RESUMEN
Multiple myeloma (MM) is characterised by intense protein folding and, consequently endoplasmic reticulum (ER) stress. The prostaglandin 15d-PGJ2 is able to raise oxidative stress levels within the cell and potentially trigger cell death. The aim of this study was to evaluate the antineoplastic effect of 15d-PGJ2 on MM in vitro and in vivo via ER and oxidative stress pathways. MM.1R and MM.1S cell lines were treated with 15d-PGJ2 at 1-10µM and evaluated with regard to proliferation, mRNA expression of PRDX1, PRDX4, GRP78, GRP94, CHOP, BCL-2 and BAX. Stress data was validated via oxidized glutathione assays. MM.1R cells were inoculated into NOD/SCID mice, which were subsequently treated daily with 15d-PGJ2 at 4mg/kg or vehicle (control), with tumour volume being monitored for 14days. 15d-PGJ2 reduced cell proliferation, induced cell death and apoptosis at 5µM and 10µM and Stress-related genes were upregulated at the same doses. Oxidized glutathione levels were also increased. 15d-PGJ2 at 4mg/kg in vivo halted tumour growth. In conclusion, 15d-PGJ2 induced myeloma cell death via ER stress in vitro. 15d-PGJ2 in vivo also inhibited tumour growth.
Asunto(s)
Antineoplásicos/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Prostaglandina D2/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Estrés Oxidativo/efectos de los fármacos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Prostaglandina D2/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo , Regulación hacia Arriba , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
OBJECTIVES: There is controversial evidence regarding the levels of antioxidant molecules in type 2 diabetes periodontitis patients. Thus, the aim of the present study was to evaluate the gene expression of antioxidant enzymes in the gingival tissue of poorly and well-controlled type 2 diabetic subjects with chronic periodontitis (CP). DESIGN: Gingival biopsies were harvested from systemically and periodontally healthy subjects (n=12), systemically healthy subjects with CP (n=15), well-controlled (n=8) and poorly controlled (n=14) diabetic subjects with CP. The messenger RNA (mRNA) levels of peroxiredoxin (PRDX) 1 and 2, catalase (CAT), glutathione peroxidase (GPX1) and superoxide dismutase (SOD) 1 and 2 were measured by quantitative polymerase chain reaction (qPCR). RESULTS: The results showed that PRDX1 and GPX1 were up-regulated by periodontitis (p<0.05), independently of the glycaemic status, whilst PRDX2 and SOD2 genes were slightly influenced by periodontitis, but significantly induced when periodontitis was associated with DM, especially under a poor glycaemic control (p<0.05). Moreover, CAT and SOD1 expressions were not significantly influenced by any of these inflammatory disorders (p>0.05). CONCLUSION: In conclusion, both PRDX1 and GPX1 were overexpressed in CP whilst PRDX2 and SOD2 were up-regulated especially in the poorly controlled diabetic group with CP.
