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1.
Int J Nanomedicine ; 14: 5257-5270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409988

RESUMO

Background: In recent years, green synthesized silver nanoparticles have been increasingly investigated for their anti-cancer potential. In the present study, we aimed at the biosynthesis of silver nanoparticles (AgNPs) using a curcumin derivative, ST06. Although, the individual efficacies of silver nanoparticles or curcumin derivatives have been studied previously, the synergistic cytotoxic effects of curcumin derivative and silver nanoparticles in a single nanoparticulate formulation have not been studied earlier specifically on animal models. This makes this study novel compared to the earlier synthesized curcumin derivative or silver nanoparticles studies. The aim of the study was to synthesize ST06 coated silver nanoparticles (ST06-AgNPs) using ST06 as both reducing and coating agent. Methods: The synthesized nanoparticles AgNPs and ST06-AgNPs were characterised for the particle size distribution, morphology, optical properties and surface charge by using UV-visible spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Elemental composition and structural properties were studied by energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction spectroscopy (XRD). The presence of ST06 as capping agent was demonstrated by Fourier transform infrared spectroscopy (FTIR). Results: The synthesized nanoparticles (ST06-AgNPs) were spherical and had a size distribution in the range of 50-100 nm. UV-Vis spectroscopy displayed a specific silver plasmon peak at 410 nm. The in vitro cytotoxicity effects of ST06 and ST06-AgNPs, as assessed by MTT assay, showed significant growth inhibition of human cervical cancer cell line (HeLa). In addition, studies carried out in EAC tumor-induced mouse model (Ehrlich Ascites carcinoma) using ST06-AgNPs, revealed that treatment of the animals with these nanoparticles resulted in a significant reduction in the tumor growth, compared to the control group animals. Conclusion: In conclusion, green synthesized ST06-AgNPs exhibited superior anti-tumor efficacy than the free ST06 or AgNPs with no acute toxicity under both in vitro and in vivo conditions. The tumor suppression is associated with the intrinsic apoptotic pathway. Together, the results of this study suggest that ST06-AgNPs could be considered as a potential option for the treatment of solid tumors.


Assuntos
Carcinoma de Ehrlich/patologia , Curcumina/farmacologia , Química Verde/métodos , Nanopartículas Metálicas/química , Prata/farmacologia , Neoplasias do Colo do Útero/patologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células HeLa , Humanos , Camundongos , Tamanho da Partícula , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual/efeitos dos fármacos , Difração de Raios X
2.
Oncol Rep ; 42(4): 1467-1474, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31322269

RESUMO

With the increasing use of poly(ADP­ribose) polymerase (PARP) inhibitors in cancer therapy, understanding their resistance is an urgent research quest. Additionally, CHFR is an E3 ubiquitin ligase, recruited to double­strand breaks (DSBs) by PAR. Furthermore, ALC1 is a new oncogene involved in the invasion and metastasis of breast cancer. Moreover, PARylated PARP1 activates ALC1 at sites of DNA damage, yet the underlying mechanism remains unclear. Mass spectrometric analysis, western blot analysis and immunoprecipitation were performed to confirm the interaction between CHFR and ALC1 in the physiological condition. Deletion mutants of CHFR and ALC1 were generated to map the interaction domain. PARP1/2 inhibitors were added to identify the ubiquitination of ALC1 by CHFR. ALC1 half­life was examined to compare the expression of ALC1 protein in the presence and absence of PARP1/2 inhibitors. The results revealed that the transcriptional level of ALC1 was not upregulated in breast cancer tissues. CHFR interacted with ALC1. The PBZ domain of CHFR, the PMD domain and the MACRO domain of ALC1 domain are the necessary regions for the interaction depending on PAR. Ubiquitination of ALC1 by CHFR was dependent on PARylation and resulted in the degradation of PARylated ALC1. PARP1/2 inhibitors decreased the ubiquitination of PAR­dependent ALC1, and the expression of ALC1 was upregulated by PARP1/2 inhibitors. Ubiquitination mediated by CHFR resulted in the degradation of ALC1. In conclusion, PARP1/2 inhibitors decrease the ubiquitination of ALC1 leading to the accumulation of ALC1, which affects the therapeutic effects of DNA damage response drugs in breast cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Neoplasias/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Células MCF-7 , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transcrição Genética , Ubiquitinação/efeitos dos fármacos
3.
Chem Commun (Camb) ; 55(61): 8919-8922, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270526

