RESUMO
A series of (E)-N-2(5H)-furanonyl sulfonyl hydrazone derivatives have been rationally designed and efficiently synthesized by one-pot reaction with good yields for the first time. This green approach with wide substrate range and good selectivity can be achieved at room temperature in a short time in the presence of metal-free catalyst. The cytotoxic activities against three human cancer cell lines of all newly obtained compounds have been evaluated by MTT assay. Among them, compound 5 k exhibits high cytotoxic activity against MCF-7 human breast cancer cells with an IC50 value of 14.35 µM. The cytotoxic mechanism may involve G2/M phase arrest pathway, which is probably caused by activating DNA damage. Comet test and immunofluorescence results show that compound 5 k can induce DNA damage in time- and dose-dependent manner. Importantly, 5 k also can effectively inhibit the proliferation of MCF-7 cells and angiogenesis in the zebrafish xenograft model. It is potential to further develop N-2(5H)-furanonyl sulfonyl hydrazone derivatives as potent drugs for breast cancer treatment with higher cytotoxic activity by modifying the structure of the compound.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Furanos/uso terapêutico , Hidrazonas/uso terapêutico , Sulfonamidas/uso terapêutico , Inibidores da Angiogênese/síntese química , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Hidrazonas/síntese química , Sulfonamidas/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
The G-quadruplex (G4) DNA, which has been developed as a potential anticancer target in drug screening and design, plays a crucial role in the oncogene transcription and translation. Tanshinone IIA derivatives with a planar heterocycle structure may function as G4 stabilizers. We present an innovative case of imidazole-based tanshinone IIA derivatives (1-8) especially compound 4 that improve the selectivity and the binding affinity with G4 DNA and enhance the target tumor inhibition. Cellular and in vivo experiments indicate that the tanshinone IIA derivative 4 inhibits the growth, metastasis, and angiogenesis of triple-negative breast cancer cells possibly through the stabilization of multiple G4 DNAs (e.g., c-myc, K-ras, and VEGF) to induce DNA damage. Further investigation of the intermolecular interaction and the molecular docking indicates that tanshinone IIA derivatives have better selective binding capability to various G4 DNAs than to double-stranded DNA. These findings provide guidance in modifying the molecular structures of tanshinone IIA derivatives and reveal their potential to function as specific G4 stabilizers.
Assuntos
Abietanos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , DNA/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Imidazóis/uso terapêutico , Abietanos/síntese química , Abietanos/metabolismo , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , DNA/genética , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Metástase Neoplásica/prevenção & controle , Regiões Promotoras Genéticas , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Peixe-ZebraRESUMO
Timosaponin B-II (TB-II; (25S)-26-(ß-D-glucopyranosyloxy)-3ß-[(2-O-ß-D-glucopyranosyl-ß-D-galactopyranosyl) oxy]-5ß-furostan-22-ol is extracted from Anemarrhena. Its anti-inflammation, anti-oxidation, and anti-asthma properties have been widely explored. However, its effect on the heart has not been reported. In this study, we used zebrafish as a research model to determine the effects of TB-II on the heart and its toxic and anti-inflammatory effects. To explore the cause of cardioprotective effects of TB-II, we used transgenic zebrafish with macrophages and neutrophils labeled with fluorescent protein. We found for the first time that TB-II had a protective effect on the zebrafish heart. It did not affect the survival and hatching rates of zebrafish embryos, indicating its low toxicity. Results showed that TB-II may have cardioprotective effects, which might be related to its anti-inflammatory effects.
