New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells.

Fabien Gueugnon,Jean-François Fonteneau,Christophe Blanquart,Marc Gregoire,Pierre-François Cartron,Philippe Bertrand,Cedric Charrier

doi:10.18632/oncotarget.2056

Abstract

Histone deacetylase inhibitors (HDACi) have shown promising antitumor effects on numerous cancer cells including malignant pleural mesothelioma (MPM) and lung adenocarcinoma (ADCA) cells. However, clinical trials using these compounds alone have shown limited efficacy against solid tumors. Therefore, new molecules are being developed and combinations with classical chemotherapeutic drugs are being tested. Here, we have evaluated on three MPM and three lung ADCA cell lines the antitumor potential of four new HDACi compounds, either alone or in combination with cisplatin. These effects were compared with those of vorinostat, an HDACi approved for cancer treatments. First, we characterized the HDAC mRNA expression profiles of tumor cells and showed an increase of the classI/classII HDAC ratio. We then treated cancer cells with these new HDACi and observed a cell-death induction and an increase of HDACi target genes and proteins expression. This was particularly evident for NODH compound (pan-HDACi) which had similar effects at nanomolar concentrations as micromolar concentrations of vorinostat. Interestingly, we observed that the HDACi/cisplatin combination strongly increased cell-death and limited resistance-phenotype emergence as compared with results obtained when the drugs were used alone. These results could be exploited to develop MPM and lung ADCA treatments combining chemotherapeutic approaches.

Highlights

Malignant pleural mesothelioma (MPM) is considered to be one of the worst cancers in terms of clinical outcome
In order to identify a particular modification of histone deacetylases (HDACs) or class of HDAC expression in our cell lines which could lead to the selection of an appropriate family of HDAC inhibitors (HDACi), we first determined by RT-PCR the expression profiles of HDACs in 3 MPM and 3 lung ADCA human cell lines
HDAC 3 seemed to be highly expressed by MPM cell lines compared to normal mesothelial cells this observation was not confirmed on our MPM mRNA biocollection (Fig.S1B)

Summary

Introduction

Malignant pleural mesothelioma (MPM) is considered to be one of the worst cancers in terms of clinical outcome. Deregulation of the histone acetyl transferases (HATs) and histone deacetylases (HDACs) balance has been observed in numerous cancer cells [10,11] resulting in histone hypoacetylation, repression of tumor suppressor genes (TSG) expression and functional alteration of proteins regulated by acetylation, such as p53 [12]. To counteract this phenomenon, HDAC inhibitors (HDACi) are used to re-induce histone acetylation and, TSG expression, with success in a large number of cancer types [13]. These compounds were demonstrated to induce principally cellcycle arrest and apoptosis or sensitization to apoptosis

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