Combined effect of histone deacetylase inhibitor suberoylanilide hydroxamic acid and anti-CD20 monoclonal antibody rituximab on mantle cell lymphoma cells apoptosis

Interactions between histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and anti-CD20 monoclonal antibody rituximab in mantle cell lymphoma have been examined both in vitro and in vivo. The combination of SAHA and rituximab synergistically induced apoptosis, concomitant with caspase activation and Bcl-2 downregulation. These events were associated with multiple perturbations in signal transduction pathways, including inactivation of cyto-protective nuclear factor (NF)-κB, Akt, extracellular signal-regulating kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) pathways, and activation of c-jun N-terminal kinase (JNK) when pretreated with the pan-caspase inhibitor. Moreover, the combination of SAHA and rituximab significantly inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. However, SAHA had no apparent effect on the CD20 expression in the two MCL cell lines. Taken together, our results demonstrate the synergistic anti-MCL activity of SAHA and rituximab, and build the framework for clinical trials using SAHA-rituximab combining regimen in the treatment of MCL.