Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Caspase 3 / metabolism
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Caspase 7 / metabolism
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Caspase Inhibitors
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Cell Cycle / drug effects
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Ciclopirox
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 2 / biosynthesis
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase 4 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclins / antagonists & inhibitors
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Cyclins / biosynthesis
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Humans
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Inhibitor of Apoptosis Proteins
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Microtubule-Associated Proteins / biosynthesis
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Phosphorylation / drug effects
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyridones / pharmacology*
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Retinoblastoma Protein / metabolism
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Survivin
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Xenograft Model Antitumor Assays
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bcl-X Protein / biosynthesis
Substances
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BCL2L1 protein, human
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BIRC5 protein, human
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CDKN1A protein, human
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Caspase Inhibitors
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyridones
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Retinoblastoma Protein
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Survivin
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bcl-X Protein
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Ciclopirox
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Poly(ADP-ribose) Polymerases
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CDK2 protein, human
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CDK4 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Caspase 3
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Caspase 7