Assuntos
Anemarrhena/química , Anti-Inflamatórios/farmacologia , Cardiotônicos/farmacologia , Saponinas/farmacologia , Esteroides/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Cardiotônicos/isolamento & purificação , Cardiotônicos/toxicidade , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Rizoma , Saponinas/isolamento & purificação , Saponinas/toxicidade , Esteroides/isolamento & purificação , Esteroides/toxicidade , Peixe-ZebraRESUMO
A series of imidazo[4,5f][1,10]phenanthroline derivatives (1-6) have been synthesized in this study, and their inhibitory activity was evaluated by MTT assay. Results showed that all of these compounds demonstrate a promising inhibitory activity against a panel of human cancer cell lines. The 6, the most effective compound with IC50 of approximately 2.3⯱â¯0.1⯵M, was against the growth and could induce autophagy of HepG2 cells. This condition was confirmed by abundant autophagic vacuoles appearing in cells and evident ultrastructural changes observed under transmission electron microscopy. The autophage induced by 6 has also been demonstrated by up-regulating LC3-II and Beclin1. The apoptosis and G2/M phase cell cycle arrest through DSB damage have also been confirmed after the HepG2 cells were treated by 6. These multiple effects, especially induction apoptosis and autophagy, indicate the potential of 6 for development as a novel anticancer drug.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Imidazóis/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Fenantrolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/síntese química , Imidazóis/química , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Fenantrolinas/síntese química , Fenantrolinas/química , Células Tumorais Cultivadas , Peixe-ZebraRESUMO
A chemotherapeutic drug exerts favorable antitumor activity and simultaneously exhibits expectable inhibition on wound healing process. Phenanthroimidazole derivatives possess potent anticancer activity. However, only a few studies focused on the discovery of its potential effects on promoting tissue regeneration. In this study, four novel phenanthroimidazole derivatives were synthesized and characterized, and they exhibited evident inhibition on different tumor cells; compound 3 is the most active one. Moreover, 3 can promote wound healing of zebrafish in a dose-dependent manner. Further study demonstrated that 3 promoted the recruitment of inflammatory cells, formation of angiogenesis, and generation of reactive oxygen species and also influenced the motor behavior of zebrafish. Results indicated that 3 can accelerate the occurrence of pro-inflammation, angiogenesis, oxidative stress, and innervation, which play key roles in the facilitation of wound healing. Therefore, 3 can act as a bifunctional drug in inhibiting tumor and promoting tissue regeneration.
Assuntos
Nadadeiras de Animais/efeitos dos fármacos , Antineoplásicos/farmacologia , Imidazóis/farmacologia , Regeneração/efeitos dos fármacos , Nadadeiras de Animais/fisiologia , Animais , Animais Geneticamente Modificados , Antineoplásicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Embrião não Mamífero/irrigação sanguínea , Embrião não Mamífero/efeitos dos fármacos , Proteínas de Fluorescência Verde/genética , Humanos , Imidazóis/toxicidade , Inflamação/imunologia , Larva/efeitos dos fármacos , Larva/imunologia , Locomoção/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Espécies Reativas de Oxigênio/imunologia , Cicatrização/efeitos dos fármacos , Peixe-Zebra/genéticaRESUMO
Herein, a series of imidazo[4,5-f][1,10] phenanthroline derivatives RPIP (PIP = imidazo [4,5-f][1,10] phenanthroline, R = NO2, 1; CF3, 2; Cl, 3; OH, 4) have been synthesized in yields of 82.3-94.7% at 100 °C under the irradiation of microwave. MTT assay has been utilized to evaluate the inhibitory activity (IC50) of these compounds against the growth of various tumor cells, and the results revealed that these compounds, especially 1, exhibited excellent inhibitory activity against the growth of A549 cells with IC50 of 15.03 µM. Moreover, it's also confirmed that 1 can penetrate into the membrane of tumor cells and distribute in mitochondria when observed under microscopy, resulting apoptosis of tumor cells. The further studies showed that 1 can bind to bcl-2 G-quadruplex DNA, which demonstrated by the increase of melting point of bcl-2 G4 DNA in the presence of 1, as well as electronic titration and emission spectra. In a word, this kind of compound may develop as a potential apoptosis inducer in cancer chemotherapy via binding and stabilizing to the bcl-2 G-quadruplex DNA.
Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Imidazóis/síntese química , Mitocôndrias/efeitos dos fármacos , Fenantrolinas/síntese química , Proteínas Proto-Oncogênicas c-bcl-2/agonistas , Células A549 , Antineoplásicos/farmacologia , Transporte Biológico , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica , Humanos , Imidazóis/farmacologia , Micro-Ondas , Mitocôndrias/metabolismo , Desnaturação de Ácido Nucleico , Fenantrolinas/farmacologia , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
A pair of chiral ruthenium(II) complexes, Λ- and Δ-[Ru(bpy)2(p-BEPIP)](ClO4)2 [Λ- and Δ-RM0627; bpy = 2,2-bipyridine; p-BEPIP = 2-(4-phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline], were prepared using the Sonogashira coupling reaction under microwave irradiation. The study shows that Λ-RM0627 emitted strong phosphorescence in the range 500-700 nm with a maximum at 594 nm when excited at 365 nm (the Stokes shift is about 227 nm), which was mainly located in the cell nucleus with red phosphorescence. Further studies using real-time phosphorescence observation confirmed that Λ-RM0627 can be taken up quickly by MDA-MB-231 cells and enriched in the nucleus. The in vitro and in vivo toxicities of Λ-RM0627 were also evaluated, and it was found that Λ-RM0627 slightly inhibited the growth of MDA-MB-231 breast cancer cells and HaCaT normal human epidermal cells and had little influence on the development of Zebrafish embryos at low concentration. In conclusion, the levoisomer of chiral ruthenium complexes can act as a potential phosphorescent probe that targets nuclei of living cells with low toxicity.
Assuntos
Neoplasias da Mama/patologia , Núcleo Celular/ultraestrutura , Complexos de Coordenação/química , Fenantrolinas/química , Compostos de Rutênio/química , Animais , Linhagem Celular Tumoral , Humanos , Análise Espectral/métodos , Estereoisomerismo , Peixe-Zebra/embriologiaRESUMO
1,10-Phenanthroline has been shown to exhibit anticancer activity. Here, a series of imidazo [4,5f][1,10] phenanthroline derivatives 1-10 were synthesized and their biological activities were further elucidated. We found that 2-(4-Brominephenyl)-imidazo [4,5f][1,10] phenanthroline (compound 3) possessed potent antiproliferation activities again a variety of tumor cell lines using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Flow cytometric analysis revealed that compound 3 induced both through apoptosis and necrosis in human lung adenocarcinoma cell line, A549. Moreover, compound 3 treatment led to up-regulation of IκBα and down-regulation of p65 and c-myc in A549 cells. Taken together, these results suggested that compound 3 inhibited cell proliferation by suppression of NF-κB activity and down-regulation of c-myc gene expression and may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially for lung cancer.
Assuntos
Antineoplásicos/farmacologia , NF-kappa B/metabolismo , Fenantrolinas/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adenocarcinoma/tratamento farmacológico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Citometria de Fluxo/métodos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Modelos Químicos , Necrose , Sais de Tetrazólio/farmacologia , Tiazóis/farmacologiaRESUMO
Phenanthroline derivatives containing fluorinated imidazole ring are effective anti-neoplastic agents. Herein, a series of four fluorinated imidazole[4,5f][1,10]phenanthroline derivatives were synthesized and investigated as potential inhibitors to fight against the growth of liver cancer cells. The inâ vitro antitumor activity of targeted compounds have been evaluated by using MTT assay, and results showed that compound 4 (2-(2,3-difluorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) exhibited excellent inhibitory effect against the growth of various tumor cells, particularly for HepG2 cells, with IC50 value of approximately 0.29â µM. This result has been further confirmed by colony formation assay, showing that compound 4 suppressed the proliferation of HepG2 cells. Moreover, cell apoptosis (AO/PI dual staining and flow cytometry) analyses as well as comet assay showed that compound 4 may induce apoptosis of HepG2 cells through triggering DNA damage. Furthermore, the inâ vivo anti-tumor activity were evaluated on zebrafish bearing HepG2 cells showed that compound 4 can observably block the growth of liver cancer cells. All in together, these compounds, particularly compound 4, may be developed as a potential agent to treat liver cancer in the future.