RESUMO

Cancer development is often associated with lipid metabolic reprogramming, including aberrant lipid accumulation. We create novel paradigms endowed with dual functions of anticancer activity and inhibition of lipid accumulation by conjugating the natural product quercetin and synthetic alkylphospholipid drugs, and harnessing the biomedical effects of both. These conjugates offer fresh perspectives in the search for anticancer candidates.


Assuntos
Fármacos Antiobesidade/farmacologia , Antineoplásicos/farmacologia , Éteres Fosfolipídicos/farmacologia , Fosforilcolina/análogos & derivados , Quercetina/análogos & derivados , Quercetina/farmacologia , Fármacos Antiobesidade/síntese química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Gotículas Lipídicas/metabolismo , Receptores X do Fígado/metabolismo , PPAR gama/metabolismo , Éteres Fosfolipídicos/síntese química , Fosforilcolina/síntese química , Fosforilcolina/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quercetina/síntese química , Transdução de Sinais/efeitos dos fármacos
4.
Drugs ; 79(11): 1231-1239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31267481

RESUMO

For more than 20 years, the combination of a platinum agent and a taxane has served as the primary chemotherapy strategy for epithelial ovarian cancer. Alternative approaches employing these drugs (intraperitoneal drug delivery, neoadjuvant therapy) have favorably impacted outcomes in selected patient populations. Multiple single agent and combination therapy strategies have been delivered in the second-line (or later) setting with the goal to prolong survival and optimize quality-of-life. The anti-angiogenic agent bevacizumab has been shown to be clinically active when added to chemotherapy and delivered as a "maintenance" strategy in the front-line, platinum-sensitive recurrent and platinum-resistant settings. Several poly-(ADP-ribose) polymerase (PARP) inhibitors are currently utilized as single-agent "second-line" treatment options or in the maintenance setting. Recent clinical research efforts in ovarian cancer have focused on the potential role of checkpoint inhibitors used alone or in combination with PARP inhibitors or anti-angiogenic agents.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Terapia Neoadjuvante , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Taxoides/uso terapêutico
5.
Nat Commun ; 10(1): 2954, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273204

RESUMO

PARP-1 is rapidly recruited and activated by DNA double-strand breaks (DSBs). Upon activation, PARP-1 synthesizes a structurally complex polymer composed of ADP-ribose units that facilitates local chromatin relaxation and the recruitment of DNA repair factors. Here, we identify a function for PARP-1 in DNA DSB resection. Remarkably, inhibition of PARP-1 leads to hyperresected DNA DSBs. We show that loss of PARP-1 and hyperresection are associated with loss of Ku, 53BP1 and RIF1 resection inhibitors from the break site. DNA curtains analysis show that EXO1-mediated resection is blocked by PARP-1. Furthermore, PARP-1 abrogation leads to increased DNA resection tracks and an increase of homologous recombination in cellulo. Our results, therefore, place PARP-1 activation as a critical early event for DNA DSB repair activation and regulation of resection. Hence, our work has direct implications for the clinical use and effectiveness of PARP inhibition, which is prescribed for the treatment of various malignancies.


