title: Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia.
abstract: Natural killer (NK) large granular lymphocyte (LGL) leukaemia features a clonal proliferation of CD3(-) NK cells that can be classified into either aggressive or chronic categories. The NKL cell line, derived from an aggressive Asian NK cell leukaemia, and patient samples from chronic NK-LGL leukaemia were used in our study to probe for synergistic efficacy of the epigenetic drugs vorinostat (SAHA) and cladribine in this disease. We demonstrate that histone deacetylases (HDACs) are over-expressed in both aggressive and chronic NK leukaemia. Administration of the HDAC inhibitor SAHA reduces class I and II HDAC expression and enhances histone acetylation in leukaemic NK cells. In vitro combination treatment with SAHA and cladribine dose-dependently exerts synergistic cytotoxic and apoptotic effects on leukaemic NK cells. Expression profiling of apoptotic regulatory genes suggests that both compounds led to caspase-dependent apoptosis through activation of intrinsic mitochondrial and extrinsic death receptor pathways. Collectively, these data show that combined epigenetic therapy, using HDAC and DNA methyltransferase inhibitors, may be a promising therapeutic approach for NK-LGL leukaemia.
authors.affiliation: The Key Laboratory of Transplantation Immunity, Department of Haematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province, China; University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Xiaoshen
authors.initials: X
authors.lastname: Sun
authors.forename: Zainul S
authors.initials: ZS
authors.lastname: Hasanali
authors.forename: Allshine
authors.initials: A
authors.lastname: Chen
authors.forename: Dianzheng
authors.initials: D
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Feith
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Kailin
authors.initials: K
authors.lastname: Xu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D017338:Cladribine / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D054066:Leukemia, Large Granular Lymphocytic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017338:Cladribine; D000077337:Vorinostat; D006655:Histone Deacetylases
keywords: cladribine; combined epigenetic therapy; histone deacetylation; natural killer large granular lymphocyte leukaemia; vorinostat (suberoylanilide hydroxamic acid)