Induction of apoptosis by HBI‐8000 in adult T‐cell leukemia/lymphoma is associated with activation of Bim and NLRP3

Adult T‐cell leukemia/lymphoma (ATL) is an aggressive T‐cell malignancy caused by human T‐cell lymphotropic virus 1. Treatment options for acute ATL patients include chemotherapy, stem cell transplantation, and recently the anti‐chemokine (C‐C motif) receptor 4 antibody, although most patients still have a poor prognosis and there is a clear need for additional options. HBI‐8000 is a novel oral histone deacetylase inhibitor with proven efficacy for treatment of T‐cell lymphomas that recently received approval in China. In the present study, we evaluated the effects of HBI‐8000 on ATL‐derived cell lines and primary cells obtained from Japanese ATL patients. In most cases HBI‐8000 induced apoptosis in both primary ATL cells and cell lines. In addition, findings obtained with DNA microarray suggested Bim activation and, interestingly, the contribution of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome pathway in HBI‐8000‐induced ATL cell death. Further investigations using siRNAs confirmed that Bim contributes to HBI‐8000‐induced apoptosis. Our results provide a rationale for a clinical investigation of the efficacy of HBI‐8000 in patients with ATL. Although the role of NLRP3 inflammasome activation in ATL cell death remains to be verified, HBI‐8000 may be part of a novel therapeutic strategy for cancer based on the NLRP3 pathway.

[1]  Z. Ning,et al.  Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[2]  P. Krammer,et al.  Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression , 2014, Cell Death and Disease.

[3]  Xin Fu,et al.  Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment , 2014 .

[4]  K. Tsukasaki,et al.  Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia–lymphoma cells , 2014, Cancer science.

[5]  G. Salvesen,et al.  Regulated cell death: signaling and mechanisms. , 2014, Annual review of cell and developmental biology.

[6]  K. Ishitsuka,et al.  Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. , 2014, The Lancet. Oncology.

[7]  R. Johnstone,et al.  Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders , 2014, Nature Reviews Drug Discovery.

[8]  Kun Zhang,et al.  Non-toxic dose chidamide synergistically enhances platinum-induced DNA damage responses and apoptosis in Non-Small-Cell lung cancer cells. , 2014, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[9]  A. Tanaka,et al.  HTLV-1 bZIP Factor Suppresses Apoptosis by Attenuating the Function of FoxO3a and Altering its Localization , 2014 .

[10]  Xin Geng,et al.  Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection , 2013, Nature.

[11]  Li-li Wang,et al.  Increased PRAME-Specific CTL Killing of Acute Myeloid Leukemia Cells by Either a Novel Histone Deacetylase Inhibitor Chidamide Alone or Combined Treatment with Decitabine , 2013, PloS one.

[12]  E. Latz,et al.  Activation and regulation of the inflammasomes , 2013, Nature Reviews Immunology.

[13]  K. Schroder,et al.  AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC , 2013, Cell Death and Differentiation.

[14]  K. Tobinai,et al.  Biology and treatment of HTLV-1 associated T-cell lymphomas. , 2013, Best practice & research. Clinical haematology.

[15]  G K Smyth,et al.  HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses , 2013, Cell Death and Disease.

[16]  M. Haneklaus,et al.  Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. , 2013, Current opinion in immunology.

[17]  M. Ressing,et al.  Inflammasomes and viruses: cellular defence versus viral offence. , 2012, The Journal of general virology.

[18]  L. O’Neill,et al.  Biochemical regulation of the inflammasome , 2012, Critical reviews in biochemistry and molecular biology.

[19]  M. Fu,et al.  Antitumor activity of Chidamide in hepatocellular carcinoma cell lines. , 2012, Molecular medicine reports.

[20]  Ke Gong,et al.  CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. , 2012, The Biochemical journal.

[21]  M. J. Newman,et al.  Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity , 2012, Cancer Chemotherapy and Pharmacology.

[22]  R. Ueda,et al.  Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  H. Mano,et al.  Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy , 2011, Haematologica.

[24]  N. Mori,et al.  LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway , 2011, Leukemia.

[25]  Wei Zhao,et al.  A novel histone deacetylase inhibitor Chidamide induces apoptosis of human colon cancer cells. , 2010, Biochemical and biophysical research communications.

[26]  P. Choong,et al.  Bim-targeted cancer therapy: A link between drug action and underlying molecular changes , 2009, Molecular Cancer Therapeutics.

[27]  Yasuaki Yamada,et al.  Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells , 2009, Leukemia.

[28]  J. Ting,et al.  The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. , 2009, Immunity.

[29]  T. Waldmann,et al.  Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25. , 2009, Blood.

[30]  H. Koeffler,et al.  Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor κB , 2008 .

[31]  T. Inaba,et al.  Cytokines direct the regulation of Bim mRNA stability by heat-shock cognate protein 70. , 2007, Molecular cell.

[32]  H. Nagai,et al.  Proviral status of HTLV-1 integrated into the host genomic DNA of adult T-cell leukemia cells. , 2005, Clinical and laboratory haematology.

[33]  M. Tomonaga,et al.  Sensitivity of adult T‐cell leukaemia lymphoma cells to tumour necrosis factor‐related apoptosis‐inducing ligand , 2005, British journal of haematology.

[34]  S. Johansson,et al.  β1‐Integrins induce phosphorylation of Akt on serine 473 independently of focal adhesion kinase and Src family kinases , 2004, EMBO reports.

[35]  S. Iida,et al.  Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  S. Grant,et al.  The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. , 2003, Cancer research.

[37]  F. Martinon,et al.  The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. , 2002, Molecular cell.

[38]  K. Matsushima,et al.  Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. , 2002, Blood.

[39]  A. Strasser,et al.  BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes , 2002, Nature.

[40]  M. Tomonaga,et al.  Fas Gene Mutation in the Progression of Adult T Cell Leukemia , 1999, The Journal of experimental medicine.

[41]  M. Shimoyama,et al.  Diagnostic criteria and classification of clinical subtypes of adult T‐cell leukaemia‐lymphoma , 1991, British journal of haematology.

[42]  Wei Zhao,et al.  Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression , 2014, Laboratory Investigation.

[43]  E. Miao,et al.  Detection of pyroptosis by measuring released lactate dehydrogenase activity. , 2013, Methods in molecular biology.

[44]  J. Wong,et al.  Application of p21 and klf2 reporter gene assays to identify selective histone deacetylase inhibitors for cancer therapy. , 2011, Bioorganic & medicinal chemistry letters.

[45]  H. Koeffler,et al.  Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor kappaB. , 2008, Leukemia research.

[46]  S. Grant,et al.  The Histone Deacetylase Inhibitor MS-275 Promotes Differentiation or Apoptosis in Human Leukemia Cells through a Process Regulated by Generation of Reactive Oxygen Species and Induction of p 21 CIP 1 / WAF 1 1 , 2003 .

[47]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.