RESUMO
Histone deacetylases (HDACs) are aberrantly expressed, and inhibitors of HDACs induce apoptosis in lymphoplasmacytic cells (LPCs) in Waldenström macroglobulinemia (WM). The molecular profile by which these agents induce apoptosis in WM LPCs remains to be delineated. We examined the activity of the histone deacetylase inhibitor, vorinostat, and dissected its pro-apoptotic pathways in WM LPCs. Vorinostat induced apoptosis in WM cells through activating specific caspases at varying times. Inhibitors of apoptosis (IAPs) were down-regulated after vorinostat treatment. Cellular stress induced in vorinostat-treated WM cells was reflected by changes in the mitogen activated protein kinase (MAPK) pathways. Activated phospho-p38 MAPK was up-regulated at 12 h, while phospho-extracellular signal-regulated kinase (Erk) abruptly decreased at 24 h. Bortezomib did not augment vorinostat induced primary WM cell killing as reported in other B-cell disorders. These studies support that stress induced apoptosis in vorinostat-treated WM LPCs is mediated through disrupting the activity of the Erk and p38 MAPK pathways.
Assuntos
Apoptose/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Macroglobulinemia de Waldenstrom/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Ácidos Borônicos/farmacologia , Ácidos Borônicos/toxicidade , Bortezomib , Caspases/metabolismo , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/toxicidade , Pirazinas/farmacologia , Pirazinas/toxicidade , VorinostatRESUMO
We studied the role of histone deacetylase inhibitors in Waldenstrom's macroglobulinemia (WM). Gene expression profiling of bone marrow CD19+ cells from 30 patients and 10 healthy donors showed overexpression of HDAC4, HDAC9, and Sirt5, with validation of HDAC9 overexpression by q-PCR in primary and BCWM.1 cells. Suberoylanilide hydroxamic acid, trichostatin A, panobinostat, and sirtinol demonstrated dose-dependent killing of BCWM.1 cells. TSA showed the greatest potency with IC50 of 70 nM. Importantly, HDAC9 activity was decreased following TSA treatment suggesting an essential role for this HDAC in WM therapy. The combination of bortezomib plus HDAC inhibitors resulted in at least additive tumor cell killing in BCWM.1 cells. TSA and bortezomib-induced apoptosis depended on a similar set of caspase activation, whereas their effect on cell cycle regulators was distinctly different. These results provided a framework for examining HDAC inhibitors as monotherapy, as well as combination therapy with bortezomib in WM.