RESUMEN
Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clinical efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clinical activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1 or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1 expression is regulated by c-Myc, and HDAC3 inhibition triggers degradation of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), respectively, triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasa 1/genética , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasas/metabolismo , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Acetilación , Animales , Apoptosis , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ratones , Modelos Biológicos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This work, using an adult anthropomorphic phantom, aimed to establish an optimised technique for ladies of child-bearing age undergoing antero-posterior (AP) pelvis and AP and lateral lumbar spine examinations. Phase one of the work involved introducing the following dose-reducing measures individually: increased kVp, increased focus-film distances, a carbon fibre cassette, a faster film/screen combination. The second phase established an optimised technique based on a combination of the parameters listed above. Radiation dose was measured using thermoluminescent dosimeters and image quality was evaluated using anatomical criteria. All dose-reducing methods were compared with a standard technique, currently being used in a Dublin hospital. The results demonstrated that the optimised procedure reduced effective dose by 77, 62 and 66% for AP pelvis and AP and lateral lumbar spine respectively (p < 0.05) compared with the standard technique, with no significant changes in image quality. Dose-reducing measures used in combination offer substantial potential for optimisation of radiological procedures.