RESUMO
One of the major symptoms of myelodysplastic syndromes (MDS) is severe cytopenia. Despite cytokine therapies, such as erythropoiesis-stimulating agents, many patients still require blood transfusions, and the development of new therapeutic approaches is needed. In this work, we studied the effects of the inosine-5'-monophosphate (IMP) dehydrogenase (IMPDH) inhibitor FF-10501 on erythropoiesis of human hematopoietic cells. Differentiation of K562 chronic myeloid leukemia cells to an erythroid lineage was promoted by FF-10501 in a dose-dependent manner. Interestingly, we found that metabolic conversion of IMP to hypoxanthine leads to elevation of reactive oxygen species (ROS). The differentiative effects of FF-10501 were abolished by the ROS scavenger dimethylthiourea or the p38 MAPK inhibitor SB203580. Furthermore, FF-10501 promoted erythropoiesis from CD34+ hematopoietic stem/progenitor cells, accompanied with ROS accumulation, while high-dose FF-10501 mainly showed cytotoxic effects. These findings denote the potential of IMPDH inhibition therapy with FF-10501 in amelioration of anemia in MDS patients.
Assuntos
Inibidores Enzimáticos/farmacologia , Eritropoese/efeitos dos fármacos , IMP Desidrogenase/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Síndromes Mielodisplásicas , Fagocitose/efeitos dos fármacos , Fagocitose/imunologiaRESUMO
Kuromoji (Lindera umbellata) essential oil (KEO) has long been used in Japan as a traditional medicine. It contains linalool (C10H18O), a naturally occurring small terpenoid. For this study, we investigated the anti-inflammatory effect of KEO in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Mouse macrophage-like RAW 264.7 cells were stimulated with LPS. Then they were treated with 25 or 50 µg/mL of KEO for 24 h. KEO suppressed LPS-induced pro-inflammatory cytokine production such as that of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in a dose-dependent manner. In addition, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression and protein levels were suppressed by treatment with KEO cells. In addition, by treatment with 25 or 50 µg/mL of linalool showed the same anti-inflammatory effect. The results suggest that KEO and linalool can be regarded as a natural resource for use in anti-inflammatory therapeutic products.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Lindera/química , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Óleos Voláteis/farmacologia , Animais , Linhagem Celular , Ciclo-Oxigenase 2/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/genética , Macrófagos/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/genética , PPAR gama/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
Essential oils diluted from certain plants have been shown to have antitumor activity against several human tumor cell lines. Kuromoji (Lindera umbellata) essential oil (KEO) has long been used in Japan as a traditional medicine. KEO and its major chemical constituent, linalool, were investigated in this study for their ability to induce apoptosis and differentiation in human leukemia HL-60 cells. HL-60 cells were treated with 5 or 50 µg/ml KEO or linalool for 24 or 48 h. Then, cell proliferation and apoptosis induction were estimated. In addition, HL-60 cells are known to differentiate into granulocyte or monocytes by a variety of compounds. Therefore, the effect of KEO or linalool on differentiation of HL-60 cells was assessed by Giemsa stain and a nitroblue tetrazolium reduction assay. Cells treated with KEO or linalool for 48 h showed significantly suppressed cell proliferation, with induced apoptosis. Moreover, KEO and linalool promoted cell differentiation. Treatment with KEO cells at the same dose as linalool showed an almost identical effect on HL-60 cells. These results suggest that KEO and linalool have efficacy as anticancer therapeutic products.