Evaluation of newly developed histone deacetylase inhibitors for the treatment of solid tumors

Abstract

The inhibition of histone deacetylases (HDACs) with small‐molecule inhibitors is a new and promising approach for innovative cancer treatment. Histones are of importance for the organization of DNA in the form of chromatin. Transcriptional regulation comprises of a complex machinery of histone modifications, DNA‐methylation as well as acetylation and deacetylation of the chromatin. Dysregulation of acetylation and deacetylation of histones plays an important role in the development and progression of cancer and is often associated with an overexpression or upregulated activity of HDACs. HDAC inhibitors (HDACi) are highly versatile, and have effects on cell cycle, DNA‐repair, DNA‐damage, mitosis, apoptosis and angiogenesis. Here we investigated the suitability of newly synthesized HDACi with enhanced antitumor efficacy as compared to the already established HDACi, such as SAHA.Studies on a set of different cancer cell models (urological cancer cells with or without cisplatin resistance, neuroendocrine gastrointestinal tumor cells and esophageal cancer cells) revealed pronounced growth inhibitory and apoptosis‐inducing effects – starting at nanomolar concentrations (180nM – 1.6µM). Moreover, in vivo tests using the CAM assay method revealed antiangiogenic effects and a concomitant reduction of tumor growth of inoculated urological tumors. Further investigations will focus on the underlying mode of action of the new HDACi in terms of apoptosis, attenuation of subtype‐specific HDAC‐activity and cell cycle regulation.