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.

Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphomain vitroandin vivo

“…Therefore, combinations with classical chemotherapeutic agents [43, 44] or new small molecule inhibitors [45] are being investigated. According to our previous study, MPT0E028 also showed synergism in combination with tyrosine kinase inhibitors, such as erlotinib and sorafenib, in non-small cell lung cancer (NSCLC) and liver cancer, respectively [13, 14].…”

Targeting chemokine pathways in esophageal adenocarcinoma

“…Most important epigenetic alterations are aberrant DNA methylation and histone modifications. [104][105][106] We conducted an analysis of genome-wide DNA methylation on endoscopic biopsies of dysplastic and malignant lesions to understand the role of epigenetic events associated with the progression of Barrett esophagus. We observed that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis and was seen in low grade dysplasia.…”

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

“…In melanoma, pan-HDAC inhibitors in combination with temozolomide have shown promise (19,20). For these reasons, we addressed the role of class I HDACs in melanoma and determined the molecular mechanism whereby these HDACs influence the response of melanomas to temozolomide.…”