Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and inhibitors of DNA methyltransferase or histone deacetylase (HDAC) enzymes have exhibited activity in preclinical AML models. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have potential beneficial clinical activity in AML, however the toxicity profiles of non-selective HDAC inhibitors in the combination setting limit their clinical utility. In this work, we describe the preclinical development of selective inhibitors of HDAC1 and HDAC2, which are hypothesized to have improved safety profiles, for combination therapy in AML. We demonstrate that selective inhibition of HDAC1 and HDAC2 is sufficient to achieve efficacy both as a single agent and in combination with azacitidine in preclinical models of AML, including established AML cell lines, primary leukemia cells from AML patient bone marrow samples and in vivo xenograft models of human AML. Gene expression profiling of AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the combination of both have identified a list of genes involved in transcription and cell cycle regulation as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients.

Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

“…Cell line and animal data have identified upregulation of epigenetically silenced genes and consequent restoration of cell-cycle checkpoints as an important potential mechanism of action and indeed previous in vitro studies have correlated the antitumor activity of both AZA and DEC with their ability to effect changes in cell-cycle gene expression and induce G 2 phase arrest (7,23,24). Consequently, the observation that heterozygous predicted loss of function mutations in CDKN2A, a cell-cycle checkpoint activator, are correlated with decreased survival in AZA-treated patients is supportive of the hypothesis that induction of cell-cycle arrest is a potentially important mechanism of action of this agent.…”

“…Although in vitro and animal studies demonstrate that induction of cell-cycle arrest and upregulation of cell-cycle genes correlates with AZA's anti-leukemic activity, the mechanism by which it exerts a clinical antitumor effect remains a matter of conjecture (7). Furthermore, although disease progression appears inevitable in patients treated with AZA little is understood of the mechanism of disease resistance (13).…”

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

“…Acetylation of lysine residues by HATs on histone tails leaves the chromatin structure intact and accessible and is responsible for transcription activation. In contrast, HDAC removes acetyl groups, leading to a more condensed chromatin structure, and, thus, repressing gene transcription [2]. HDACs are also involved in the regulation of cell differentiation, apoptosis, and cell cycle.…”

Model regulatory networks for proteins that are activated and inhibited in the process of induced granulocyte differentiation

“…Целевое фармакологическое воздействие на деацетилазы гистонов может представлять собой альтернативный подход к терапии ОПЛ. К настоящему моменту ингибиторы HDACs, такие как вальпроевая кислота, использовали в комбинации с ATRA или ингибитором ДНК-метилтрансферазы азацитидином для лечения пациентов с острым миелоидным лейкозом (ОМЛ), для которых не применим стандартный терапевтический подход [16,17]. Примечательно, что HDAC1 является ключевым регулятором именно активируемого кластера, на основании чего можно предположить, что транскрипция генов, соответствующих белкам с увеличенной экспрессией, регулируется за счет эпигенетических механизмов.…”