Abstract
Purpose:
Histone deacetylase (HDAC) inhibitors and ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma) have been shown previously to induce growth arrest and differentiation in a variety of cancer cell lines. The purpose of this study was to determine whether HDAC inhibitors function similarly in non-small cell lung cancer (NSCLC) and whether combination treatment with HDAC inhibitors and PPARgamma ligands is more efficacious than either agent alone.
Experimental design and results:
Nanomolar concentrations of trichostatin A induced growth arrest in five of seven NSCLC cell lines, whereas sodium phenylbutyrate (PB) was markedly less potent. In adenocarcinomas, trichostatin A up-regulated general differentiation markers (gelsolin, Mad, and p21/WAF1) and down-regulated markers of the type II pneumocyte progenitor cell lineage (MUC1 and SP-A), indicative of a more mature phenotype. PB had a similar effect. Simultaneous treatment with a PPARgamma ligand and PB enhanced the growth inhibition in adenocarcinomas but not in nonadenocarcinomas. Growth arrest was accompanied by markedly decreased cyclin D1 expression but not enhanced differentiation.
Conclusions:
The present study demonstrates potent growth-inhibitory and differentiation-inducing activity of HDAC inhibitors in NSCLC and suggests that combination differentiation therapy should be explored further for the treatment of lung adenocarcinomas.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Blotting, Western
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Differentiation / drug effects*
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Cell Division / drug effects
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / genetics
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Cyclins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Drug Synergism
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Gelsolin / genetics
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Gelsolin / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Histone Deacetylase Inhibitors*
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Histone Deacetylases / metabolism
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Humans
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Hydroxamic Acids / pharmacology
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Ligands
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Phenylbutyrates / pharmacology
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RNA / genetics
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RNA / metabolism
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Repressor Proteins*
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Thiazoles / pharmacology
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Thiazolidinediones*
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Transcription Factors / metabolism*
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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Gelsolin
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Ligands
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MXD1 protein, human
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Phenylbutyrates
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Receptors, Cytoplasmic and Nuclear
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Repressor Proteins
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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trichostatin A
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RNA
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Histone Deacetylases
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ciglitazone