Assuntos
Síndrome de Behçet/complicações , Músculo Esquelético/diagnóstico por imagem , Mialgia/etiologia , Miosite/diagnóstico , Dermatopatias Vasculares/etiologia , Tromboflebite/diagnóstico por imagem , Adolescente , Diagnóstico Diferencial , Humanos , Perna (Membro) , Imageamento por Ressonância Magnética , Masculino , Tromboflebite/etiologiaRESUMO
Sinodielide A (SA) is a naturally occurring guaianolide, which is isolated from the root of Sinodielsia yunnanensis. This root, commonly found in Yunnan province, is used in traditional Chinese medicine as an antipyretic, analgesic and diaphoretic agent. A number of studies have reported that agents isolated from a species of Umbelliferae (Apiaceae) have antitumor activities. We previously reported, using combined treatments with this medicinal herb and hyperthermia at various temperatures, an enhanced cytotoxicity in the human prostate cancer androgenindependent cell lines, PC3 and DU145, and analyzed the related mechanisms. In the present study, we investigated the effects of treatment with SA prior to hyperthermia on the thermosensitivity of DU145 cells, and the mechanisms related to the induction of apoptosis and G(2)/M cell cycle arrest via the activation of extracellular-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathways, as well as the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. Cells were exposed to hyperthermia alone (40-44ËC) or hyperthermia in combination with SA. Lethal damage to cells treated with mild hyperthermia (40 or 42ËC) for up to 6 h was slight; however, hyperthermia in combination with SA synergistically enhanced thermosensivity. Lethal damage to cells treated with acute hyperthermia (43 or 44ËC) was more severe, but these effects were also enhanced and were more significant by the combined treatment with SA. The kinetics of apoptosis induction and cell cycle distribution were analyzed by flow cytometry. In addition, the levels of ERK1/2, JNK and Akt were determined by western blot analysis. The incidence of apoptotic cells after treatment with SA (20.0 µM) at 37ËC for 4 h, hyperthermia (44ËC) alone for 30 min, and the combination in sequence were examined. The sub-G1 division (%) in the diagram obtained by flow cytometry was applied to that assay. The percentage of apoptotic cells (10.53±5.02%) was higher at 48 h as compared to 0, 12 and 24 h after treatment. The distribution of DU145 cells in the G2/M cell cycle phase was markedly increased after 24 h of heating at 44ËC and after the combined treatment with heating and SA. The phosphorylation of ERK1/2 was reduced following treatment with heating and SA, while the levels of phosphorylated JNK (p-JNK) were markedly increased immediately after heating at 44ËC and when heating was combined with SA. By contrast, the levels of phosphorylated Akt (p-Akt) were immediately increased only after heating at 44ËC. Thus, we concluded that SA exerts its thermosensitizing effects on DU145 cells by inhibiting the activation of the MAPK/ERK1/2 and PI3K/Akt signaling pathways.
Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Neoplasias da Próstata/patologia , Transdução de Sinais , Apiaceae/química , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Terapia Combinada , Fase G2/fisiologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Raízes de Plantas/química , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , TemperaturaRESUMO
Parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, has a significant thermo-enhancement effect. Modification of thermosensitivity by treatment with PTL prior to hyperthermia was investigated in the human prostate cancer androgen-independent cell lines PC3 and DU145. In addition, we analyzed the mechanisms related to induction of apoptosis or G2/M cell-cycle arrest via the effects of ERK1/2, p38 and SAPK/JNK signaling on mitogen-activated protein kinase (MAPK). Lethal damage caused by mild hyperthermia at 41.0ËC or 42.0ËC in both cell lines resulted in a low level of thermosensitivity, while sequential combination with PTL showed significant thermosensitization. Step-up hyperthermia (SUH) (42ËC for 30 min, 43.0ËC or 43.5ËC for various periods) reduced the thermosensitivity of the cells to second heating. However, PTL given as pre-treatment prior to SUH prevented SUH-induced thermal tolerance and resulted in significant thermosensitization. Induction of apoptosis by the combination of PTL and hyperthermia at 44.0ËC was determined by the ratio of sub-G1 division cells using flow cytometry, which was increased significantly in comparison with single treatment, and was more effective in PC3 than DU145 cells. The behavior of ERK1/2, p38, and SAPK/JNK signaling in the MAPK cascade by treatment with PTL and hyperthermia were examined by Western blotting. As for PC3 cells, ras-downstream p-ERK1/2 was activated and p-p38 slightly activated by combined treatment with PTL and hyperthermia in comparison with each alone. As for DU145 cells, ERK1/2 was not changed, while p38 and SAPK/JNK were slightly activated by combination treatment. These results were related to increases in the induction of apoptosis, G2/M cell cycle arrest, and lethal damage of cells via the MAPK cascade. Together, our findings demonstrate that PTL is an effective thermosensitizing agent for multidisciplinary therapy for human prostate cancer.
Assuntos
Antineoplásicos/farmacologia , Terapia Combinada/métodos , Hipertermia Induzida/métodos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Neoplasias da Próstata , Sesquiterpenos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Western Blotting , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Temperatura Alta , Humanos , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Sesquiterpenos/uso terapêuticoRESUMO
We disclose here the synthesis of a novel trifluoroethoxy-coated binuclear Pc which is the first example of a never-closing clamshell Pc.
RESUMO
A novel covalently linked binuclear phthalocyanine 1 was synthesized by the "double-click" reaction. The UV-vis and fluorescence spectra and electrochemistry revealed that the geometry of 1 is a closed clamshell conformation in which a strong electronic interaction is observed between the two Pc moieties.
RESUMO
A genuine example of non-aggregated highly fluorescent binuclear phthalocyanines is reported; spectroscopic studies and computations revealed that the two halves of trifluoroethoxy-coated binuclear phthalocyanine are rotated in the same directions so as to contact each other as much as possible.
RESUMO
OBJECTIVE: Selection criteria for active surveillance (AS) program of localized prostate cancer remain to be standardized. The purpose was to evaluate the validity of selection criteria and investigate the feasibility of this AS program. METHODS: Patients meeting the criteria (i) stage T1cN0M0, (ii) age 50-80, (iii) serum prostate-specific antigen (PSA) =20 ng/ml, (iv) one or two positive cores per 6-12 systematic biopsy cores, (v) Gleason score =6, and (vi) cancer involvement in positive core =50% were enrolled and encouraged to start AS for at least 6 months during the period between January 2002 and December 2003. PSA was measured bimonthly for 6 months and every 3 months thereafter. Trigger of treatment recommendation was PSA-doubling time (PSADT) of =2 years or pathological progression at re-biopsy. Primary endpoint was '%PSADT > 2y', which was defined as the proportion of patients who showed PSADT assessed at 6 months >2 years out of all the patients who chose AS. Point estimate of '%PSADT > 2y' was expected to be >80%. RESULTS: One hundred and eighteen patients opted for AS and 16 chose immediate treatment at enrollment. PSADT for the initial 6 months based on four measurements could be assessed in 106 patients. Intent-to-treat analysis of '%PSADT > 2y' was 71.2% (84/118, 95% CI: 62.1-79.2). Pathological progression rate at 1-year re-biopsy was 33%. Fifty-four (46%) patients remained on AS for maximal observation of 54 months. General health-related QOL in patients undergoing AS was not impaired. CONCLUSIONS: The primary endpoint, '%PSADT > 2y', did not meet the pre-specified decision criteria. Further prospective study with revised program and endpoint is needed.