Assuntos
Quebras de DNA de Cadeia Dupla , DNA/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Cromatina/metabolismo , Técnicas de Silenciamento de Genes , Células HeLa , Recombinação Homóloga/genética , Humanos , Camundongos , Modelos Biológicos , Proteínas Nucleares/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas de Ligação a Telômeros/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
6.
Environ Pollut ; 252(Pt A): 917-923, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226516

RESUMO

Glyphosate-based herbicides (GBH) are the most widely used pesticides in the world. The extensive use of them increases the potential human health risk, including the human inhalation toxicity risk. We studied the effect of the most famous GBH Roundup® (RDP) in the concentration range from 50 to 125 µg/mL on Mitochondria-Associated apoptosis and DNA damage in Human alveolar carcinoma cells (A549 cells). Alkaline comet assay, immunofluorescence assay and Flow Cytometric Analysis assay were employed to detect DNA damages and apoptosis of A549 cells. We found RDP caused concentration-dependent increases in DNA damages and proportion of apoptotic cells in A549 cells. RDP induced the DNA single-strand breaks and double-strand breaks; the collapse of mitochondrial membrane by increasing Bax/Bcl-2, resulting in the release of cytochrome c into cytosol and then activated caspase-9/-3, cleaved poly (ADP-ribose) polymerase (PARP) in human lung tissue cells. The results demonstrate that RDP can induce A549 cells cytotoxic effects in vitro at the concentration lower than the occupational exposures level of workers, which means RDP has a potential threat to human health.


Assuntos
Apoptose/efeitos dos fármacos , Glicina/análogos & derivados , Herbicidas/toxicidade , Pulmão/patologia , Mitocôndrias/efeitos dos fármacos , Células A549 , Adenocarcinoma Bronquioloalveolar/genética , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Ensaio Cometa , Citocromos c/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Glicina/toxicidade , Humanos , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
7.
BMC Complement Altern Med ; 19(1): 151, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242894

RESUMO

BACKGROUND: Costunolide, a sesquiterpene lactone extracted from Radix Aucklandiae, has the activity against multiple cancers. However, the effect of costunolide on gastric cancer (GC) have remained to be ambiguous. In this study, we investigated the underlying mechanisms of apoptosis induced by costunolide in human gastric adenocarcinoma BGC-823 cells in vitro and in vivo. METHODS: The viability of BGC-823 cells was detected by MTT assay. The apoptosis and mitochondrial membrane potential (ΔΨm) of BGC-823 cells induced by costunolide were analyzed by flow cytometry. The inhibiton of costunolide on human gastric adenocarcinoma was estimated in xenografts in nude mice. Apoptosis related proteins and genes were detected by Western blot and Q-PCR. RESULTS: Costunolide inhibited the viability of BGC-823 cells in a time and concentration dependent manner. Costunolide induced the apoptosis and lowered the ΔΨm of BGC-823 cells significantly. Costunolide increased the expression of Bax, cleaved caspase 9, cleaved caspase 7, cleaved caspase 3 and cleaved poly ADP ribose polymerase (PARP) proteins and decreased the expression of Bcl-2, pro-caspase 9, pro-caspase 7, pro-caspase 3 and PARP proteins. Costunolide upregulated the expression of puma, Bak1 and Bax mRNA and downregulated the expression of Bcl-2 mRNA. In addition, we demonstrated that costunolide inhibited the growth and induced apoptosis of BGC-823 cells xenografted in athymic nude mice. Costunolide increased the expression of cleaved caspase 9, cleaved caspase 3 and Bax proteins and decreased the expression of Bcl-2 protein in xenografted tumor. Costunolide upregulated the expression of puma and Bax mRNA and decreased the expression of Bcl-2 mRNA in xenografted tumor. CONCLUSIONS: Collectively, our results suggested that costunolide induced mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells and could be the candidate drug against GC in clinical practice.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Animais , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/fisiopatologia
8.
Environ Toxicol ; 34(8): 891-901, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31157515

