RESUMEN
BACKGROUND: Alzheimer's disease (AD) is the most prevalent age-related dementia, and, despite numerous attempts to halt or reverse its devastating progression, no effective therapeutics have yet been confirmed clinically. However, one class of agents that has shown promise is certain metal chelators. OBJECTIVE: For the novel assessment of the effect of oral administration of 1,10-phenanthroline-5-amine (PAA) on the severity of amyloid plaque load, we used a transgenic (Tg) mouse model with inserted human autosomally dominant (familial) AD genes: amyloid-ß protein precursor (AßPP) and tau. METHODS: AßPP/Tau transgenic mice that model AD were allotted into one of two groups. The control group received no treatment while the experimental group received PAA in their drinking water starting at 4 months of age. All animals were sacrificed at 1 year of age and their brains were stained with two different markers of amyloid plaques, Amylo-Glo+ and HQ-O. RESULTS: The control animals exhibited numerous dense core plaques throughout the neo- and allo- cortical brain regions. The experimental group treated with PAA, however, showed 62% of the amyloid plaque burden seen in the control group. CONCLUSIONS: Oral daily dosing with PAA will significantly reduce the amyloid plaque burden in transgenic mice that model AD. The underlying mechanism for this protection is not fully known; however, one proposed mechanism involves inhibiting the "metal-seeding" of Aß.
Asunto(s)
Enfermedad de Alzheimer , Ratones , Humanos , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Fenantrolinas/uso terapéutico , Fenantrolinas/metabolismo , Fenantrolinas/farmacología , Placa Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ratones Transgénicos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Péptidos beta-Amiloides/metabolismoRESUMEN
In the present study, we investigated the antitumor effect and associated molecular mechanisms of the copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)] against hepatocellular carcinoma (HCC). Cu(sal)(phen) inhibited the proliferation of HCC cells (HepG2 and HCC-LM9) and induced apoptosis of HCC cells in a dose-dependent manner by upregulating mitochondrial reactive oxygen species (ROS) production. The expression of the antiapoptotic proteins survivin and Bcl-2 was decreased, while the expression of the DNA damage marker γ-H2 AX and the apoptotic marker cleaved PARP was upregulated with Cu(sal)(phen) treatment. In vivo, the growth of HepG2 subcutaneous xenograft tumors was greatly attenuated by Cu(sal)(phen) treatment. Immunohistochemistry staining showed that the expression of survivin, Bcl-2, and Ki67 in the tumor was downregulated by Cu(sal)(phen). Toxicity experiments with BALB/c mice revealed that Cu(sal)(phen) is a relatively safe drug. Our results indicate that Cu(sal)(phen) possesses great potential as a therapeutic drug for HCC.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Humanos , Carcinoma Hepatocelular/patología , Survivin/farmacología , Survivin/uso terapéutico , Cobre/toxicidad , Cobre/química , Fenantrolinas/farmacología , Fenantrolinas/química , Fenantrolinas/uso terapéutico , Neoplasias Hepáticas/patología , Salicilatos/farmacología , Salicilatos/química , Salicilatos/uso terapéutico , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2 , Proliferación Celular , Línea Celular Tumoral , Antineoplásicos/uso terapéutico , Células Hep G2RESUMEN
Trichophyton rubrum (T. rubrum) is the most common causative agent of dermatophytosis worldwide. The development of antifungal drugs will contribute to treating the disease. In this study, we suggest that a hemiprotonic compound phenanthroline-phenanthroline+ (ph-ph+) is active in inhibiting the growth and reproduction of T. rubrum, and the minimum inhibitory concentration and minimum fungicidal concentration values were 2 µg/ml and 8 µg/ml, respectively. In an in vitro onychomycosis model, ph-ph+ killed T. rubrum by inducing apoptosis, which was evaluated by transmission electron microscopy and Annexin V-FITC/propidium iodide staining. Transcriptomic analysis and biochemical assay showed that ph-ph+ elevated iron ion content in T. rubrum cells and reduced glutathione antioxidant system level, leading to an increase in the contents of ROS and malondialdehyde. Therefore, the antifungal mechanism of ph-ph+ would be associated with iron ion-induced cell apoptosis, which is different from other known antifungal drugs. Furthermore, ph-ph+ was prepared into gel for application in guinea pigs with dermatophytosis caused by T. rubrum. The results showed that the ph-ph+ gel eliminated the fungus in the animals without causing skin irritation or other adverse reactions. The study would not only provide a potential compound to treat dermatophytosis, but also suggest that iron ion-induced cell apoptosis might be a new approach to killing fungi.
