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: Hui-Jen Tsai, Neng-Yao Shih, Sung-Hsin Kuo, Ann-Lii Cheng, Hui-You Lin, Tsai-Yun Chen, Kung-Chao Chang, Sheng-Fung Lin, Jeffrey S Chang, Li-Tzong Chen
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 56 Issue 9 Pg. 2674-82 ( 2015) ISSN: 1029-2403 [Electronic] United States
• PMID: 25535814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Isoxazoles
• NF-kappa B
• Resorcinols
• Caspase 3
• Caspase 9

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• B-Lymphocytes (drug effects, metabolism)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromosome Aberrations
• Chromosomes, Human, Pair 14
• Chromosomes, Human, Pair 18
• Disease Models, Animal
• Down-Regulation
• Enzyme Activation (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Isoxazoles (pharmacology)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, genetics, metabolism, pathology)
• Male
• Mice
• Mitochondria (drug effects, metabolism)
• NF-kappa B (metabolism)
• Neoplasm Grading
• Resorcinols (pharmacology)
• Signal Transduction (genetics)
• Translocation, Genetic
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays