The histone deacetylase inhibitor SAHA sensitizes acute myeloid leukemia cells to a combination of nucleoside analogs and the DNA-alkylating agent busulfan

Abstract

Fludarabine (Flu), clofarabine (Clo) and busulfan (Bu) are used in allogeneic hematopoietic stem cell transplant (allo-HSCT). We reported that combining [Flu + Clo + Bu] had a synergistic cytotoxicity in AML cells. We hypothesized that combining [Flu + Clo + Bu] with the histone deacetylase inhibitor SAHA will further enhance cytotoxicity. We exposed the acute myeloid leukemia (AML) cell lines KBM3/Bu2506 and OCI-AML3 to Flu, Clo, Bu and SAHA alone and in various combinations. [Flu + Clo + Bu + SAHA] resulted in synergistic cytotoxicity, which can be attributed to (1) activated DNA-damage response and cell cycle checkpoint activation through the ATM–CHK2–P53 (or P73) pathway or ATM–CHK2–cdc25–cdc2 pathway, (2) histone modifications and (3) activated apoptosis pathway. The [Flu + Clo + Bu + SAHA] combination causes mitochondrial outer membrane permeabilization, leakage of cytochrome c and Smac/Diablo into the cytosol with caspase activation, and release of apoptosis-inducing factor (AIF) into the nucleus resulting in nuclear fragmentation and cell death. These results provide a mechanistic basis for using SAHA in future clinical trials with double nucleoside analog-busulfan combinations in pretransplant conditioning therapy.

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

“…The most important studies are presented in detail in Table 1 [49,[83][84][85][86][87][88][89][90][91], but it should be emphasized that several of these studies are relatively small, describe observations mainly in AML cell lines or used methodological strategies that would not be regarded as optimal today. Thus, knowledge about CDC25 in human AML is in our opinion incomplete, but despite this CDC25 should be regarded as a possible therapeutic target in human AML.…”

Synergistic Cytotoxicity of Sorafenib with Busulfan and Nucleoside Analogs in Human FMS-like Tyrosine Kinase 3 Internal Tandem Duplications–Positive Acute Myeloid Leukemia Cells

“…We previously showed activation of the DNA-damage response (DDR) in AML and lymphoma cells exposed to combinations of nucleoside analogs, DNA alkylating agents and a histone deacetylase inhibitor [20, 21]. We, therefore, opted to determine whether [Bu+Clo+Flu+Sor] combination also activates DDR in MV-4-11 cells.…”

“…These combinations activate DNA damage response, induce histone modifications and lead to cell cycle checkpoint activation and apoptosis [19-21]. A combination of these three drugs also contributes to increased antileukemic efficacy/patient benefit without an apparent concomitant increase in clinical normal-organ toxicity [22].…”

NPAS2 regulates proliferation of acute myeloid leukemia cells via CDC25A‐mediated cell cycle progression and apoptosis

“…The effects of CDC25 on AML have been the subject of considerable work in recent years. Song and his colleagues showed that suppressed expression of CDC25A was present in AML cells subsequent to supplementation with antiproliferative as well as cytotoxic agents . Experiments by Madlener and his team suggested that CDC25A deactivation could counteract CCA‐linked proliferation and cytotoxicity .…”