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: Laura Gatti, Alexandra Sevko, Michelandrea De Cesare, Noemi Arrighetti, Giacomo Manenti, Emilio Ciusani, Paolo Verderio, Chiara M Ciniselli, Denis Cominetti, Nives Carenini, Elisabetta Corna, Nadia Zaffaroni, Monica Rodolfo, Licia Rivoltini, Viktor Umansky, Paola Perego
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 12 Pg. 4516-28 (Jun 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24980831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Histone Deacetylase Inhibitors
• Dacarbazine
• Temozolomide

Topics

• Animals
• Apoptosis
• Cell Survival
• Chemokines (metabolism)
• Dacarbazine (analogs & derivatives, metabolism)
• Disease Models, Animal
• Drug Synergism
• Histone Deacetylase Inhibitors (metabolism)
• Humans
• Melanoma (genetics)
• Mice
• Mice, Transgenic
• Temozolomide
• Tumor Microenvironment