Asunto(s)
Antifúngicos , Tiña , Animales , Cobayas , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Fenantrolinas/farmacología , Fenantrolinas/uso terapéutico , Trichophyton , Tiña/tratamiento farmacológico , Pruebas de Sensibilidad MicrobianaRESUMEN
Type-I photodynamic therapy (PDT) with less oxygen consumption shows great potential for overcoming the vicious hypoxia typically observed in solid tumors. However, the development of type-I PDT is hindered by insufficient radical generation and the ambiguous design strategy of type-I photosensitizers (PSs). Therefore, developing highly efficient type-I PSs and unveiling their structure-function relationship are still urgent and challenging. Herein, we develop two phenanthro[9,10-d]imidazole derivatives (AQPO and AQPI) with aggregation-induced emission (AIE) characteristics and boost their reactive oxygen species (ROS) generation efficiency by reducing singlet-triplet splitting (ΔEST). Both AQPO and AQPI show ultrasmall ΔEST values of 0.09 and 0.12 eV, respectively. By incorporating electron-rich anisole, the categories of generated ROS by AIE PSs are changed from type-II (singlet oxygen, 1O2) to type-I (superoxide anion radical, O2â¢- and hydroxyl radical, â¢OH). We demonstrate that the assembled AQPO nanoparticles (NPs) achieve a 3.2- and 2.9-fold increase in the O2â¢- and â¢OH generation efficiencies, respectively, compared to those of AQPI NPs (without anisole) in water, whereas the 1O2 generation efficiency of AQPO NPs is lower (0.4-fold) than that of AQPI NPs. The small ΔEST and anisole group endow AQPO with an excellent capacity for type-I ROS generation. In vitro and in vivo experiments show that AQPO NPs achieve an excellent hypoxia-overcoming PDT effect by efficiently eliminating tumor cells upon white light irradiation with good biosafety.
Asunto(s)
Imidazoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Fenantrolinas/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Hipoxia Tumoral/efectos de los fármacos , Células A549 , Animales , Portadores de Fármacos/química , Femenino , Humanos , Imidazoles/síntesis química , Imidazoles/efectos de la radiación , Luz , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células 3T3 NIH , Nanopartículas/química , Fenantrolinas/síntesis química , Fenantrolinas/efectos de la radiación , Fosfatidiletanolaminas/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/efectos de la radiación , Polietilenglicoles/químicaRESUMEN
Currently, cancer patients with microbial infection are a severe challenge in clinical treatment. To address the problem, we synthesized hemiprotonic compounds based on the unique structure of hemiprotonic nucleotide base pairs in a DNA i-motif. These compounds were produced from phenanthroline (ph) dimerization with phenanthroline as a proton receptor and ammonium as a donor. The biological activity shows that the compounds have a selective antitumor effect through inducing cell apoptosis. The molecular mechanism could be related to specific inhibition of transcription factor PLAGL2 of tumor cells, assessed by transcriptomic analysis. Moreover, results show that the hemiprotonic ph-ph+ has broad-spectrum antibacterial and antifungal activities, and drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, are sensitive to the compound. In animal models of liver cancer with fungal infection, the ph-ph+ retards proliferation of hepatoma cells in tumor-bearing mice and remedies pneumonia and encephalitis caused by Cryptococcus neoformans. The study provides a novel therapeutic candidate for cancer patients accompanied by infection.
