Assuntos
Anilidas/farmacologia , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Linfoma não Hodgkin/genética , Mieloma Múltiplo/genética , Anilidas/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Concentração Inibidora 50 , Linfoma não Hodgkin/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Células Estromais/efeitos dos fármacosRESUMO
PURPOSE: Selenium is a trace element that is fundamental to human health. Research has mainly focussed on its role in cancer prevention, but recent evidence supports its role in established cancer, with high concentrations inducing tumour cell death and non-toxic concentrations sensitising cells to chemotherapy. However, the precise mechanism of selenium action is not clear. The effect of methylseleninic acid (MSA), an organic selenium compound, on histone deacetylase (HDAC) activity in diffuse large B-cell lymphoma cell lines is reported here. METHODS: Lymphoma cell lines were exposed to MSA under normoxic and hypoxic conditions. Protein expression was determined by western blotting, HDAC activity and VEGF concentration by fluorimetric and electrochemiluminescence assays, respectively, and intracellular selenium metabolites quantified by mass spectrometry. RESULTS: MSA inhibited HDAC activity, which resulted in the acetylation of histone H3 and α-tubulin. However, cellular metabolism of MSA to methylselenol was required for this effect. Dimethylselenide, the methylation product of methylselenol, was found to be the major intracellular metabolite. MSA also inhibited HIF-1α expression and VEGF secretion, a possible consequence of HDAC inhibition. CONCLUSION: The ability of methylselenol to inhibit HDAC activity has not been previously reported, thus providing a novel mechanism of selenium action.