Ketoconazole potentiates the antitumor effects of nocodazole: In vivo therapy for human tumor xenografts in nude mice

Ying Jan Wang, Jiiang Huei Jeng, Rong Jane Chen, How Tseng, Li Ching Chen, Yu Chih Liang, Chien Huang Lin, Chien Ho Chen, Jan Show Chu, Wei Lu Ho, Yuan Soon Ho

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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.

Original languageEnglish
Pages (from-to)199-210
Number of pages12
JournalMolecular Carcinogenesis
Volume34
Issue number4
DOIs
Publication statusPublished - 2002 Aug 14

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

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    Wang, Y. J., Jeng, J. H., Chen, R. J., Tseng, H., Chen, L. C., Liang, Y. C., Lin, C. H., Chen, C. H., Chu, J. S., Ho, W. L., & Ho, Y. S. (2002). Ketoconazole potentiates the antitumor effects of nocodazole: In vivo therapy for human tumor xenografts in nude mice. Molecular Carcinogenesis, 34(4), 199-210. https://doi.org/10.1002/mc.10066