Asunto(s)
Antiinfecciosos/uso terapéutico , Antineoplásicos/uso terapéutico , Encefalitis/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Fenantrolinas/uso terapéutico , Neumonía/tratamiento farmacológico , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/toxicidad , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Antiinfecciosos/toxicidad , Antifúngicos/síntesis química , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Antifúngicos/toxicidad , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Encefalitis/complicaciones , Humanos , Masculino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Neoplasias/complicaciones , Fenantrolinas/síntesis química , Fenantrolinas/farmacología , Fenantrolinas/toxicidad , Neumonía/complicaciones , Protones , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Endometriosis is a chronic inflammatory disease which increasingly affects young women under 35 years of age and leads to subfertility even infertility. Analysis of the cytotoxic effect of zinc(II) niflumato complex with neocuproine ([Zn(neo)(nif)2] or Zn-Nif) on immortalized human endometriotic cell line (12Z) and on control immortalized human endometrial stromal cell line (hTERT) was performed using xCELLigence technology for approximately 72 h following the treatment with Zn-Nif as well as cell viability Trypan Blue Assay. 12Z cell line proliferated more slowly compared to unaffected cells, whereas hTERT cells did not show similar behavior after treatment. The complex probably reduces the effect of pro-inflammatory pathways due to the effect of NSAID, while presence of zinc might reduce the level of ROS and regulate ER2 levels and MMP activity. The observed effects and high selectivity for rapidly proliferating cells with increased inflammatory activity suggest a good prognosis of successful decrease of endometriosis stage with this complex.
Asunto(s)
Endometriosis/tratamiento farmacológico , Metaloproteinasas de la Matriz/metabolismo , Compuestos Organometálicos/farmacología , Fenantrolinas/farmacología , Zinc/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Endometriosis/patología , Endometrio/citología , Endometrio/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Compuestos Organometálicos/uso terapéutico , Fenantrolinas/uso terapéutico , Zinc/uso terapéuticoRESUMEN
The new ligand BBIP (BBIP = 2-(7-bromo-2H-benzo[d]imidazole-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) with its iridium(III) complexes: [Ir(ppy)2(BBIP)](PF6) (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)2(BBIP)](PF6) (bzq = benzo[h]quinolone, Ir2) and [Ir(piq)2(BBIP)](PF6) (piq = 1-phenylisoquinoline, Ir3) were synthesized and characterized by elemental analysis, High Resolution Mass Spectrometer (HRMS), 1H NMR and 13C{1H} NMR. The cytotoxicity of the complexes against A549, HepG2, SGC-7901, BEL-7402, HeLa and normal LO2 was evaluated through 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. The results show that Ir1 exhibits high cytotoxic activity against A549 cells with a low IC50 value of 4.9 ± 0.5 µM. A series of biological activities such as cell cycle arrest, endoplasmic reticulum localization assay, apoptosis, western blotting, cellular uptake determination and in vivo antitumor activity were investigated. The assays implied that the complexes inhibit cancer cell migration through blocking mitotic progress. Cell cycle distribution stated that the complexes depress cell growth at G0/G1 phase. Additionally, the complexes acted on the endoplasmic reticulum and induce apoptosis through endoplasmic reticulum stress pathway. Especially, the western blotting showed that the complexes activated Bcl-2 (B-cell lymphoma-2) family and decreased PI3K (phosphoinositide-3 kinase) and AKT (protein kinase B), up-regulated the expression of mTOR (mammalian target of rapamycin) and p-mTOR (phosphorylated mammalian target of rapamycin). Therefore, the complexes induce apoptosis through activating PI3K-AKT-mTOR pathway. Antitumor in vivo demonstrated that Ir1 can effectively prevent the tumor growth with an inhibitory rate of 48.89%.
Asunto(s)
Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Complejos de Coordinación/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Fenantrolinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Iridio/química , Ligandos , Ratones Desnudos , Fenantrolinas/síntesis química , Fenantrolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The selective recognition and imaging of oncogene specific G-quadruplex (GQ) structures holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity. We report selective recognition of GQ by a small molecule through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential implications for GQ-targeted cancer theranostics. Methods: Biophysical investigation reveal the turn on far-red emission property of TGP18 for selective recognition of GQ. In cellulo studies including DNA damage and oxidative stress evaluation guided us to perform in vitro (3D spheroid) and in vivo (xenograft mice model) anti-cancer activity, and tumor tissue imaging to assess the theranostic potential of TGP18. Results: Neocuproine-based far-red turn on fluorescence probe TGP18 shows GQ-to-duplex selectivity and specifically recognizes BCL-2 GQ with high affinity through a unique hybrid binding mode involving loop-stacking and groove interactions. Our study reveals that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity. TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing apoptosis in cancer cells. We deciphered that inhibition of BCL-2 transcription synergized with signaling cascade of nucleolar stress, DNA damage and oxidative stress in triggering apoptosis signaling pathway. Conclusion: Intervention of GQ mediated lethality by TGP18 has translated into anti-cancer activity in both in vitro 3D spheroid culture and in vivo xenograft models of lung and breast cancer with superior efficacy for the former. In vivo therapeutic efficacy supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics.
