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.

• Authors: Yin Li, Kai Chen, Yong Zhou, Yiren Xiao, Manman Deng, Zhiwu Jiang, Wei Ye, Xiangmeng Wang, Xinru Wei, Jie Li, Jiabao Liang, Zhongxin Zheng, Yao Yao, Weiguang Wang, Peng Li, Bing Xu
• Journal: Current cancer drug targets (Curr Cancer Drug Targets) Vol. 15 Issue 6 Pg. 493-503 ( 2015) ISSN: 1873-5576 [Electronic] Netherlands
• PMID: 26282548 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Antineoplastic Agents
• Benzamides
• CD40 Antigens
• Histone Deacetylase Inhibitors
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide
• Poly(ADP-ribose) Polymerases
• JNK Mitogen-Activated Protein Kinases
• CASP3 protein, human
• Caspase 3

Topics

• Adult
• Aminopyridines (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• CD40 Antigens (metabolism)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Female
• Hematopoietic Stem Cells (drug effects, enzymology, pathology)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Leukemia, Myeloid, Acute (drug therapy, enzymology, pathology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Middle Aged
• Molecular Targeted Therapy
• NF-kappa B (metabolism)
• Neoplastic Stem Cells (drug effects, enzymology, pathology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Time Factors
• Tumor Cells, Cultured
• Young Adult