The histone deacetylase inhibitor LBH589 inhibits expression of mitotic genes causing G2/M arrest and cell death in head and neck squamous cell carcinoma cell lines.

Abstract

Head and neck squamous cell carcinoma represents a complex set of neoplasms arising in diverse anatomical locations. The site and stage of the cancer determine whether patients will be treated with single or multi-modality therapy. The HDAC inhibitor LBH589 is effective in treating some haematological neoplasms and shows promise for certain epithelial neoplasms. As with other human cancer cell lines, LBH589 causes up-regulation of p21, G2/M cell cycle arrest, and cell death of human HNSCC cell lines, as measured using flow cytometry and cDNA microarrays. Global RNA expression studies following treatment of the HNSCC cell line FaDu with LBH589 reveal down-regulation of genes required for chromosome congression and segregation (SMC2L1), sister chromatid cohesion (DDX11), and kinetochore structure (CENP-A, CENP-F, and CENP-M); these LBH589-induced changes in gene expression coupled with the down-regulation of MYC and BIRC5 (survivin) provide a plausible explanation for the early mitotic arrest and cell death observed. When LBH589-induced changes in gene expression were compared with gene expression profiles of 41 primary HNSCC samples, many of the genes that were down-regulated by LBH589 showed increased expression in primary HNSCC, suggesting that some patients with HNSCC may respond to treatment with LBH589.

• Authors: Michael B Prystowsky, Alfred Adomako, Richard V Smith, Nicole Kawachi, Wendy McKimpson, Peter Atadja, Quan Chen, Nicolas F Schlecht, Joanna L Parish, Geoffrey Childs, Thomas J Belbin
• Journal: The Journal of pathology (J Pathol) Vol. 218 Issue 4 Pg. 467-77 (Aug 2009) ISSN: 1096-9896 [Electronic] England
• PMID: 19402126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Panobinostat

Topics

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Squamous Cell (pathology)
• Cell Death
• Cell Line, Tumor
• Down-Regulation
• Enzyme Inhibitors (pharmacology)
• Female
• Flow Cytometry
• G2 Phase
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Head and Neck Neoplasms (pathology)
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• Indoles
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Panobinostat