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    Effects of chidamide and its combination with decitabine on proliferation and apoptosis of leukemia cell lines. Mao Jianping,Li Shan,Zhao Huihui,Zhu Yu,Hong Ming,Zhu Han,Qian Sixuan,Li Jianyong American journal of translational research Chidamide, a novel histone deacetylase inhibitor (HDACI), shows anticancer ability against leukemia and solid tumors. Decitabine (5-Aza-2'-deoxycytidine, DAC), an anti-leukemic drug, is effective in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In our study, we investigated the anti-leukemic ability of chidamide, as well as its combination with decitabine in leukemia cells (HL60 and NB4). The results showed that the inhibitive effect of chidamide was dose- and time-dependent at concentration of 0.25-8 μM. The proliferation of HL60 and NB4 cells were significantly inhibited by chidamide or its combination with decitabine. The combination had a remarkable synergistic anti-leukemic effect. Chidamide increased the levels of acetylated histone H3 in both HL60 and NB4 cells by effectively inhibiting histone deacetylases (HDAC) enzymatic activities. The cells were blocked in G/G phase by chidamide, but when chidamide was combined with decitabine, the cell cycle was mainly blocked in G/M phase, accompanied by the induction of p21 expression. In both cases (chidamide or chidamide combined with decitabine), apoptosis of tumor cells was induced through up-regulation of Bax and Caspase-3, and down-regulation of Bcl-2, showing a synergistic cytotoxicity. In conclusion, our results suggested that chidamide in combination with decitabine might be an effective therapy for AML.
    Chidamide in FLT3-ITD positive acute myeloid leukemia and the synergistic effect in combination with cytarabine. Li Xia,Yan Xiao,Guo Wenjian,Huang Xin,Huang Jiansong,Yu Mengxia,Ma Zhixin,Xu Yu,Huang ShuJuan,Li Chenying,Zhou Yile,Jin Jie Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Chidamide, a novel histone deacetylase inhibitor (HDACi), has been approved for treatment of T-cell lymphomas in multiple clinical trials. It has been demonstrated that chidamide can inhibit cell cycle, promote apoptosis and induce differentiation in leukemia cells, whereas its effect on acute myeloid leukemia (AML) patients with FLT3-ITD mutation has not been clarified. In this study, we found that chidamide specifically induced G0/G1 arrest and apoptosis in FLT3-ITD positive AML cells in a concentration and time-dependent manner. We also found chidamide had the cytotoxicity effect on FLT3-ITD positive and negative AML cells. Moreover, with respect to relapsed/refractory patients, chidamide showed the same effectiveness as that in de novo AML patients. Notably, chidamide synergistically enhanced apoptosis caused by cytarabine. Our results support chidamide alone or combine with cytarabine may be used as an alternative therapeutic choice for AML patients especially those with FLT3-ITD mutation or relapsed/refractory ones. 10.1016/j.biopha.2017.04.037
    A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor. Li Yin,Chen Kai,Zhou Yong,Xiao Yiren,Deng Manman,Jiang Zhiwu,Ye Wei,Wang Xiangmeng,Wei Xinru,Li Jie,Liang Jiabao,Zheng Zhongxin,Yao Yao,Wang Weiguang,Li Peng,Xu Bing Current cancer drug targets 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. 10.2174/156800961506150805153230
    A novel histone deacetylase inhibitor Chidamide induces G0/G1 arrest and apoptosis in myelodysplastic syndromes. Liu Zhaoyun,Ding Kai,Li Lijuan,Liu Hui,Wang Yihao,Liu Chunyan,Fu Rong Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Chidamide as a newly designed and synthesized histone deacetylase inhibitor induces an antitumor effect in various cancer, and it has been used in several clinical trials such as peripheral T cell lymphoma (PTCL). Here we demonstrate that Chidamide was able to increase the acetylation levels of histone H3 and decrease HDAC activity in MDS cell lines(SKM-1,MUTZ-1)and AML cell line(KG-1). In vitro, at low concentration (<250nM) of Chidamide inhibited cell proliferation and delayed G0/G1 cell cycle progression by down-regulating CDK2 and regulating p-P53 and P21 protein expression. Meanwhile,it also induced cell apoptosis by down-regulating Bcl-2 and up-regulating cleaved Caspase-3 and Bax protein expression.The results of the present study demonstrates the potential utility of Chidamide for the treatment of Myelodysplastic syndromes. 10.1016/j.biopha.2016.08.023
    Chidamide, a novel histone deacetylase inhibitor, inhibits the viability of MDS and AML cells by suppressing JAK2/STAT3 signaling. Zhao Sida,Guo Juan,Zhao Youshan,Fei Chengming,Zheng Qingqing,Li Xiao,Chang Chunkang American journal of translational research Many studies have indicated that histone deacetylase (HDAC) activity is always increased in a lot of human tumors, and inhibition of HDAC activity is a promising new strategy in the treatment of cancers. Chidamide, a novel HDAC inhibitor of the benzamide class, is currently under clinical trials. In this study, we aimed to investigate the antitumor activity of Chidamide on myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) cell lines and explore the possible mechanism. Chidamide exhibited efficient anti-proliferative activity on MDS and AML cells in a time- and dose-dependent manner, accompanied by cell cycle arrest at G0/G1 phase and cell apoptosis. Importantly, Chidamide possessed potent HDAC inhibition property, as evaluated by HDAC activity analysis and acetylation of histone H3 and H4. Moreover, Chidamide significantly increased the expression of Suppressors of cytokine signaling 3 (SOCS3), reduced the expression of Janus activated kinases 2 (JAK2) and Signal transducer and activator of transcription 3 (STAT3), and inhibited STAT3 downstream genes, including c-Myc, Bcl-xL, and Mcl-1, which are involved in cell cycle progression and anti-apoptosis. Therefore, we demonstrate that Chidamide exhibits potent inhibitory effect on cell viability of MDS and AML cells, and the possible mechanism may lie in the downregulation of JAK2/STAT3 signaling through SOCS3 upregulation. Our data provide rationale for clinical investigations of Chidamide in MDS and AML.