A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor
2015
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.
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