Chidamide inhibits t(8;21) AML cell proliferation and AMK1/ETO and C-KIT expression by inhibiting ERK1/2 signaling pathway

被引:7
作者
Liu, Jing [1 ]
Lv, Na [2 ,3 ,4 ]
Zhou, Lei [3 ,4 ]
Li, Yan [3 ,4 ]
Yu, Li [2 ,3 ,4 ]
机构
[1] Chinese Peoples Liberat Army Gen Hosp, Med Ctr 1, Dept Outpatient, Clin Cadre, Beijing 100853, Peoples R China
[2] Shenzhen Univ, Sch Med, Carson Int Canc Ctr, Dept Hematol, Shenzhen 518060, Peoples R China
[3] Chinese Peoples Liberat Army Gen Hosp, Med Ctr 1, Dept Hematol, Beijing 100853, Peoples R China
[4] Chinese Peoples Liberat Army Gen Hosp, Med Ctr 1, BMT Ctr, Beijing 100853, Peoples R China
关键词
t(8; 21) acute myeloid leukemia; chidamide; ERK1/2; AML1/ETO; C-KIT; HISTONE DEACETYLASE INHIBITOR; ACUTE MYELOID-LEUKEMIA; LOW-DOSE DECITABINE; VALPROIC ACID; APOPTOSIS; AGENTS;
D O I
10.21037/tcr.2019.12.07
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: t(8;21) acute myeloid leukemia (AML) is a highly heterogenous hematological malignancy. Histone deacetylases inhibitors (HDACi) are a group of small-molecule compounds with extensive anti-tumor activity. Chidamide (CS055) is a selective HDACi independently developed by China. We aimed to investigate its anti-tumor activity and mechanism in t(8;21) AML cells. Methods: Human AML SKNO-1 cells were transfected with AML1/ETO-siRNA to obtain SKNO-1-si-A/E cells. Human acute monocytic leukemia U937 cells were transfected with AML1/ETO fusion gene to obtain U937-A/E cells. AML1/ETO-positive (Kasumi-1, U937-A/E and SKNO-1) and AML1/ETO-negative AML cells (HL-60, U937, SKNO-1-siA/E) were treated with chidamide (0.125, 0.25 and 0.5 mu M). Cell proliferation was evaluated by CCK-8 assay. Cell apoptosis and cell cycle was detected by flow cytometry. Microarray profiling of SKNO-1 cells was performed. The level of histone 3 acetylation and ERK1/2 phosphorylation was determined by Western blot. AML1/ETO and C-KIT mRNA expression was detected by real time quantitative PCR (RT-qPCR). Kasumi-1 and SKNO-1 cells were treated with U0126, a special inhibitor of ERK1/2, and cell proliferation and ERK1/2 phosphorylation level was examined. Results: Chidamide inhibited the proliferation, induced cell cycle arrest, and stimulated cell apoptosis of AML1/ETO-positive AML cells. Microarray profiling showed that 13 differentially expressed genes were involved both in the "ERK1/2" pathway and "apoptosis" functions. Chidamide inhibited histone 3 acetylation and ERK1/2 phosphorylation in AML1/ETO-positive AML cells. U0126 inhibited the proliferation of AML1/ETO-positive AML cells via regulating the ERK1/2 pathway. Conclusions: Our results suggested that chidamide inhibits t(8;21) AML cell proliferation and AMK1/ETO and C-KIT expression by inhibiting ERK1/2 signaling pathway.
引用
收藏
页码:827 / 839
页数:13
相关论文
共 18 条
  • [1] PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives
    Asati, Vivek
    Mahapatra, Debarshi Kar
    Bharti, Sanjay Kumar
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2016, 109 : 314 - 341
  • [2] Ayatollahi Hossein, 2017, Hematol Oncol Stem Cell Ther, V10, P1, DOI 10.1016/j.hemonc.2016.08.005
  • [3] Chen Li-ping, 2013, Zhonghua Xue Ye Xue Za Zhi, V34, P741, DOI 10.3760/cma.j.issn.0253-2727.2013.09.002
  • [4] BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of c-KIT-Driven Myeloid Leukemia
    Chen, Li-Tzong
    Chen, Chiung-Tong
    Jiaang, Weir-Torn
    Chen, Tsai-Yun
    Butterfield, Joseph H.
    Shih, Neng-Yao
    Hsu, John Tsu-An
    Lin, Hui-You
    Lin, Sheng-Fung
    Tsai, Hui-Jen
    [J]. MOLECULAR CANCER THERAPEUTICS, 2016, 15 (10) : 2323 - 2333
  • [5] Modulation of Sensitivity to Antitumor Agents by Targeting the MAPK Survival Pathway
    Cossa, Giacomo
    Gatti, Laura
    Cassinelli, Giuliana
    Lanzi, Cinzia
    Zaffaroni, Nadia
    Perego, Paola
    [J]. CURRENT PHARMACEUTICAL DESIGN, 2013, 19 (05) : 883 - 894
  • [6] CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells
    Gong, Ke
    Xie, Jia
    Yi, Hong
    Li, Wenhua
    [J]. BIOCHEMICAL JOURNAL, 2012, 443 : 735 - 746
  • [7] Development and validation of a sensitive HPLC-MS/MS method for determination of chidamide (epidaza), a new benzamide class of selective histone deacetylase inhibitor, in human plasma and its clinical application
    Gu, Ruolan
    Liu, Taoyun
    Zhu, Xiaoxia
    Gan, Hui
    Wu, Zhuona
    Li, Jian
    Zheng, Ying
    Dou, Guifang
    Meng, Zhiyun
    [J]. JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, 2015, 1000 : 181 - 186
  • [8] Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy
    Gyurkocza, B.
    Lazarus, H. M.
    Giralt, S.
    [J]. BONE MARROW TRANSPLANTATION, 2017, 52 (08) : 1083 - 1090
  • [9] Results of Phase 2 Randomized Study of Low-Dose Decitabine With or Without Valproic Acid in Patients With Myelodysplastic Syndrome and Acute Myelogenous Leukemia
    Issa, Jean-Pierre
    Garcia-Manero, Guillermo
    Huang, Xuelin
    Cortes, Jorge
    Ravandi, Farhad
    Jabbour, Elias
    Borthakur, Gautam
    Brandt, Mark
    Pierce, Sherry
    Kantarjian, Hagop M.
    [J]. CANCER, 2015, 121 (04) : 556 - 561
  • [10] Lam K, FRONT BIOSCI