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.

Tsg-Hui Chang, Eva Szabo

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2002;8(4):1206-12

PMID: 11948134

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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.

Address: Molecular Physiology and Biophysics Unit, National Institute of Neurologic Diseases and Stroke, Bethesda, Maryland 20892, USA.

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Other Literature Sources:

https://www.lens.org/lens/search/patent/list?q=ref...

Miscellaneous:

https://assays.cancer.gov/CPTAC-146

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-CCND1-3

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