RESUMO

Nepenthes plants are regarded as a kind of Traditional Chinese Medicine for several diseases but its anticancer activity remain unclear. The subject of this study is to evaluate the antiproliferation effects on oral cancer cells by Nepenthes plants using ethyl acetate extract of Nepenthes adrianii x clipeata (EANA). Cell viability was detected using MTS assay. Its detailed mechanisms including cell cycle, apoptosis, oxidative stress, and DNA damage were explored by flow cytometry or western blotting. For 24 hours EANA treatment, five kinds of oral cancer cells (CAL 27, Ca9-22, OECM-1, HSC-3, and SCC9) show IC50 values of cell viability ranging from 8 to 17 µg/mL but the viability of normal oral cells (HGF-1) remains over 80%. Subsequently, CAL 27 and Ca9-22 cells with high sensitivity to EANA were chosen to investigate the detailed mechanism. EANA displays the time course and concentration effects for inducing apoptosis based on flow cytometry (subG1 and annexin V analyses) and western blotting [cleaved poly (ADP-ribose) polymerase (c-PARP)]. Oxidative stress and DNA damage were induced by EANA treatments in oral cancer cells through reactive oxygen species (ROS), mitochondrial membrane potential disruption, mitochondrial superoxide, and γH2AX. All these changes of EANA treatments in oral cancer cells were reverted by the ROS scavenger N-acetylcysteine pretreatment. Therefore, EANA induces preferential killing, apoptosis, and DNA damage against oral cancer cells through oxidative stress.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Bucais/tratamento farmacológico , Estresse Oxidativo , Traqueófitas , Acetatos , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Bucais/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
Drugs ; 79(11): 1217-1230, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31254268

RESUMO

While the outcomes for patients diagnosed with hormone receptor positive (HR+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast cancers have continued to improve with the development of targeted therapies, the same cannot be said yet for those affected with triple-negative breast cancer (TNBC). Currently, the mainstay of treatment for the 10-15% of patients diagnosed with TNBC remains cytotoxic chemotherapy, but it is hoped that through an enhanced characterization of TNBC biology, this disease will be molecularly delineated into subgroups with targetable oncogenic drivers. This review will focus on recent therapeutic innovations for TNBC, including poly-ADP-ribosyl polymerase (PARP) inhibitors, phosphoinositide 3-kinase (PI3K) pathway inhibitors, immune checkpoint inhibitors, and cyclin-dependent kinase (CDK) inhibitors.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Quinases Ciclina-Dependentes/metabolismo , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo
10.
Am J Vet Res ; 80(7): 663-669, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31246122

RESUMO

OBJECTIVE: To evaluate effects of poly(ADP-ribose) polymerase-1 (PARP1) inhibitors on the production of tumor necrosis factor-α (TNF-α) by interferon-γ (IFN-γ)- and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) of horses as an in vitro model of inflammation in horses. SAMPLE: 1,440 samples of PBMCs from 6 healthy research horses. PROCEDURES: From heparinized whole blood samples, PBMC cultures were obtained. An initial dose-response trial on 48 PBMC samples from 2 horses (24 samples each) was used to determine concentrations of IFN-γ and LPS for use as low- and high-level stimulation concentrations. Seventy-two PBMC samples from 6 horses were assigned equally to 1 of 4 PARP1 inhibition categories: no PARP1 inhibitor (PARP1 inhibition control); 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carbozamide dihydrochloride (ABT888);4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (AZD2281); or N-(6-oxo-5,6-dihydrophenanthridin-2-yl) -N,N-dimethylacetamide hydrochloride (PJ34). Samples of PBMCs from each horse and each PARP1 inhibition category were then assigned to 1 of 3 levels of IFN-γ and LPS stimulation: none (control), low stimulation, or high stimulation. After a 24-hour incubation period, a TNF-α ELISA was used to measure TNF-α concentration in the supernatant. Results were compared across treatments and for each horse. Data were analyzed with repeated-measures ANOVA. RESULTS: Median TNF-α concentration was significantly lower for PJ34-treated, high-level stimulated PBMCs than for PARP1 inhibition control, high-level stimulated PBMCs; however, no other meaningful differences in TNF-α concentration were detected among the inhibition and stimulation combinations. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that PJ34 PARP1 inhibition may reduce TNF-α production in horses, a potential benefit in reducing inflammation and endotoxin-induced damage in horses.


