title: Induction of apoptosis by HBI-8000 in adult T-cell leukemia/lymphoma is associated with activation of Bim and NLRP3.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.|Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: HUYA Bioscience International, San Diego, California, USA.
authors.forename: Reid P
authors.initials: RP
authors.lastname: Bissonnette
authors.affiliation: HUYA Bioscience International, San Diego, California, USA.
authors.forename: Mireille
authors.initials: M
authors.lastname: Gillings
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sasaki
authors.affiliation: Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kitanosono
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Tsuruda
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Kosai
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Uno
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Morinaga
authors.affiliation: Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Imaizumi
authors.affiliation: Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.|Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.|Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017304:Annexin A5 / Q000378:metabolism; D000906:Antibodies; D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism* / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D040081:Protein Array Analysis; D011725:Pyridines / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000906:Antibodies; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; C000613826:HBI-8000; D006657:Histones; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011725:Pyridines; D025521:Tumor Suppressor Proteins; D053148:Caspase 3
keywords: Adult T-cell leukemia lymphoma; Bim; NLRP3; apoptosis; histone deacetylase inhibitors