Asunto(s)
Antineoplásicos/farmacología , G-Cuádruplex , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Nanomedicina Teranóstica/métodos , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carbazoles/farmacología , Carbazoles/uso terapéutico , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Microscopía Intravital/métodos , Ratones , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Simulación de Dinámica Molecular , Neoplasias/diagnóstico , Neoplasias/genética , Estrés Oxidativo/efectos de los fármacos , Fenantrolinas/farmacología , Fenantrolinas/uso terapéutico , Medicina de Precisión/métodos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/uso terapéutico , Esferoides Celulares , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive cancers worldwide, especially in China, with poor prognosis due to the lack of effective therapeutic strategies. Here, the anticancer effect and pharmacological mechanism of a newly synthesized Fe(II) phenanthroline complex was studied in ESCC. Our data showed that transferrin receptor 1 (TFR1) was specifically overexpressed in ESCC tissues compared to its expression in normal esophageal tissues, a finding further supported by public datasets. The newly synthesized Fe(II) complex was selectively transported into ESCC cells overexpressing TFR1 through TFR1-mediated endocytosis and exhibited anticancer activity in a dose-dependent manner. The mechanistic study elucidated that the Fe(II) complex caused cell cycle arrest at the G0/G1 phase by blocking the CDK4/6-cyclin D1 complex and induced mitochondria-mediated apoptosis. Furthermore, exposure to the Fe(II) complex led to excessive reactive oxygen species (ROS) accumulation by thioredoxin reductase (TrxR) inhibition and DNA double-strand breaks (DSBs), which in turn sequentially activated ATM, CHK1/2 and p53. Moreover, combination treatment with cisplatin and the Fe(II) complex exhibited a synergistic effect in ESCC cells. Taken together, our results initially suggest the potential application of the Fe(II) complex in ESCC chemotherapy, especially for patients with TFR1 overexpression.
Asunto(s)
Antígenos CD/biosíntesis , Antineoplásicos/uso terapéutico , Daño del ADN/efectos de los fármacos , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Fenantrolinas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Receptores de Transferrina/biosíntesis , Antígenos CD/genética , Antineoplásicos/química , Antineoplásicos/farmacología , Daño del ADN/fisiología , Relación Dosis-Respuesta a Droga , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Compuestos de Hierro/química , Compuestos de Hierro/farmacología , Compuestos de Hierro/uso terapéutico , Fenantrolinas/química , Fenantrolinas/farmacología , Receptores de Transferrina/genéticaRESUMEN
Five novel silver(I) complexes with 4,7-phenanthroline (4,7-phen), [Ag(NO3-O)(4,7-phen-µ-N4,N7)]n (1), [Ag(ClO4-Ð)(4,7-phen-µ-N4,N7)]n (2), [Ag(CF3COO-O)(4,7-phen-µ-N4,N7)]n (3), [Ag2(H2O)0.58(4,7-phen)3](SbF6)2 (4) and {[Ag2(H2O)(4,7-phen-µ-N4,N7)2](BF4)2}n (5) were synthesized, structurally elucidated and biologically evaluated. These complexes showed selectivity towards Candida spp. in comparison to the tested bacteria and effectively inhibited the growth of four different Candida species, particularly of C. albicans strains, with minimal inhibitory concentrations (MICs) in the range of 2.0-10.0⯵M. In order to evaluate the therapeutic potential of 1-5, in vivo toxicity studies were conducted in the zebrafish model. Based on the favorable therapeutic profiles, complexes 1, 3 and 5 were selected for the evaluation of their antifungal efficacy in vivo using the zebrafish model of lethal disseminated candidiasis. Complexes 1 and 3 efficiently controlled and prevented fungal filamentation even at sub-MIC doses, while drastically increased the survival of the infected embryos. Moreover, at the MIC doses, both complexes totally prevented C. albicans filamentation and rescued almost all infected fish of the fatal infection outcome. On the other side, complex 5, which demonstrated the highest antifungal activity in vitro, affected the neutrophils occurrence of the infected host, failed to inhibit the C. albicans cells filamentation and showed a poor potential to cure candidal infection, highlighting the importance of the in vivo activity evaluation early in the therapeutic design and development process. The mechanism of action of the investigated silver(I) complexes was related to the induction of reactive oxygen species (ROS) response in C. albicans, with DNA being one of the possible target biomolecules.
