title: Histone deacetylase inhibitor-temozolomide co-treatment inhibits melanoma growth through suppression of Chemokine (C-C motif) ligand 2-driven signals.
abstract: 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.
authors: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. These authors contributed equally to this work.
authors: Laura
authors: L
authors: Gatti
authors: 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. These authors contributed equally to this work.
authors: Alexandra
authors: A
authors: Sevko
authors: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Michelandrea
authors: M
authors: De Cesare
authors: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Noemi
authors: N
authors: Arrighetti
authors: Genetic Epidemiology and Pharmacogenomics Unit,Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Giacomo
authors: G
authors: Manenti
authors: Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
authors: Emilio
authors: E
authors: Ciusani
authors: Medical Statistics, Biometry and Bioinformatics Unit,Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Paolo
authors: P
authors: Verderio
authors: Medical Statistics, Biometry and Bioinformatics Unit,Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Chiara M
authors: CM
authors: Ciniselli
authors: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Denis
authors: D
authors: Cominetti
authors: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Nives
authors: N
authors: Carenini
authors: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Elisabetta
authors: E
authors: Corna
authors: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Nadia
authors: N
authors: Zaffaroni
authors: Immunotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Monica
authors: M
authors: Rodolfo
authors: Immunotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Licia
authors: L
authors: Rivoltini
authors: 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. These authors contributed equally to this work.
authors: Viktor
authors: V
authors: Umansky
authors: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. These authors contributed equally to this work.
authors: Paola
authors: P
authors: Perego
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D018925:Chemokines / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D000077204:Temozolomide; D059016:Tumor Microenvironment
chemical_list: D018925:Chemokines; D056572:Histone Deacetylase Inhibitors; D003606:Dacarbazine; D000077204:Temozolomide