RESUMEN
BACKGROUND: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, can selectively kill cancer cells with little or no cytotoxicity toward normal human cells and is regarded as a potential relatively safe antitumor drug. However, some cancer cells are resistant to TRAIL-induced apoptosis. Thus, reagents that potentiate TRAIL-induced cytotoxicity are needed. Herein, we investigated whether shikonin, a natural compound from the root of Lithospermum erythrorhizon, can sensitize TRAIL-resistant cells to TRAIL-induced cytotoxicity. RESULTS: The viability of A549 cells, which were resistant to TRAIL, was significantly decreased after treatment with TRAIL followed by shikonin. The underlying mechanisms by which shikonin sensitizes cells to TRAIL-induced cytotoxicity were also examined. Combined treatment with shikonin and TRAIL activated the caspase and JNK pathways, inhibited the STAT3 and AKT pathways, downregulated the expression of Mcl-1, Bcl-2, Bcl-xL, c-FLIP and XIAP and upregulated the expression of Bid. CONCLUSIONS: In conclusion, the results indicated that shikonin sensitized resistant cancer cells to TRAIL-induced cytotoxicity via the modulation of the JNK, STAT3 and AKT pathways, the downregulation of antiapoptotic proteins and the upregulation of proapoptotic proteins.
Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Naftoquinonas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Células A549 , Muerte Celular/efectos de los fármacos , Sinergismo Farmacológico , Células HEK293 , Humanos , Fosforilación/efectos de los fármacosRESUMEN
OBJECTIVE: To study changes to CD4(+)CD25(high+)CD127(low) regulatory T cells (Treg) in peripheral blood from children with bronchiolitis, and to explore its clinical significance. METHODS: Thirty-one children with bronchiolitis and aged under two years were randomly enrolled as the bronchiolitis group, and 25 under two-year-olds with bronchopneumonia were randomly enrolled as the bronchopneumonia group. A further twenty-five children with non-infectious diseases such as hernia and renal calculus served as the control group. The level of CD4(+)CD25(high+)CD127(low) Treg in peripheral blood was measured by multi-color detection and multi-parameter flow cytometry. RESULTS: The proportion of CD4(+)CD25(high+)CD127(low) Treg in peripheral blood in the bronchiolitis group (8.0%±2.1%) was significantly lower than in the bronchopneumonia (9.6%±2.6%; P<0.05) and control groups (11.3%±2.9%; P<0.05). CONCLUSIONS: CD4(+)CD25(high+)CD127(low) Treg level in peripheral blood may be an index of immunological function in infants. A decreased level of CD4(+)CD25(high+)CD127(low) Treg in peripheral blood suggests that Treg cells may be involved in the pathogenesis and development of bronchiolitis.