New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells
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Fabien Gueugnon1,2,3, Pierre-François Cartron1,2,3,4, Cedric Charrier5, Philippe Bertrand4,5, Jean-François Fonteneau1,2,3, Marc Gregoire1,2,3 and Christophe Blanquart1,2,3,4
1 Inserm, U892, F-44000, Nantes, France
2 CNRS, UMR6299, F-44000, Nantes, France
3 Université Nantes, F-44000, Nantes, France
4 Réseau Epigénétique du Canceropôle Grand Ouest
5 CNRS, UMR7285, Institut de Chimie des Milieux et Matériaux de Poitiers, Université de Poitiers, France
Christophe Blanquart1, email:
Keywords: Mesothelioma, lung cancer, chemotherapy and epigenetic
Received: April 2, 2014 Accepted: June 1, 2014 Published: June 3, 2014
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.
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