Asunto(s)
Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Complejos de Coordinación/uso terapéutico , Fenantrolinas/uso terapéutico , Animales , Antifúngicos/síntesis química , Antifúngicos/toxicidad , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/toxicidad , Pruebas de Sensibilidad Microbiana , Fenantrolinas/síntesis química , Fenantrolinas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Plata/química , Pez Cebra/embriologíaRESUMEN
A promising cancer-targeting agent for the induction of apoptosis in tumor necrosis factor (TNF) proteins, the TNF-related apoptosis-inducing ligand (TRAIL) ligand, has found limited applications in the treatment of cancer cells, owing to its resistance by cancer cell lines. Therefore, the rational design of anticancer agents that could sensitize cancer cells towards TRAIL is of great significance. Herein, we report that synthetic iron(II)-polypyridyl complexes are capable of inhibiting the proliferation of glioblastoma cancer cells and efficiently enhancing TRAIL-induced cell apoptosis. Mechanistic studies demonstrated that the synthesized complexes induced cancer-cell apoptosis through triggering the activation of p38 and p53 and inhibiting the activation of ERK. Moreover, uPA and MMP-2/MMP-9, among the most important metastatic regulatory proteins, were also found to be significantly alerted after the treatment. Furthermore, we also found that tumor growth in nude mice was significantly inhibited by iron complex Fe2 through the induction of apoptosis without clear systematic toxicity, as indicated by histological analysis. Taken together, this study provides evidence for the further development of metal-based anticancer agents and chemosensitizers of TRAIL for the treatment of human glioblastoma cancer cells.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Complejos de Coordinación/uso terapéutico , Compuestos Ferrosos/uso terapéutico , Glioblastoma/tratamiento farmacológico , Fenantrolinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Transporte Biológico , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/toxicidad , Regulación hacia Abajo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/farmacología , Compuestos Ferrosos/toxicidad , Humanos , Ligandos , Masculino , Metaloproteinasa 9 de la Matriz/genética , Ratones Desnudos , Fenantrolinas/síntesis química , Fenantrolinas/farmacología , Fenantrolinas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
INTRODUCTION: This phase I, multicenter, open-label, single-arm, dose-escalation study evaluated the safety, pharmacokinetics and antitumor activity of APTO-253, an inducer of the transcription factor KLF4, in adults with advanced solid tumors. METHODS: APTO-253 was administered IV on days 1 and 2, and 15 and 16 of each 28 day cycle; the dose were escalated from 20 to 387 mg/m(2) in 9 cohorts until DLT was observed. RESULTS: Thirty-two patients were treated on this trial (50 % colon cancer, 22 % other gastrointenstinal malignancies and 18 % non-small cell lung cancer). Fatigue was the only drug-related treatment-emergent adverse event to occur in >10 % of patients. Dose-limiting toxicities of hypersensitivity reaction and transient hypotension despite prophylaxis occurred at 387 mg/m(2) which led to identification of 298 mg/m(2) as the MTD. Only 1 patient had any drug-related treatment-emergent grade 3 adverse event at or below 229 mg/m(2). A total of 21 patients underwent at least one restaging after 2 cycles; 11 patients discontinued prior to the end of cycle 2 due to adverse events (9) or disease progression (2). The best overall response was stable disease (SD) in 5 of these 21 (23.8 %) with durations ranging from 3.6 to 8.4 months. CONCLUSION: APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m(2) was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Factores de Transcripción de Tipo Kruppel/biosíntesis , Neoplasias/tratamiento farmacológico , Fenantrolinas/uso terapéutico , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Factor 4 Similar a Kruppel , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Fenantrolinas/administración & dosificación , Fenantrolinas/efectos adversos , Fenantrolinas/farmacocinéticaRESUMEN
Glioblastoma multiforme is an extremely aggressive and invasive form of central nervous system tumor commonly treated with the chemotherapeutic drug Temozolomide. Unfortunately, even with treatment, the median survival time is less than 12 months. 2,9-Di-sec-butyl-1,10-phenanthroline (SBP), a phenanthroline-based ligand originally developed to deliver gold-based anticancer drugs, has recently been shown to have significant antitumor activity in its own right. SBP is hypothesized to initiate tumor cell death via interaction with non-DNA targets, and considering most glioblastoma drugs kill tumors through DNA damage processes, SBP was tested as a potential novel drug candidate against glial-based tumors. In vitro studies demonstrated that SBP significantly inhibited the growth of rodent GL-26 and C6 glioma cells, as well as human U-87, and SW1088 glioblastomas/astrocytomas. Furthermore, using a syngeneic glioma model in mice, in vivo administration of SBP significantly reduced tumor volume and increased survival time. There was no significant toxicity toward nontumorigenic primary murine and human astrocytes in vitro, and limited toxicity was observed in ex vivo tissues obtained from noncancerous mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining and recovery assays suggest that SBP induces apoptosis in gliomas. This exploratory study suggests SBP is effective in slowing the growth of tumorigenic cells in the brain while exhibiting limited toxicity to normal cells and tissues and should therefore be further investigated for its potential in glioblastoma treatment.