CS055 (Chidamide/HBI-8000) is a novel benzamide-type HDACi (histone deacetylase inhibitor), which has entered Phase I clinical trials in the U.S. and Phase II/III in China. In the present study, we investigated the effects of CS055 on proliferation, differentiation and apoptosis in human leukaemia cell lines and primary myeloid leukaemia cells. The results showed that at low concentrations (<1 μM), CS055 induced G1 arrest. At moderate concentrations (0.5 μM–2 μM), CS055 induced differentiation, as determined by the increased expression of the myeloid differentiation marker CD11b. At relatively high concentrations (2 μM–4 μM), CS055 potently induced caspase-dependent apoptosis. Co-treatment with the ROS (reactive oxygen species) scavengers N-acetyl-L-cysteine or Tiron blocked CS055-induced cell differentiation and apoptosis, suggesting an essential role for ROS in these effects. Cytochrome c release and ROS-mediated mitochondrial dysfunction are involved in CS055-induced apoptosis of leukaemia. In addition to cell lines, CS055 also exhibits therapeutic effects in human primary leukaemia cells. Moreover, daily oral CS055 treatment of nude mice bearing HL60 cell xenografts suppressed tumour growth, induced tumour cell apoptosis and prolonged the survival of tumour-bearing mice. In conclusion, our findings demonstrate that CS055 is a novel HDACi with potential chemotherapeutic value in several haematological malignancies, especially leukaemia.
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Research Article|
April 16 2012
CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells
Ke Gong;
Ke Gong
1College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China
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Jia Xie;
Jia Xie
1College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China
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Hong Yi;
Hong Yi
1College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China
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Wenhua Li
Wenhua Li
1
1College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China
1To whom correspondence should be addressed (email whli@whu.edu.cn).
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Publisher: Portland Press Ltd
Received:
September 17 2011
Revision Received:
January 13 2012
Accepted:
February 17 2012
Accepted Manuscript online:
February 17 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (3): 735–746.
Article history
Received:
September 17 2011
Revision Received:
January 13 2012
Accepted:
February 17 2012
Accepted Manuscript online:
February 17 2012
Citation
Ke Gong, Jia Xie, Hong Yi, Wenhua Li; CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 1 May 2012; 443 (3): 735–746. doi: https://doi.org/10.1042/BJ20111685
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