RESUMEN
Neurofibromatosis type 2 (NF2) is a genetic condition characterized by inactivation of the NF2 tumor suppressor gene and the development of schwannomas. The NF2 gene product, merlin, is activated (dephosphorylated) by contact inhibition and promotes growth suppression. We investigated the effect of curcumin (diferuloylmethane), a molecule with anti-inflammatory and antitumorigenic properties, on human schwannoma cell growth and the regulation of merlin by curcumin in both NF2 cells and neuroblastoma (non-NF2) cells. Curcumin inhibited the growth of HEI-193 schwannoma cells in vitro and downregulated the phosphorylation of Akt and extracellular signal-regulated kinase 1/2. Curcumin also activated MYPT1-pp1δ (a merlin phosphatase), which was associated with dephosphorylation of merlin on serine 518, an event that results in the folding of merlin to its active conformation. In addition, curcumin induced apoptosis and generated reactive oxygen species in HEI-193 cells. Consequently, hsp70 was upregulated at the mRNA and protein levels, possibly serving as a mechanism of escape from curcumin-induced apoptosis and growth inhibition. Endogenous merlin and hsp70 proteins interacted in HEI-193 schwannoma and SK-N-AS neuroblastoma cells. The combination of curcumin and an hsp inhibitor synergistically suppressed schwannoma cell growth. Our results provide a rationale for combining curcumin and KNK437 in the treatment of NF2.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Compuestos de Bencidrilo/farmacología , Curcumina/farmacología , Proteínas de Choque Térmico/antagonistas & inhibidores , Neurofibromatosis 2/tratamiento farmacológico , Pirrolidinonas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Compuestos de Bencidrilo/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Curcumina/uso terapéutico , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas del Choque Térmico HSP72/genética , Proteínas del Choque Térmico HSP72/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Fosfatasa de Miosina de Cadena Ligera/metabolismo , Neurofibromatosis 2/genética , Neurofibromatosis 2/metabolismo , Neurofibromina 2/metabolismo , Fosforilación , Unión Proteica , Pirrolidinonas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Two naturally occurring compounds, curcumin, the active ingredient in the spice turmeric, and the green tea extract epigallocatechin-3-gallate, have marked effects on the apoptotic machinery in chronic lymphocytic leukemia. These results provide a preclinical foundation for future clinical use of these compounds in this disease.