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// Chiara Ciardiello 1, * , Maria Serena Roca 1, * , Alessia Noto 1 , Francesca Bruzzese 1 , Tania Moccia 1 , Carlo Vitagliano 1 , Elena Di Gennaro 1 , Gennaro Ciliberto 2 , Giuseppe Roscilli 3 , Luigi Aurisicchio 3 , Emanuele Marra 3 , Rita Mancini 4 , Alfredo Budillon 1 , Alessandra Leone 1 1 Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy 2 Scientific Direction, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy 3 Takis s.r.l., University, 00161 Rome, Italy 4 Department of Surgery "P.Valdoni” and Department of Clinical and Molecular Medicine, “La Sapienza” University, 00161 Rome, Italy * These author contributed equally to this work Correspondence to: Alfredo Budillon, e-mail: a.budillon@istitutotumori.na.it Keywords: NSCLC, HDAC inhibitor, ErbB3, valproic acid, primary tumor cultures Received: September 14, 2015 Accepted: January 23, 2016 Published: February 04, 2016 ABSTRACT ErbB3, a member of the ErbB family receptors, has a key role in the development and progression of several cancers, including non-small cell lung cancer (NSCLC), and in the establishment of resistance to therapies, leading to the development of anti-ErbB3 therapies. In this study we demonstrated, in a set of malignant pleural effusion-derived cultures of NSCLC, the synergistic antitumor effect of a histone deacetylase inhibitor (HDACi), such as vorinostat or valproic acid (VPA), in combination with the anti-ErbB3 monoclonal antibody (MoAb) A3. Synergistic interaction was observed in 2D and in 3D cultures conditions, both in fully epithelial cells expressing all ErbB receptors, and in cells that had undergone epithelial to mesenchymal transition and expressed low levels of ErbB3. We provided evidences suggesting that differential modulation of ErbB receptors by vorinostat or VPA, also at low doses corresponding to plasma levels easily reached in treated patients, is responsible for the observed synergism. In details, we showed in epithelial cells that both vorinostat and VPA induced time- and dose-dependent down-regulation of all three ErbB receptors and of downstream signaling. On the contrary, in A3-resistant mesenchymal cells, we observed time- and dose-dependent increase of mRNA and protein levels as well as surface expression of ErbB3, paralleled by down-regulation of EGFR and ErbB2. Our results suggest that the combination of a HDACi plus an anti-ErbB3 MoAb represents a viable strategy that warrants further evaluation for the treatment of NSCLC patients. |