Assuntos
Cavalos/sangue , Interferon gama/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Modelos Animais de Doenças , Doenças dos Cavalos/fisiopatologia , Técnicas In Vitro , Inflamação/fisiopatologia , Leucócitos Mononucleares/enzimologia , Lipopolissacarídeos/farmacologia
11.
Chem Biol Interact ; 307: 167-178, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059704

RESUMO

Polyether compounds, a large group of biologically active metabolites produced by Streptomyces species have been reported to show a variety of bioactivity such as antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Since some of these compounds target cancer stem cells and multi-drug resistant cancer cells, this family of compounds have become of high interest. In this study, three polyether-type metabolites (1-3), one of which was a new natural product (3), were isolated from the marine derived Streptomyces cacaoi via antimicrobial activity-guided fractionation studies. As several polyether compounds with structural similarity such as monensin have been linked with autophagy and cell death, we first assessed the cytotoxicity of these three compounds. Compounds 2 and 3, but not 1, were found to be cytotoxic in several cell lines with a higher potency towards cancer cells. Furthermore, 2 and 3 caused accumulation of both autophagy flux markers LC3-II and p62 along with cleavage of caspase-3, caspase-9 and poly (ADP-ribose) polymerase 1 (PARP-1). Interestingly, prolonged treatment of the compounds caused a dramatic downregulation of the proteins related to autophagasome formation in a dose dependent manner. Our findings provide insights on the molecular mechanisms of the polyether-type polyketides, and signify their potency as chemotherapeutic agents through inhibiting autophagy and inducing apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Produtos Biológicos/farmacologia , Streptomyces/química , Produtos Biológicos/isolamento & purificação , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Conformação Molecular , Poli(ADP-Ribose) Polimerases/metabolismo , Streptomyces/metabolismo
12.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083300

RESUMO

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp-/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp-/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp-/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp-/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp-/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp-/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp-/- mice. Our study reveals that Tiparp-/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.


Assuntos
Ascite Quilosa/induzido quimicamente , Ascite Quilosa/enzimologia , Metilcolantreno/toxicidade , Poli(ADP-Ribose) Polimerases/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Compostos Azo/farmacologia , Ascite Quilosa/patologia , Citocinas/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Knockout , Poli(ADP-Ribose) Polimerases/genética , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Análise de Sobrevida
13.
Eur J Med Chem ; 176: 1-10, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31082759

RESUMO

A class of vanadium complexes were prepared and investigated for their antiproliferative effects by MTT assay. The structure-activity relationship was extensively studied through the ligand variation. The results showed that the synthetic vanadium complexes demonstrated moderate to good antiproliferative activities against the four cancer cell lines including MGC803, EC109, MCF7 and HepG2, respectively. Of note was that most of the complexes showed preferential growth inhibitory activity to some degree toward gastric cancer line MGC803. Among them, complex 19 exhibited the most and broad-spectrum proliferative inhibition against the tested cell lines. In addition, mechanism studies illustrated that complex 19 could prevent the colony formation, migration and EMT process, as well as induce apoptosis of MGC803 cells. Furthermore, Western blot experiments revealed that the expression of apoptosis-related proteins changed, including up-regulation of Bax, PARP and caspase-3/9, as well as down-regulation of Bcl-2.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Vanádio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Regulação para Baixo , Humanos , Estrutura Molecular , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
14.
Cell Mol Life Sci ; 76(17): 3283-3299, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31055645

RESUMO

Poly(ADP-ribosyl)ation (PARylation) is an important post-translational modification in which an ADP-ribose group is transferred to the target protein by poly(ADP-riboses) polymerases (PARPs). Since the discovery of poly-ADP-ribose (PAR) 50 years ago, its roles in cellular processes have been extensively explored. Although research initially focused on the functions of PAR and PARPs in DNA damage detection and repair, our understanding of the roles of PARPs in various nuclear and cytoplasmic processes, particularly in gene expression, has increased significantly. In this review, we discuss the current advances in understanding the roles of PARylation with a particular emphasis in gene expression through RNA biogenesis and processing. In addition to updating PARP's significance in transcriptional regulation, we specifically focus on how PARPs and PARylation affect gene expression, especially inflammation-related genes, at the post-transcriptional levels by modulating RNA processing and degrading. Increasing evidence suggests that PARP inhibition is a promising treatment for inflammation-related diseases besides conventional chemotherapy for cancer.