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Imidazóis/farmacologia , Fenantrolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Halogenação , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Fenantrolinas/síntese química , Fenantrolinas/química , Relação Estrutura-AtividadeRESUMO
Herein, a derivate from tanshinone IIA, 1,6,6-trimethyl-11-phenyl-7,8,9,10-tetrahydro-6H-furo[2',3':1,2]phenanthro[3,4-d]imidazole (TA25), has been synthesized and investigated as potential inhibitor against the proliferation, migration and invasion of lung cancer cells. MTT assay and cell colony formation assay results showed that TA25 exhibits acceptable inhibitory effect against the proliferation of lung cancer A549 cells, and the value of IC50 was about 17.9 µM. This result was further confirmed by the inhibition of TA25 against the growth of xenograft lung cancer cells on zebrafish bearing tumor (A549 lung cancer cells). The results of wound-healing assay and FITC-gelatin invasion assay displayed that TA25 could inhibit the migration and invasion of lung cancer A549 cells. Moreover, the studies on the binding properties of TA25 interact with c-myc G-quadruplex DNA suggested that TA25 can bind in the G-quarter plane formed from G7, G11, G16 and G20 with c-myc G-quadruplex DNA through π-π stacking. Further study of the potential anti-cancer mechanism indicated that TA25 can induce S-phase arrest in lung cancer A549 cells, and this phenomenon resulted from the promotion of the production of reactive oxygen species and DNA damage in A549 cells under the action of TA25. Further research revealed that TA25 could inhibit the PI3K/Akt/mTOR signal pathway and increase the expression of p53 protein. Overall, TA25 can be developed into a promising inhibitor against the proliferation, migration and invasion of lung cancer cells and has potential clinical application in the near future.
Assuntos
Abietanos/farmacologia , Antineoplásicos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Fase S/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Abietanos/química , Abietanos/uso terapêutico , Abietanos/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Quadruplex G/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-ZebraRESUMO
Guanine-rich DNA sequences can spontaneously fold into four-stranded structures called G-quadruplexes (G4s). G4s have been identified extensively in the promoter regions of several proto-oncogenes, including c-myc, as well as telomeres. G4s have attracted an increasing amount of attention in the field of nanotechnology because of their use as versatile building blocks of DNA-based nanostructures. In this study, we report the self-assembly of c-myc G-quadruplex DNA controlled by a pair of chiral ruthenium(ii) complexes coordinated by 2-(4-phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline (PBEPIP), Λ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Λ-RM0627, bpy = bipyridine) and Δ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Δ-RM0627). Λ-RM0627 could promote the high-order self-assembly of c-myc G-quadruplex DNA into a nanowire structure, whereas Δ-RM0627 could induce DNA condensation into G-quadruplex aggregates. Moreover, in vitro studies on human liver carcinoma HepG2 cells showed that the nanowire of c-myc G-quadruplex DNA promoted by Λ-RM0627 could be localized in the nuclei of cells, whereas the nanoparticle of c-myc G-quadruplex DNA generated by Δ-RM0627 was taken up and localized in the cytoplasm. This study provides examples of the enantioselective self-assembly of G4 DNA molecules controlled by chiral ruthenium(ii) complexes and suggests the potential applications of assembled nanostructures as non-viral DNA vectors for gene therapy.
