The synergistic effect of BCR signaling inhibitors combined with an HDAC inhibitor on cell death in a mantle cell lymphoma cell line

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• 作者：Kazumi Hagiwara ; Shinji Kunishima ; Hiroatsu Iida ; Yasuhiko Miyata ; Tomoki Naoe…
• 关键词：Mantle cell lymphoma ; BCR signaling ; HDAC inhibitor ; Apoptosis
• 刊名：Apoptosis
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：20
• 期：7
• 页码：975-985
• 全文大小：1,181 KB
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• 作者单位：Kazumi Hagiwara (1)
  Shinji Kunishima (1)
  Hiroatsu Iida (1)
  Yasuhiko Miyata (1)
  Tomoki Naoe (2)
  Hirokazu Nagai (1)
  
  1. Clinical Research Center, National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya, Japan
  2. National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya, Japan
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  Cancer Research
  Cell Biology
  Biochemistry
  Virology
  
• 出版者：Springer Netherlands
• ISSN：1573-675X

文摘

Mantle cell lymphoma (MCL) is a B cell malignancy characterized by aberrant expression of cyclin D1 due to a t(11;14) translocation. MCL is refractory to conventional chemotherapy, and treatment remains challenging. We investigated the efficacy of the histone deacetylase (HDAC) inhibitor vorinostat combined with one of several B-cell receptor (BCR) signaling inhibitors on MCL cell death and the underlying mechanisms, using MCL cell lines. The Bruton’s tyrosine kinase inhibitor PCI-32765 and the spleen tyrosine kinase inhibitor R406 showed synergistic effects with vorinostat on growth inhibition. Treatment with PCI-32765 or R406 alone induced 27.3?±?2.1 or 25.1?±?3.2?% apoptosis. When combined with vorinostat, these apoptotic fractions significantly increased to 50.8?±?4.9 and 63.1?±?5.0?%, respectively. Activation of caspase-3 and poly-(ADP-ribose) polymerase cleavage were markedly increased. We performed gene expression profiling following treatment with the combination of vorinostat and individual BCR signaling inhibitors using a microarray, and differentially expressed genes were identified. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the nuclear factor (NF)-κB signaling pathway was significantly enriched following treatment with the combination of vorinostat and R406. Protein expression analysis confirmed the down-regulation of NF-κB1/p105 and cyclin D1, suggesting inhibition of the NF-κB pathway. Taken together, the combination of an HDAC inhibitor and a BCR signaling inhibitor may be a novel therapeutic strategy for MCL.