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Fenantrolinas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Etiquetado Corte-Fin in Situ , Ratones , Ratones Endogámicos C57BL , Fenantrolinas/química , Temozolomida , Factores de TiempoRESUMEN
OBJECTIVE: To investigate the effect of active components of Danshen and Shanzha of different matching proportions on atherosclerosis (AS), in the expectation of obtaining the optimum combination method. METHOD: Atherosclerotic rats were fed with high fat diet, and injected with vitamin D3 and ovalbumin. Aqueous extracts of Danshen (DSA) and Shanzha (SZA) and lipophilic extracts of danshen (DSL) were adopted for a low, medium and high-dose orthogonal experiment, to observe the effect of their different matching proportions on lipid level, oxidative stress, endothelial function and inflammatory reaction. The principal component analysis and cluster analysis were adopted for the multi-objective optimization of experimental results. RESULT: Compared with the model group, all of samples with different proportions of DSA, DSL and SZA showed effect in lowering lipid level, scavenging free radicals, reducing endothelial dysfunction and inhibiting inflammation. According to the variance analysis, DSA2-SZA2-DSL1, DSA3-SZA2-DSL1, DSA3-SZA3 -DSL3 and DSA3-SZA1-DSL1 were the optimal proportions for lowering lipid level, scavenging free radicals, reducing endothelial dysfunction and inhibiting inflammation, respectively. According to the results of the multi-objective optimization, DSA2-SZA1-DSL2 was the optimal proportions of anti-AS. CONCLUSION: All of active components of Danshen and Shanzha of different matching proportions show the anti-AS effect in rats to varying degrees, but with different focus in different matching proportions.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Fitoterapia , Salvia miltiorrhiza , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Endotelio Vascular/efectos de los fármacos , Lípidos/sangre , Masculino , Fenantrolinas/uso terapéutico , Ratas , Salvia miltiorrhiza/químicaRESUMEN
OBJECTIVES: Excessive iron can accumulate in the kidney and induce tissue damage. Danshen (Salvia miltiorrhiza) injection is a traditional Chinese medicinal preparation used for preventing and treating chronic renal failure. The aim of the present study was to evaluate the effects of treatment with Danshen injection on iron overload-induced kidney damage. METHODS: Mice were mock-treated with saline (control group) or given a single dose of iron dextran without treatment (iron overload group, 50 mg/kg/day for 2 weeks) or with daily treatments of low-dose Danshen (3 g/kg/day), high-dose Danshen (6 g/kg/day) or deferoxamine (100 mg/kg/day). RESULTS: Treatment of iron-overloaded mice with Danshen injection led to significant improvements of body weight and decreased iron levels in the kidney. Danshen injection treatment also reduced concentrations of blood urea nitrogen, creatinine and malondialdehyde and enhanced glutathione peroxidase and superoxide dismutase activities. Histopathological examinations showed that Danshen injection ameliorated pathological changes and reduced iron deposition in kidneys of iron overloaded mice. Furthermore, the treatment was demonstrated to suppress apoptosis in nephrocytes. CONCLUSIONS: These results indicated that Danshen injection exerted significant renal protective effects in iron-overloaded mice, which were closely associated with the decrease of iron deposition and suppression of lipid peroxidation and apoptosis in the kidney.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Sobrecarga de Hierro/complicaciones , Riñón/efectos de los fármacos , Fenantrolinas/uso terapéutico , Salvia miltiorrhiza/química , Animales , Nitrógeno de la Urea Sanguínea , Glutatión Peroxidasa/metabolismo , Riñón/lesiones , Riñón/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Ratones , Superóxido Dismutasa/metabolismoRESUMEN
New water soluble antofine C-13a analogues were designed, synthesized, and evaluated for antiproliferative activity against cancer cells. Particularly, (-)-(R)-13a-hydroxymethylantofine ((-)-(R)-4b) demonstrated notable growth inhibition against a panel of human cancer cell lines. This growth inhibition was associated with the arrest of the cell cycle in the G0/G1 phases and suppression of mTOR signaling in human lung A549 cancer cells. Compound (-)-(R)-4b also overcame paclitaxel-resistance in human lung cancer cells (A549-Pa) by suppressing P-glycoprotein expression. Furthermore, compound (-)-(R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model, which suggests it is a promising novel antitumor agent with sufficient aqueous solubility.