Assuntos
Núcleo Celular/metabolismo , Complexos de Coordenação/metabolismo , Citoplasma/metabolismo , Rutênio/metabolismo , Transporte Biológico , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , DNA/química , DNA/metabolismo , Quadruplex G , Células Hep G2 , Humanos , Nanopartículas/química , Nanofios , Fenantrolinas/química , Fenantrolinas/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rutênio/química , Rutênio/farmacocinética , EstereoisomerismoRESUMO
Chemotherapy drugs exerts beneficial antitumor activity before and after cancer surgery. Post-injury complications are a potential hazard after surgical tumor resection. Inflammation caused by surgical stress is known to promote the progression of post-injury complications. Recent studies have found that chemotherapy drugs can promote post-injury inflammatory response, leading to increased post-injury complications. Imidazole derivatives have effective anticancer activity. However, the impact of post-operative inflammation caused by imidazole derivatives is unclear. In this study, two novel phenanthroimidazole derivatives (L082 and L142) were synthesized and characterized. These compounds showed significant inhibitory effects on different tumor cells. The compound L082 also inhibited liver cancer in vivo. In addition, L082 played a significant role in inhibiting the accumulation of inflammatory cells and promoting the elimination of inflammatory cells at the incision, which may be related to inhibiting the production of ROS and NO in oxidative and nitric stress. These results suggest that L082 can be used as a bifunctional drug to suppress tumors and reduce post-injury inflammation complications.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Fenantrenos/síntese química , Fenantrenos/uso terapêutico , Células A549 , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Células HeLa , Células Hep G2 , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fenantrenos/farmacologia , Peixe-ZebraRESUMO
In the present study, shRNA plasmid of pSi-p21 targeting p21 mRNA was constructed and the effect of p21 shRNA on curcumin-induced apoptosis of human hepatoma Huh7 cells was investigated. The effect of curcumin on the expression of p21 mRNA and protein and the silence efficiency of pSi-p21 were detected with RT-PCR and Western blotting. The effect of pSi-p21 on curcumin-induced apoptosis of Huh7 cells was evaluated with DAPI staining. The results showed that curcumin significantly upregulated p21 mRNA and protein expression, which was knocked down by pSi-p21 of Huh7 cells. DAPI staining results showed that pSi-p21 significantly decreased curcumin-induced apoptosis of Huh7 cells. The data suggested that curcumin induced apoptosis of Huh7 cells via upregulation of p21 expression.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Curcumina/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias Hepáticas/patologia , RNA Interferente Pequeno/genética , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Plasmídeos , RNA Mensageiro/metabolismo , Transfecção , Regulação para CimaRESUMO
The effect of curcumin on JAK-STAT signaling pathway was investigated in hepatoma cell lines Huh7 and Hep3B. Curcumin inhibited cell proliferation and induced apoptosis of both cell lines, but Huh7 cells were more sensitive to curcumin than Hep3B cells. Curcumin (50 micromol x L(-1)) significantly increased phosphorylations of p38 (T180/Y182) and STAT-1 (S727) in Huh7 and Hep3B cells, and caused relocalization of phosphorylated-STAT-1 (Y701) from cytoplasm to nucleus in Hep3B cells. In addition, curcumin (25 and 50 micromol x L(-1)) dramatically suppressed the phosphorylation level of STAT-1 (Y701) and resulted in a significant reduction of nuclear phosphorylated-STAT-1 (Y701) in Huh7 cells.
Assuntos
Carcinoma Hepatocelular/patologia , Curcumina/farmacologia , Janus Quinases/metabolismo , Neoplasias Hepáticas/patologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Curcuma/química , Curcumina/isolamento & purificação , Humanos , Neoplasias Hepáticas/metabolismo , Fosforilação , Plantas Medicinais/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Combining radiosensitizers with ionizing radiation (IR) is an effective strategy to increase the radiation therapeutic effect for hepatocellular carcinoma (HCC) patients. A phenanthroline derivative, 2-phenyl-imidazo [4, 5â¯f] [1, 10] phenanthroline (L02), had been synthesized. This study investigated the radiosensitization and mechanisms of L02 combined with IR against HCC. The radiosensitization of L02 combined with IR was evaluated by the sensitivity enhancement ratio (SER) and the isobolographic analysis. The toxicity of L02 and cisplatin were compared by the zebrafish model. The cell cycle and apoptosis were examined by flow cytometry. DNA damage was measured by comet assay and the expressions of apoptosis related proteins were analyzed by western blotting. L02 was effective in sensitizing HCC to IR. The SERs in HepG2 and BEL7402 were 1.41 and 1.28, respectively. The sensitization of L02 was comparable with cisplatin. L02 treatment with IR had synergistic anti-tumor effect. L02 enhanced the percentage of IR induced apoptosis cells. L02 increased comet tail in comet assay when combined with IR. L02 sensitized HCC to IR by the activation of P53 signaling, the decrease in Bcl-2, up-regulation of cytochrome c and the subsequent activation of caspase-3. L02 sensitizes HCC to IR, mostly likely by inhibiting cell proliferation, inducing DNA damage and mitochondria-dependent apoptosis. L02 may be a novel radiosensitizer for HCC.
