Histone deacetylase inhibitor-temozolomide co-treatment inhibits melanoma growth through suppression of Chemokine (C-C motif) ligand 2-driven signals
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Laura Gatti1,*, Alexandra Sevko2,*, Michelandrea De Cesare1, Noemi Arrighetti1, Giacomo Manenti3, Emilio Ciusani4, Paolo Verderio5, Chiara M. Ciniselli5, Denis Cominetti1, Nives Carenini1, Elisabetta Corna1, Nadia Zaffaroni1, Monica Rodolfo6, Licia Rivoltini6, Viktor Umansky2,* and Paola Perego1,*
1 Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Heidelberg, Germany
3 Genetic Epidemiology and Pharmacogenomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
4 Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
5 Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
6 Immunotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
* These authors contributed equally to this work
Paola Perego, email:
Keywords: melanoma, CCL2, JNK, histone deacetlylase inhibition, temozolomide
Received: May 30, 2014 Accepted: June 5, 2014 Published: June 6, 2014
Target-specific agents used in melanoma are not curative, and chemokines are being implicated in drug-resistance to target-specific agents. Thus, the use of conventional agents in rationale combinations may result in optimization of therapy. Because histone deacetylases participate in tumor development and progression, the combination of the pan-inhibitor SAHA and temozolomide might provide a therapeutic advantage. Here, we show synergism between the two drugs in mutant BRAF cell lines, in association with decreased phosphorylation of cell survival proteins (e.g., C-Jun-N-terminal-kinase, JNK). In the spontaneous ret transgenic mouse melanoma model, combination therapy produced a significant disease onset delay and down-regulation of Chemokine (C-C motif) ligand 2 (CCL2), JNK, and of Myeloid-derived suppressor cell recruitment. Co-incubation with a CCL2-blocking-antibody enhanced in vitro cell sensitivity to temozolomide. Conversely, recombinant CCL2 activated JNK in human tumor melanoma cells. In keeping with these results, the combination of a JNK-inhibitor with temozolomide was synergistic. By showing that down-regulation of CCL2-driven signals by SAHA and temozolomide via JNK contributes to reduce melanoma growth, we provide a rationale for the therapeutic advantage of the drug combination. This combination strategy may be effective because of interference both with tumor cell and tumor microenvironment.
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