Enhancing the antitumor activity of ErbB blockade with histone deacetylase (HDAC) inhibition.

Abstract

Molecular inhibition of the ErbB signaling pathway represents a promising cancer treatment strategy. Preclinical studies suggest that enhancement of antitumor activity can be achieved by maximizing ErbB signaling inhibition. Using cDNA microarrays, we identified histone deacetylase (HDAC) inhibitors as having strong potential to enhance the effects of anti-ErbB agents. Studies using a 20,000 element (20K) cDNA microarray demonstrate decreased transcript expression of ErbB1 (epidermal growth factor receptor) and ErbB2 in DU145 (prostate) and ErbB2 in SKBr3 (breast) cancer cell lines. Additional changes in the DU145 gene expression profile with potential interaction to ErbB signaling include down-regulation of caveolin-1 and hypoxia inducible factor 1-alpha (HIF1-alpha), and up-regulation of gelsolin, p19(INK4D) and Nur77. Findings were validated using real time RT-PCR and Western blot analysis. Enhanced proliferative inhibition, apoptosis induction and signaling inhibition were demonstrated when combining HDAC inhibition with ErbB blockade. These results suggest that used cooperatively, anti-ErbB agents and HDAC inhibitors may offer a promising strategy of dual targeted therapy. Additionally, microarray data suggest that the beneficial interaction of these agents may not derive solely from modulation of ErbB expression, but may result from effects on other oncogenic processes including angiogenesis, invasion and cell cycle kinetics.

• Authors: Prakash Chinnaiyan, Sooryanarayana Varambally, Scott A Tomlins, Soma Ray, Shyhmin Huang, Arul M Chinnaiyan, Paul M Harari
• Journal: International journal of cancer (Int J Cancer) Vol. 118 Issue 4 Pg. 1041-50 (Feb 15 2006) ISSN: 0020-7136 [Print] United States
• PMID: 16152586 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• ErbB Receptors
• Receptor, ErbB-2
• Histone Deacetylases

Topics

• Apoptosis
• Blotting, Western
• Breast Neoplasms (pathology)
• Cell Proliferation
• Down-Regulation
• Enzyme Inhibitors (pharmacology)
• ErbB Receptors (antagonists & inhibitors, physiology)
• Female
• Gene Expression Profiling
• Histone Deacetylase Inhibitors
• Histone Deacetylases (metabolism)
• Humans
• Male
• Neovascularization, Pathologic
• Oligonucleotide Array Sequence Analysis
• Prostatic Neoplasms (pathology)
• Receptor, ErbB-2 (antagonists & inhibitors, biosynthesis)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Tumor Cells, Cultured
• Up-Regulation