Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
Int J Cancer. 2010 Nov 15;127(10):2467-77. doi: 10.1002/ijc.25255.
Ciclopirox olamine (CPX) is a synthetic antifungal agent clinically used to treat mycoses of the skin and nails. Here, we show that CPX inhibited tumor growth in human breast cancer MDA-MB-231 xenografts. To unveil the underlying mechanism, we further studied the antitumor activity of CPX in cell culture. The results indicate that CPX inhibited cell proliferation and induced apoptosis in human rhabdomyosarcoma (Rh30), breast carcinoma (MDA-MB231) and colon adenocarcinoma (HT-29) cells in a concentration-dependent manner. By cell cycle analysis, CPX induced accumulation of cells in G(1)/G(0) phase of the cell cycle. Concurrently, CPX downregulated cellular protein expression of cyclins (A, B1, D1 and E) and cyclin-dependent kinases (CDK2 and CDK4) and upregulated expression of the CDK inhibitor p21(Cip1), leading to hypophosphorylation of retinoblastoma protein. CPX also downregulated protein expression of Bcl-xL and survivin and enhanced cleavages of Bcl-2. Z-VAD-FMK, a pan-caspase inhibitor, partially prevented CPX-induced cell death, suggesting that CPX-induced apoptosis of cancer cells is mediated at least in part through caspase-dependent mechanism. The results indicate that CPX is a potential antitumor agent.
环吡酮胺（CPX）是一种合成抗真菌药物，临床上用于治疗皮肤和指甲的真菌感染。在这里，我们表明 CPX 抑制了人乳腺癌 MDA-MB-231 异种移植物的肿瘤生长。为了揭示潜在的机制，我们进一步研究了 CPX 在细胞培养中的抗肿瘤活性。结果表明，CPX 以浓度依赖性方式抑制人横纹肌肉瘤（Rh30）、乳腺癌（MDA-MB231）和结肠腺癌（HT-29）细胞的增殖并诱导细胞凋亡。通过细胞周期分析，CPX 诱导细胞在细胞周期的 G(1)/G(0)期积累。同时，CPX 下调细胞周期蛋白（A、B1、D1 和 E）和细胞周期蛋白依赖性激酶（CDK2 和 CDK4）的细胞蛋白表达，并上调 CDK 抑制剂 p21(Cip1) 的表达，导致视网膜母细胞瘤蛋白的低磷酸化。CPX 还下调了 Bcl-xL 和 survivin 的蛋白表达，并增强了 Bcl-2 的裂解。泛半胱天冬酶抑制剂 Z-VAD-FMK 部分阻止了 CPX 诱导的细胞死亡，表明 CPX 诱导癌细胞凋亡至少部分是通过半胱天冬酶依赖性机制介导的。结果表明 CPX 是一种潜在的抗肿瘤药物。
