Mechanisms Of Apoptosis Induced By Histone Deactylase Inhibitors (CS055) And/or Rituximab In Mantle Cell Lymphoma Cell Lines

Background:Many studies have found the anti-proliferation and apoptosis-inducing ability of histone deactylase inhibitors(HDACIs) in mantle cell lymphoma(MCL) cell lines. And rituximab is an effective agent in the treatment of CD20~+ B-cell lymphomas.Objectives:To observe the effect of CS055,a new HDACI agent,rituximab,or combination of these two drugs on MCL cell lines and explore the possible mechanisms.Material and methods:G519 and Jeko-1 MCL cell lines were used for cell proliferation and apoptosis study.Western blot analysis was employed to explore the possible mechanisms.Results:In vitro study found,CS055 could inhibit cell proliferation and induce cell apoptosis in both MCL cell lines.These effects would be more prominent if incubation time was prolonged to 48 hours.Rituximab showed minimal effect on cell proliferation but no effect on apoptosis in vitro study.However,it could enhance the anti-proliferation and apoptosis inducing effect of CS055 on MCL cells when combined with CS055.These results were further validated using murine model, which both agents showed ability to suppress the growth of xeno-graft tumors.And significantly longer survival was achieved in combination treatment group.Western blot analysis showed,CS055 could induce activation of caspase-8 and caspase-3 in Jeko-1 cell line.And these effects could be further enhanced when rituximab was combined.In G519 cell line,however,similar effect could only be found in the activation of caspase-3.Using Caspase inhibitor Z-VAD-fmk,tumor cells could be partially protected from the drug-induced apoptosis.And only the activation of caspase-8 and caspase-3 were completely blocked by Z-VAD-fmk,while the activation of caspase-9 not.Conclusions:CS055 is an effective agent which could inhibit proliferation and induce apoptosis in MCL cells lines.And this effect could be further enhanced when rituximab was combined.Cell signaling pathway concerning caspase may be one of the mechanisms which are involved in the drug-induced cell apoptosis.