatment increased p53, p21/Cip1, and p27/Kip1 protein levels in COLO 205 cells, an effect dependent on functional p53.
- Cyclin D3 and CDK4 protein levels were decreased by ketoconazole in both sensitive and resistant cell lines.
Conclusions:
- The p53-associated signaling pathway plays a crucial role in mediating ketoconazole-induced cancer cell growth arrest.
- Ketoconazole exhibits potential as a therapeutic agent for cancer chemotherapy by inhibiting cancer cell proliferation through molecular mechanisms involving cell cycle regulation.
- Further research into ketoconazole's anti-cancer properties could lead to significant advancements in cancer treatment strategies.