Assuntos
Mitocôndrias/efeitos dos fármacos , Fenantrolinas/farmacologia , Radiossensibilizantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Mitocôndrias/efeitos da radiação , Tolerância a Radiação/efeitos dos fármacos , Raios XRESUMO
Chiral ruthenium(II) complexes have long been considered as potential anticancer agents. Herein, in vivo inhibitory activity of a chiral ruthenium(II) complex coordinated by ligand 2-(2'-trifluoromethyphenyl) imidazo [4,5-f][1,10]phenanthroline, Δ-[Ru(bpy)2(o-FMPIP)] (D0402) on Kunming(KM) mice bearing tumor (H22 hepatic cancer) has been evaluated, and the results showed that the tumor weight of mice treated with 0.22â¯mg/(kg·day) D0402 via i.v. administration for 7 days decreased about 31.79% compared to the control group, while the body weight, as well as the thymus, spleen, liver, lung, and kidney indices of mice treated with D0402 observed almost no loss compared to the control group. Furthermore, the mechanism studies on anti-angiogenic showed that D0402 could inhibit the formation of angiogenesis in the transgenic Tg(fli1a: EGFP) zebrafish. After treated with D0402, the sub-intestinal vessels(SIVs) of the zebrafish became disordered and chaotic, and was dosage dependent. Moreover, the TUNEL analysis and comet assays revealed that D0402 can induce apoptosis of HepG2 cell through DNA damage, and this was further demonstrated by immunofluorescence analysis with the number of γ-H2AX increased following the increasing amount of D0402. Besides, in vivo toxicity of D0402 has also been investigated on the development of zebrafish embryo, and the results showed that there were no death or development delay occurred for zebrafish embryo treated with D0402 up to concentration of 60⯵M. All in together, this study suggested that D0402 can be developed as a potential inhibitor against liver cancer through co-junction of anti-angiogenesis and apoptosis-inducing via DNA damage in the near future.
Assuntos
Apoptose/efeitos dos fármacos , Dano ao DNA , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fenantrolinas/química , Piridinas/química , Rutênio/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/toxicidade , Animais , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Camundongos , Compostos Organometálicos/toxicidade , Estereoisomerismo , Peixe-ZebraRESUMO
A series of mixed-valence rare earth borotungsto-heteropoly blues, K15H2[Ln(BW9W2O39)2].28H2O (Ln2, Ln=La, Ce, Pr, Nd, Sm, Eu, Gd), have been prepared and characterized by IR, UV, XPS, ESR and electrochemistry. The cytotoxicity and antiviral activity of these rare earth borotungstate heteropoly blues were investigated against influenza A(FluVA) strain (A/H1N1/Jingfang/1/91 and A/H3N2/Jingfang/30/95) and influenza virus B(FluVB) (B/Hufang/1/87) in MDCK cells. The results show that K15H2[Pr(BW9W2O39)2].28H2O (Pr2) exhibits the highest antiviral activity against FluVA with EC50 of less than 4.0 microg/ml (A/H1N1/Jingfang/1/91) and 6.0 microg/ml (A/H3N2/Jingfang/30/95), respectively, and has the lowest toxicity with CC50 of more than 480 microg/ml against MDCK cells. Additionally, both K15H2[Pr(BW9W2O39)2].28H2O (Pr2) and K15H2[Eu(BW9W2O39)2].28H2O (Eu2) showed excellent antiviral activities against FluVB by inhibiting FluVB replication at an EC50 of less than 8.0 microg/ml. Furthermore, investigation on in vivo antiviral activity of Pr2 against FluVA(FM1) in mice by giving the dosage either orally (p.o.) or intraperitoneally (i.p.), indicates that Pr2 exhibits higher inhibitory activity than that of positive control, virazole, and that it's more effective when administered by i.p.