Chen R J, Lee W S, Liang Y C, Lin J K, Wang Y J, Lin C H, Hsieh J Y, Chaing C C, Ho Y S
Graduate Institute of Medical Sciences, Taipei Medical College, Taiwan.
Toxicol Appl Pharmacol. 2000 Dec 1;169(2):132-41. doi: 10.1006/taap.2000.9062.
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.
酮康唑是一种口服抗真菌剂，已在全球范围内用于治疗某些激素依赖性人类癌症。在本研究中，我们证明酮康唑（20微摩尔）可诱导各类人类癌细胞在G0/G1期生长停滞。我们的结果显示，酮康唑诱导的生长停滞在COLO 205和Hep G2（具有野生型p53）细胞中比在HT 29（p53 His(273)突变体）和Hep 3B（p53缺失）细胞中更为显著。在COLO 205细胞中，酮康唑（10微摩尔）处理可显著提高p53、p21/Cip1和p27/Kip1的蛋白水平，但在HT 29细胞中则不然。p53特异性反义寡脱氧核苷酸（20微摩尔）处理可减弱酮康唑诱导的COLO 205细胞G0/G1期停滞。这些结果表明，p53相关信号通路参与了酮康唑诱导的癌细胞生长停滞的调控。通过蛋白质印迹分析，我们证明在COLO 205和HT 29细胞中，酮康唑处理均可降低细胞周期蛋白D3和CDK4蛋白水平，但不影响其他G0/G1期调节蛋白水平。我们的研究为酮康唑抑制人类癌细胞生长的分子机制提供了依据，这些结果可能在癌症化疗中有重要应用。
