Combined effects of histone deacetylase inhibitor and rituximab on non-Hodgkinʹs B-lymphoma cells apoptosis

Objective The anti-CD20 monoclonal antibody rituximab has shown promising results in the clinical treatment of patients with B-cell non-Hodgkinʹs lymphoma (B-NHL). However, its therapeutic effect could still be improved. Methods This study examined the anti-tumor activity of rituximab combined with histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in CD20-positive B-NHL cell lines, as well as in primary B-NHL cells and a murine B-NHL model. Results The combination treatment sensitized B-NHL cells to apoptosis in a synergistic manner, concomitant with mitochondrial instability and Bcl-2/Bcl-XL downregulation. Particularly in Daudi cells relatively resistant to rituximab, these events were associated with nuclear factor-κB (NF-κB) inactivation and c-Myc degradation. SAHA presented functional complementation with rituximab, through decreasing IKKα/β and IκBα phosphorylation, thus preventing NF-κB nuclear translocation. In addition, SAHA induced IκBα cleavage to a stable inhibitory form and caused NF-κB degradation in response to caspase-3 activation. More importantly, rituximab-SAHA combination significantly promoted primary B-NHL cells apoptosis and improved survival time of a severe combined immunodeficient mouse lymphoma model established with intravenous injection of Daudi cells. Conclusion These findings emphasized the value of targeting apoptosis signaling pathway in lymphoma therapy. Rituximab in conjunction with histone deacetylase inhibitor may represent a novel strategy in treating patients with B-NHL.