Asunto(s)
Antineoplásicos/síntesis química , Diseño de Fármacos , Indoles/química , Fenantrolinas/química , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Células HCT116 , Células HEK293 , Humanos , Indoles/uso terapéutico , Indoles/toxicidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Fenantrolinas/uso terapéutico , Fenantrolinas/toxicidad , Transducción de Señal/efectos de los fármacos , Estereoisomerismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Trasplante Heterólogo , Agua/químicaRESUMEN
OBJECTIVE: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in postmenopausal women. Danshen, the dried root of Salvia miltiorrhiza Bunge, has been used clinically in China to treat CVD and dyslipidemia in postmenopausal women, and its major active ingredients have been found to have an estrogenic effect. The aim of this study was to elucidate the underlying mechanism of danshen's protective effects on vascular function in an ovariectomized (OVX) hyperlipidemic rat model. METHODS: Thirty-five 6-month-old female Sprague-Dawley rats were randomly divided into five groups: sham-operated rats with low-fat control diet + vehicle, sham-operated rats with high-fat diet (HFD) + vehicle, OVX rats with HFD + vehicle, OVX rats with HFD + 17ß-estradiol (1 mg kg d, PO), and OVX rats with HFD + danshen aqueous extract (600 mg kg d, PO). After 12 weeks of treatment, gains in body weight and serum lipid profile levels in rats were measured and histological examination of livers was carried out. Vascular function was evaluated by measuring relaxation responses. Molecular mechanisms were also analyzed in isolated aorta. RESULTS: Treatment with danshen aqueous extract reduced body weight gain, improved serum lipid profiles, and prevented formation of fatty liver induced by HFD and OVX. In addition, danshen could increase endothelial-dependent vasorelaxation and displayed vasoprotection in OVX rats fed with HFD, primarily by stimulating nitric oxide (NO) production, up-regulating the mRNA expression of endothelial NO synthase, and down-regulating the mRNA expression of tumor necrosis factor α, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1 in the isolated aortas. CONCLUSIONS: We conclude for the first time that danshen aqueous extract could protect OVX rats fed with HFD from endothelial dysfunction. Its effect may be related to its abilities to normalize serum lipid profiles and enhance NO availability in the vascular system. Our findings indicate that danshen aqueous extract could be a promising natural supplement for postmenopausal women for preventing CVD.
