A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor

Abstract

Leukemia stem cells (LSCs) are responsible for treatment failure and relapse in acute myeloid leukemia (AML). Therefore, development of novel LSCs-targeting therapeutic strategies is of crucial clinical importance to improve the treatment outcomes of AML. Histone deacetylase (HDAC) inhibitors have shown potent and specific anticancer stem cell activities in preclinical studies. Chidamide, a novel benzamide-type selectively HDAC inhibitor, has been reported to induce G1 arrest and apoptosis in the relatively mature progenitor population, whereas its effect on primitive LSCs has not been clarified. In this study, we demonstrated that chidamide specifically induces apoptosis in LSC-like cells and primary AML CD34(+) cells in a concentration- and time-dependent manner. Our further molecular mechanistic study uncovered that chidamide induces LSCs death by activation of reactive oxygen species (ROS). It compromises the mitochondria membrane potential, modulates antiapoptotic and pro-apoptotic proteins in BCL2 family and activates caspase-3 leading to PARP degradation. Meanwhile, chidamide activates CD40 and modulates its downstream signaling pathways, JNK and NFκB. The results of this study suggest that chidamide may be a novel LSC-targeting agent for AML therapeutics.

Complete molecular remission in relapsed and refractory acute myeloid leukaemia with MLL-AF9 treated with chidamide-based chemotherapy

“…A possible mechanism may be the downregulation of JAK2/STAT3 signalling through SOCS3 upregulation. 33 Li et al 34 also observed that chidamide specifically induced apoptosis in LSC-like cells and primary AML CD34 + cells in a concentration-and time-dependent manner by activation of reactive oxygen species.…”

Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by aldehyde dehydrogenase 1 A1 inhibition

“…The effect of the inhibitor on the resistance of Cal-27 CisR cell line to Cisplatin was assessed by cell viability assay. The cells were treated with the IC50 concentration of Cisplatin (20 mM) in combination with NCT-501 at varied concentration (10,20,40, and 80 nM). Cytotoxicity assays showed a 16% decrease in cell viability (56 AE 1.7% vs. 40 AE 6.4%) in the Cal-27 CisR cell line at 20nM concentration of the inhibitor, though the difference was not statistically significant ( Figure 7E).…”

Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

“…Thus, this has become a major hindrance to success of AML treatment. 5 To prolong the duration of DFS as well as overall survival, new therapeutic agents targeting LSCs with low/non systemic toxicity are urgently needed for AML treatment.…”