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.
Keywords:
ABC-DLBCL; AUY922; Hsp90 inhibitor; MALT lymphoma; NF-κB.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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B-Lymphocytes / drug effects*
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B-Lymphocytes / metabolism*
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Caspase 3 / metabolism
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Caspase 9 / metabolism
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Cell Cycle Checkpoints / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Chromosome Aberrations*
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Chromosomes, Human, Pair 14
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Chromosomes, Human, Pair 18
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Disease Models, Animal
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Down-Regulation
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Enzyme Activation / drug effects
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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Humans
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Isoxazoles / pharmacology*
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Lymphoma, Large B-Cell, Diffuse / drug therapy
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Lymphoma, Large B-Cell, Diffuse / genetics*
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Lymphoma, Large B-Cell, Diffuse / metabolism*
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Lymphoma, Large B-Cell, Diffuse / pathology
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Male
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Mice
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Mitochondria / drug effects
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Mitochondria / metabolism
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NF-kappa B / metabolism*
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Neoplasm Grading
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Resorcinols / pharmacology*
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Signal Transduction / genetics
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Translocation, Genetic
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
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Antineoplastic Agents
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HSP90 Heat-Shock Proteins
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Isoxazoles
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NF-kappa B
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Resorcinols
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Caspase 3
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Caspase 9