Enhanced growth inhibition by combination differentiation therapy with ligands of peroxisome proliferator-activated receptor-gamma and inhibitors of histone deacetylase in adenocarcinoma of the lung

Clin Cancer Res. 2002 Apr;8(4):1206-12.

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

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Differentiation / drug effects*
  • Cell Division / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics
  • Cyclins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Gelsolin / genetics
  • Gelsolin / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Ligands
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Phenylbutyrates / pharmacology
  • RNA / genetics
  • RNA / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Repressor Proteins*
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Gelsolin
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Ligands
  • MXD1 protein, human
  • Phenylbutyrates
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • trichostatin A
  • RNA
  • Histone Deacetylases
  • ciglitazone