title: AUY922 effectively targets against activated B cell subtype of diffuse large B-cell lymphoma and low-grade lymphoma cells harboring genetic alteration-associated nuclear factor-κB activation.
abstract: Recurrent genetic alterations that are frequently observed in some low-grade lymphomas, such as activated B cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL) and mucosa-associated lymphoid tissue type lymphoma (MALT lymphoma) are usually associated with nuclear factor-κB (NF-κB) activation and confer resistance to therapy. In this study, we investigated the therapeutic efficacy and molecular mechanisms of AUY922, a novel Hsp90 inhibitor, in representative cell lines OCI-Ly3 (ABC-DLBCL) and MA-1 (a low-grade lymphoma cell line with t(14;18)/IgH-MALT1translocation) to explore its potential use in the treatment of refractory B-cell lymphoma. Our results showed that AUY922 effectively induced growth inhibition and apoptosis of OCI-Ly3 and MA-1 cells, which were accompanied by down-regulation of the expression levels of NF-κB and Bcl-2 family proteins, as well as molecules of multiple signaling pathways involving cell proliferation, growth and survival. The growth inhibitory effect of AUY922 was further confirmed in a mouse xenograft model. These findings indicate the potential use of AUY922 in B cell lymphomas.
authors.affiliation: a National Institute of Cancer Research, National Health Research Institutes , Tainan , Taiwan.|b Division of Hematology/Oncology, Department of Internal Medicine , National Cheng Kung University Hospital , Tainan , Taiwan.|c Division of Hematology/Oncology, Department of Internal Medicine , Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung , Taiwan.|d Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.
authors.forename: Hui-Jen
authors.initials: HJ
authors.lastname: Tsai
authors.affiliation: a National Institute of Cancer Research, National Health Research Institutes , Tainan , Taiwan.
authors.forename: Neng-Yao
authors.initials: NY
authors.lastname: Shih
authors.affiliation: e Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.
authors.forename: Sung-Hsin
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: e Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: a National Institute of Cancer Research, National Health Research Institutes , Tainan , Taiwan.
authors.forename: Hui-You
authors.initials: HY
authors.lastname: Lin
authors.affiliation: b Division of Hematology/Oncology, Department of Internal Medicine , National Cheng Kung University Hospital , Tainan , Taiwan.
authors.forename: Tsai-Yun
authors.initials: TY
authors.lastname: Chen
authors.affiliation: f Department of Pathology , National Cheng Kung University Hospital , Tainan , Taiwan.
authors.forename: Kung-Chao
authors.initials: KC
authors.lastname: Chang
authors.affiliation: c Division of Hematology/Oncology, Department of Internal Medicine , Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung , Taiwan.
authors.forename: Sheng-Fung
authors.initials: SF
authors.lastname: Lin
authors.affiliation: a National Institute of Cancer Research, National Health Research Institutes , Tainan , Taiwan.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Chang
authors.affiliation: a National Institute of Cancer Research, National Health Research Institutes , Tainan , Taiwan.|b Division of Hematology/Oncology, Department of Internal Medicine , National Cheng Kung University Hospital , Tainan , Taiwan.|g Division of Gastroenterology, Department of Internal Medicine , Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung , Taiwan.|h Institute of Molecular Medicine, National Cheng Kung University , Tainan , Taiwan.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002869:Chromosome Aberrations; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D060787:Neoplasm Grading; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000235:genetics; D014178:Translocation, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D016328:NF-kappa B; D012118:Resorcinols; D053148:Caspase 3; D053453:Caspase 9
keywords: ABC-DLBCL; AUY922; Hsp90 inhibitor; MALT lymphoma; NF-κB