Ketoconazole induces G0/G1 arrest in human colorectal and hepatocellular carcinoma cell lines

Citation
Rj. Chen et al., Ketoconazole induces G0/G1 arrest in human colorectal and hepatocellular carcinoma cell lines, TOX APPL PH, 169(2), 2000, pp. 132-141
Citations number
64
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN journal
0041008X → ACNP
Volume
169
Issue
2
Year of publication
2000
Pages
132 - 141
Database
ISI
SICI code
0041-008X(200012)169:2<132:KIGAIH>2.0.ZU;2-1
Abstract
Ketoconazole is an oral-antifungal agent that has been used worldwide in th e treatment of some hormone-dependent human cancer. In this study, we demon strated that ketoconazole (20 muM) induced various types of human cancer ce ll 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 significantl y elevated by ketoconazole (10 muM) treatment in COLO 205 but not in HT 29 cells. The ketoconazole-induced G0/G1 phase arrest in COLO 205 cells was at tenuated by p53-specific antisense oligodeoxynucleotides (20 muM) treatment . These results suggested that the p53-associated signaling pathway is invo lved in the regulation of ketoconazole-induced cancer cell growth arrest. B y Western blot analysis, we demonstrated that cyclin D3 and CDK4 protein bu t not other G0/G1 phase regulatory protein levels were decreased by ketocon azole-treatment in both COLO 205 and HT 29 cells. Our study provides the ba sis of molecular mechanisms for ketoconazole in growth inhibition of human cancer cells and such results may have significant applications for cancer chemotherapy. (C) 2000 Academic Press.