TSA And MG-132 Synergistically Induce Apoptosis Of Lymphoma And Multiple Myeloma Cells Involving Variations Of IRF4 And C-Myc Expression

Purpose:To examine the cytotoxicity,mechanisms and interferon regulatory factor4 (IRF4) expression level of the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA),alone and combined with the proteasome inhibitor MG-132 in lymphoma and multiple myeloma (MM) cells.Experimental Design:The cytotoxicity and combinataion effects on the growth of lymphoma and MM cells were assessed by Trypan Blue assay .Apoptosis and cell cycle were mueasured by flow cytometry,whereas caspase activation,IRF4 expression were determined by Western blot.Results : In all lymphoma and MM cells , TSA or MG-132 alone induced concentration- dependent cytotoxicityand apoptosis that was associated with prominent G0/G1 arrest,decreased CyclinD1, increased p21 proteins,Combined TSA/MG-132 treatment resulted in strong synergistic cytotoxicity and apoptosis, Apoptosis induced by TSA/MG-132 alone or combination was shown to be caspase-dependent,further, resulted in increased caspase cleavage and Bax,decrease Bcl-2.In MM cells,with high level of IRF4 expression,TSA or MG-132 alone significantly IRF4 and c-Myc expression compared with either agent alone,effects that were enhanced further by combination and in lymphoma cells,with low level of IRF4 expression,gradually down-regulated level of c-Myc expression also,but level of IRF4 expression is no significant variation.Conclusion:We show that TSA/MG-132 alone or combination results in dose-dependent or synergistic effects of cytotoxicity and apoptosis which depends activation of caspase.We also show that levels of IRF4 and c-Myc expression are alternative in apoptosis of lymphoma and MM. This may have potential therapeutic value in lymphoma and MM.