The Apoptotic Effects And Interaction Of Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid And Anti-CD20 Monoclonal Antibody Rituximab In Human Mantle Cell Lymphoma Cells

Background and Objective:Mantle cell lymphoma (MCL) carries the most dismal prognosis of all the NHL. The extremely high morality rate is due to aggressive growth characteristics and the inadequacy of current therapy options. Recent genetic and molecular studies are revealing the complexity of MCL. Therefore, much hope is placed in the molecular targeted therapies. Anti-CD20 monoclonal antibody rituximab has been widely used in MCL. Histone deacetylases inhibitors (HDACi) may induce apoptosis via multiple mechanisms. In our study, we studied the interaction between the HDAC inhibitor SAHA and rituximab in MCL both in vitro and in vivo.Methods:Cell viability was evaluated by MTS assays, and AnnexinV/PI assays were used to evaluate cell apoptosis both in MCL cell lines and freshly isolated MCL. The ability of peripheral mononuclear blood cells (PMBCs) to lyse MCL cells was examined using the LDH release assays. Western blot analysis was employed to explore the possible mechanisms. We also established a MCL-SCID mouse model and examined the efficacy and side-effects of the combination of rituximab and SAHA in vivo.Results:Rituximab alone had no apparent apoptotic effect on MCL cells. SAHA induced apoptosis in a dose-dependent manner in both cell lines and freshly isolated MCL cells, and combined incubation with SAHA and rituximab resulted in increased apoptosis of MCL cell lines and freshly isolated primary tumor cells in vitro, concomitant with multiple perturbations in apoptotic and survival pathways, finally resulted in caspases activation and Bcl-2 down-regulation. Also, SAHA sensitized MCL cells for cell death induction by PMBCs. Of importance, the xenograft MCL-SCID mouse model demonstrated combined SAHA-rituximab prolonged the survival of tumor-bearing mice compared with control group and either single agent group, indicating the SAHA-rituximab combination was effective and therapeutic to MCL in vivo.Conclusion:SAHA is an effective agent which could inhibit proliferation and induce apoptosis in MCL cells lines, and this effect could be further enhanced with the addition of rituximab. Our findings provide an insight into the future clinical applications of SAHA-rituximab combination in treating MCL.