|Title:||Ketoconazole potentiates the antitumor effects of nocodazole: In vivo therapy for human tumor xenografts in nude mice||Authors:||Wang Y.-J.
|Keywords:||Apoptosis; Ketoconazole; Nocodazole; Nude mice; p27/KIP1||Issue Date:||2002||Journal Volume:||34||Journal Issue:||4||Start page/Pages:||199-210||Source:||Molecular Carcinogenesis||Abstract:||
Our previous studies demonstrated that the oral antifungal agent Ketoconazole (KT) induces apoptosis and G0/G1 phase cell cycle arrest in human cancer cell lines. In this study, we first demonstrated that KT (1 μM) potentiated the apoptotic effects of nocodazole (ND, 1 nM) in COLO 205 cancer cells. We further demonstrated the therapeutic efficacy of a combined treatment of KT (50 mg/kg/three times per week) and ND (5 mg/kg/three times per week) in vivo by treating athymic mice bearing COLO 205 tumor xenografts. The antitumor effects of ND were significantly potentiated by KT in mice after 6 wk of treatment. No gross signs of toxicity were observed in mice receiving these treatment regimens. The apoptotic cells were detected in a microscopic view of the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and by observation of DNA fragmentation in KT + ND-treated tumor tissues. The levels of cell cycle regulatory proteins were determined by Western blot analysis. Treatment with KT inhibits tumor growth through elevation of p53, p21/CIP1, and p27/KIP1 as well as inhibition of cyclin D3 and cyclin-dependent kinase 4 protein expression. Immunohistochemical staining analysis showed that p53, p21/CIP1, and p27/KIP1 immunoreactivity were induced in the tumor tissues. To clarify the roles of the p21/CIP1 and p27/KIP1 protein expression involved in G0/G1 arrest and/or apoptosis induced by a combined treatment with KT and ND, antisense oligodeoxynucleotides (ODNs) specific to p21/CIP1 and p27/KIP1 were used. Our results demonstrated that apoptotic phenomena, including BAX induction and cytochrome C released from mitochondria induced by KT + ND, were significantly attenuated by pretreatment the cells with the p27/KIP1-specific antisense ODNs. These results indicate that p27/KIP1 protein does indeed play a critical role in the KT + ND-induced apoptosis. Our study revealed the molecular mechanism of KT + ND in regression of the tumor growth. The apoptotic effects of KT in a great variety of cancer cells make it a very attractive agent for cancer chemotherapy. ? 2002 Wiley-Liss, Inc.
|ISSN:||0899-1987||DOI:||10.1002/mc.10066||SDG/Keyword:||antisense oligodeoxynucleotide; cyclin D3; cyclin dependent kinase 4; cytochrome c; DNA fragment; DNA nucleotidylexotransferase; ketoconazole; nocodazole; protein Bax; protein p21; protein p27; animal experiment; animal model; antineoplastic activity; article; cancer cell culture; cancer inhibition; cell cycle G0 phase; cell cycle G1 phase; controlled study; drug activity; drug effect; drug mechanism; drug potentiation; enzyme release; gene induction; human; human cell; immunohistochemistry; mouse; nick end labeling; nonhuman; priority journal; protein expression; toxicity; tumor growth; tumor xenograft; Western blotting; Adenocarcinoma; Animals; Antifungal Agents; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Carrier Proteins; Colonic Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Cyclins; Cytochrome c Group; Drug Synergism; Humans; Intracellular Signaling Peptides and Proteins; Ketoconazole; Mice; Mice, Nude; Nocodazole; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays; Mus musculus
|Appears in Collections:||臨床牙醫學研究所|
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