OBJECTIVE: The anti-CD20 monoclonal antibody rituximab has shown promising results in the clinical treatment of patients with B-cell non-Hodgkin's 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-kappaB (NF-kappaB) inactivation and c-Myc degradation. SAHA presented functional complementation with rituximab, through decreasing IKKalpha/beta and IkappaBalpha phosphorylation, thus preventing NF-kappaB nuclear translocation. In addition, SAHA induced IkappaBalpha cleavage to a stable inhibitory form and caused NF-kappaB 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.
OBJECTIVE: The anti-CD20 monoclonal antibody rituximab has shown promising results in the clinical treatment of patients with B-cell non-Hodgkin's 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-kappaB (NF-kappaB) inactivation and c-Myc degradation. SAHA presented functional complementation with rituximab, through decreasing IKKalpha/beta and IkappaBalpha phosphorylation, thus preventing NF-kappaB nuclear translocation. In addition, SAHA induced IkappaBalpha cleavage to a stable inhibitory form and caused NF-kappaB 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.
Authors: Sarit E Assouline; Torsten Holm Nielsen; Stephen Yu; Miguel Alcaide; Lauren Chong; David MacDonald; Axel Tosikyan; Vishal Kukreti; Abbas Kezouh; Tina Petrogiannis-Haliotis; Marco Albuquerque; Daniel Fornika; Sepideh Alamouti; Remi Froment; Celia M T Greenwood; Kathleen Klein Oros; Errol Camglioglu; Ayushi Sharma; Rosa Christodoulopoulos; Caroline Rousseau; Nathalie Johnson; Michael Crump; Ryan D Morin; Koren K Mann Journal: Blood Date: 2016-05-10 Impact factor: 22.113
Authors: Sarah Frys; Zachary Simons; Qiang Hu; Matthew J Barth; Juan J Gu; Cory Mavis; Joseph Skitzki; Liu Song; Myron S Czuczman; Francisco J Hernandez-Ilizaliturri Journal: Br J Haematol Date: 2015-02-23 Impact factor: 6.998
Authors: Sean H Lim; Stephen A Beers; Ruth R French; Peter W M Johnson; Martin J Glennie; Mark S Cragg Journal: Haematologica Date: 2009-09-22 Impact factor: 9.941