Synergistic effect of novel HDAC inhibitors with chemotherapy drugs in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a highly heterogeneous malignant disease characterized by uncontrolled proliferation, differentiation arrest and accumulation of immature myeloid progenitors. Despite recent developments and the approval of new therapeutic agents in the last few years, outcome remains poor for most patients, particularly in elderly patients, being an urgent unmet need for therapeutic improvements. After rigorous studies, our group identified and characterized two novel HDACi (histone deacetylases inhibitors), CM-444 and CM-1758, exhibiting higher capacity to promote in vitro and in vivo myeloid differentiation in all subtypes of AML at low non-cytotoxic doses in comparison with commercial HDACi. The acetylome analysis after CM-444 and CM-1758 treatment showed the modulation of a specific non-histone protein acetylation pattern in AML cells. CM-444 and CM-1758 led to acetylation of bromodomain proteins (BRDs), especially BRD4 and BRD1, and other non-histone proteins involved in the enhancer-promoter chromatin regulatory complex. This is essential to enhance the expression of key transcription factors that induce myeloid differentiation and play a very important role in the differentiation therapy exerted by CM-444 or CM-1758 in AML cells. Interestingly, the complete transcriptome analysis after CM-444 and CM-1758 treatment showed changes in genes implicated in chemo-sensitivity, suggesting that CM-444 and CM-1758 could also enhance the efficacy of conventional chemotherapy for AML treatment. CM-444 and CM-1758 led to promising synergistic effect in combination with Doxorubicin and 5-AZA agents in vitro. Moreover, a slight improvement on Doxorubicin treatment was obtained in those AML cells that were previously induced to overexpress the chemo-sensitive gene ALOX5. Proposing that ALOX5 overexpression induced by CM-444 and CM-1758 is one of the possible molecular mechanisms underlying the synergistic effect previously obtained between HDACi (CM-444 and CM-1758) and Doxorubicin or 5-AZA. In summary, on the one hand these new epigenetic compounds might be an effective differentiation-based therapy with a novel mechanism to be tested in AML. And on the other hand, these novels HDACi could also be combined with therapeutic agents to improve their therapeutic effect, in part due to chemo-sensitive gene expression induced by the compounds themselves.