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Metais Terras Raras/química , Compostos de Tungstênio/síntese química , Compostos de Tungstênio/farmacologia , Animais , Antivirais/uso terapêutico , Antivirais/toxicidade , Peso Corporal/efeitos dos fármacos , Compostos de Boro/uso terapêutico , Compostos de Boro/toxicidade , Linhagem Celular , Efeito Citopatogênico Viral/efeitos dos fármacos , Eletroquímica , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/fisiologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/fisiologia , Camundongos , Análise Espectral , Taxa de Sobrevida , Compostos de Tungstênio/uso terapêutico , Compostos de Tungstênio/toxicidadeRESUMO
Two new ligands, 3-(pyrazin-2-yl)-as-triazino[5,6-f]-5-methoxylisatin (dtmi), 3-(pyrazin-2-yl)-as-triazino[5,6-f]-5-nitroisatin (dtni) and their ruthenium(II) complexes [Ru(phen)2(dtmi)](ClO4)2 (1) and [Ru(phen)2(dtni)](ClO4)2 (2) have been prepared and characterized by elemental analysis, FAB-MS, ES-MS and 1H NMR. The DNA-binding behaviors of complexes have been studied by spectroscopic titration, viscosity measurements, thermal denaturation and circular dichromism (CD). The results indicate that the complexes 1 and 2 interact with calf thymus DNA (CT-DNA) by intercalative mode. The DNA-binding affinity of the complexes 2 is larger than that complex 1 does.
Assuntos
DNA/metabolismo , Substâncias Intercalantes/química , Compostos Organometálicos/química , Fenantrolinas/química , Pirazinas/química , Rutênio/química , Animais , Bovinos , Dicroísmo Circular , DNA/química , Temperatura Alta , Substâncias Intercalantes/metabolismo , Ligantes , Microquímica/métodos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Desnaturação de Ácido Nucleico , Compostos Organometálicos/metabolismo , Fenantrolinas/metabolismo , Pirazinas/metabolismo , Espectrometria de Massas por Ionização por Electrospray , ViscosidadeRESUMO
[This corrects the article DOI: 10.1039/C0MD00060D.].
RESUMO
The development of Ru(ii) complexes as luminescent probes has attracted increasing attention in recent decades. In this study, the nanosized polymers of two Ru(ii) complexes [Ru(phen)2(dppz)](ClO4)2 (1, phen = 1,10-phenanthrolin; dppz = dipyrido[3,2-a:2',3'-c]phenazine) and [Ru(phen)2(Br-dppz)](ClO4)2 (2, Br-dppz = 11-bromodipyrido[3,2-a:2',3'-c]phenazine) with oligonucleotides were prepared and investigated as potential tumor-imaging probes. The formation of the nanosized polymers, which had an average width of 125-438 nm and an average height of 3-6 nm, for 1 and 2@oligonucleotides were observed through atomic force microscopy. The emission spectra indicated that the luminescence of 1 and 2 markedly increased after binding to oligonucleotides and double-strand DNA (calf thymus DNA), respectively. Moreover, further studies indicated that 1@oligonucleotides and 2@oligonucleotides can easily enter into tumor cells and selectively highlight the tumor area in the zebrafish bear xenograft tumor (MDA-MB-231). In summary, this study demonstrated that 1@oligonucleotides and 2@oligonucleotides could be developed as potential tumor-imaging luminescent probes for clinical diagnosis and therapy.