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

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 +/- A 2.1 or 25.1 +/- A 3.2 % apoptosis. When combined with vorinostat, these apoptotic fractions significantly increased to 50.8 +/- A 4.9 and 63.1 +/- A 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)-kappa B signaling pathway was significantly enriched following treatment with the combination of vorinostat and R406. Protein expression analysis confirmed the down-regulation of NF-kappa B1/p105 and cyclin D1, suggesting inhibition of the NF-kappa B pathway. Taken together, the combination of an HDAC inhibitor and a BCR signaling inhibitor may be a novel therapeutic strategy for MCL.