Asunto(s)
Dieta Alta en Grasa , Medicamentos Herbarios Chinos/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Ovariectomía , Fenantrolinas/uso terapéutico , Salvia miltiorrhiza/química , Animales , Aorta Torácica/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Endotelio Vascular/fisiopatología , Hígado Graso/etiología , Hígado Graso/prevención & control , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/genética , Lípidos/sangre , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo III/genética , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/genética , Molécula 1 de Adhesión Celular Vascular/genética , Vasodilatación/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Danshen (Salvia miltiorrhiza) has been widely prescribed in traditional folk medicine for treatment of hepatic and cardiovascular diseases in China and other Asian countries for several hundred years. MATERIALS AND METHODS: Sixty male mice were randomly divided into five groups: control, iron overload, low-dose Danshen (L-Danshen, 3g/kg/day), high-dose Danshen (H-Danshen, 6g/kg/day) and deferoxamine (DFO) groups (n=12 per group). Iron dextran was injected intraperitoneally (i.p.) at 50mg/kg body weight/day to establish the iron overload model. While control mice received saline, mice of the treated groups simultaneously received (i.p.) injections of L-Danshen, H-Danshen or DFO daily for 2 weeks. At the end of the experiment, changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), glutathione peroxidase (GSH-Px), superoxide desmutase (SOD) and malondialdehyde (MDA) were measured, and histological changes were observed by Prussian blue or hematoxylin and eosin staining of the liver. Apoptosis was detected by terminal-deoxynucleotidyl transferase mediated nick end labeling. RESULTS: Treatment of iron overloaded mice with either low or high doses of Danshen not only significantly attenuated the hepatic dysfunction (ALT/AST levels), decreased the content of MDA and increased the activities of GSH-Px and SOD, it also suppressed apoptosis in hepatocytes. Histopathological examination showed that treatment with Danshen reduced iron deposition and ameliorated pathological changes in the liver of iron overloaded mice. CONCLUSIONS: Danshen demonstrated significant protective effects in the liver of iron overloaded mice, which were at least partly due to the decrease of iron deposition and inhibition of lipid peroxidation and hepatocyte apoptosis.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéutico , Sobrecarga de Hierro/prevención & control , Fenantrolinas/uso terapéutico , Fitoterapia/métodos , Alanina Transaminasa/metabolismo , Animales , Animales no Consanguíneos , Antiinflamatorios no Esteroideos/farmacología , Apoptosis/efectos de los fármacos , Aspartato Aminotransferasas/metabolismo , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Glutatión Peroxidasa/metabolismo , Hepatocitos/efectos de los fármacos , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/patología , Complejo Hierro-Dextran , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Malondialdehído/metabolismo , Ratones , Fenantrolinas/farmacología , Salvia miltiorrhiza , Superóxido DismutasaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia Miltiorrhiza Bunge (also known as herb Danshen in Chinese) is a widely used Chinese herbal medicine. Tanshinone IIA (TSN IIA) is considered to be the most important bioactive ingredient in Danshen and exhibits an anti-atherosclerotic activity. AIM OF STUDY: To evaluate the protective effect of TSN IIA on the human endothelial EA.hy926 cells injured by hydrogen peroxide in vitro and its possible mechanism. MATERIALS AND METHODS: The EA.hy926 cells were incubated for 24h with different concentrations of TSN IIA (5, 10 and 20 µg/µL ) or DMEM. Subsequently, cells were treated with 300 µmol/L H(2)O(2) for another 4h. Then, the percentage of cell viability was evaluated by 3-(4, 5-di-methylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The apoptosis of EA.hy926 cells was detected by flow cytometry with AnnexinV-FITC/PI double staining and laser scanning spectral confocal technique. The generation of intracellular reactive oxygen species (ROS) generation was analyzed by flow cytometry. The mRNA expressions of caspase-3, Bcl-2 and Bax were tested by real time-reverse transcription polymerase chain reaction (real time RT-PCR). The protein expression of Bcl-2 and Bax was determined by Western blotting. MDA levels, NO production, LDH leakage, and SOD as well as caspase-3 activities were also measured using standard methods. RESULTS: Loss of cell viability and excessive cell apoptosis were observed in EA.hy926 cells after 4h of challenge with H(2)O(2) (300 µmol/L). However, cell apoptosis was attenuated in different concentrations of TSN IIA (5, 10 and 20 µg/µL) pretreated cells. Furthermore, TSN IIA markedly inhibited the elevation of ROS evoked by H(2)O(2). Real time RT-PCR and Western blotting analysis showed that TSN IIA significantly decreased the expressions of pro-apoptotic proteins (Bax and caspase-3) while significantly increased the expression of anti-apoptotic protein Bcl-2, and resulted in obvious reduction of Bax/Bcl-2 ratio in EA.hy926 cells induced by H(2)O(2). CONCLUSION: These observations provide preliminary evidence that TSN IIA protects EA.hy926 cells against H(2)O(2) damage, which is mainly associated with the ROS generation, followed by the imbalance of the Bax/Bcl-2 ratio, and caspase-3 activation leading to apoptosis.