Assuntos
Poli(ADP-Ribose) Polimerases/genética , RNA/metabolismo , Transporte Ativo do Núcleo Celular , Cromatina/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Poliadenilação , RNA/genética , Processamento de RNA , Proteínas de Ligação a RNA/metabolismo
15.
Mol Med Rep ; 19(6): 5079-5086, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059038

RESUMO

The antitumor effects of SM­164 and adriamycin (ADM) on human osteosarcoma U2­OS cells, the underlying mechanism are yet to be investigated. In the present study, U2­OS cells were divided into control, ADM, SM­164, and ADM + SM­164 groups. In addition, cells treated with both SM­164 and ADM were further divided into three subgroups: SM­164 + ADM, SM­164 + ADM + vector and SM­164 + ADM + X­linked inhibitor of apoptosis protein (XIAP) silencing groups. XIAP expression was achieved via transfection with shRNA lentiviral vectors. Reverse transcription­quantitative polymerase chain reaction and western blotting were used to detect the expression of caspases­7, ­9, and ­3, poly ADP­ribose polymerase (PARP), XIAP, cellular inhibitor of apoptosis protein­1 (cIAP­1) and survivin. Cell viability and apoptosis were evaluated using MTT and flow cytometry assays, respectively. Compared with the control group, cell viability decreased, while apoptosis was increased in the ADM and SM­164­treatment group. ADM and SM­164 treatment promoted the expression of caspases­7, ­9 and ­3, and PARP, but reduced the expression of XIAP, survivin and cIAP­1. Compared with ADM + SM­164 group, XIAP silencing with ADM + SM­164 treatment further reduced cell viability, promoted apoptosis, increased caspase­7, ­9 and ­3, and PARP expression; however the expression of survivin and cIAP­1 were reduced. Combined ADM and SM­164 treatment may be considered as potential therapeutic agent in the treatment of osteosarcoma, possibly via reductions XIAP expression.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Triazóis/farmacologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Survivina/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
16.
Nat Commun ; 10(1): 1686, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975996

RESUMO

Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression. Genomic analyses have identified that the cohesin subunit STAG2 is frequently inactivated by mutations in cancer. However, the reason STAG2 mutations are selected during tumorigenesis and strategies for therapeutically targeting mutant cancer cells are largely unknown. Here we show that STAG2 is essential for DNA replication fork progression, whereby STAG2 inactivation in non-transformed cells leads to replication fork stalling and collapse with disruption of interaction between the cohesin ring and the replication machinery as well as failure to establish SMC3 acetylation. As a consequence, STAG2 mutation confers synthetic lethality with DNA double-strand break repair genes and increased sensitivity to select cytotoxic chemotherapeutic agents and PARP or ATR inhibitors. These studies identify a critical role for STAG2 in replication fork procession and elucidate a potential therapeutic strategy for cohesin-mutant cancers.


Assuntos
Antígenos Nucleares/metabolismo , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Neoplasias/genética , Mutações Sintéticas Letais , Antígenos Nucleares/genética , Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Cromátides/metabolismo , Quebras de DNA de Cadeia Dupla , Replicação do DNA , Ensaios de Seleção de Medicamentos Antitumorais , Técnicas de Inativação de Genes , Humanos , Mutagênese , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , RNA Interferente Pequeno/metabolismo , Reparo de DNA por Recombinação
17.
Int J Mol Sci ; 20(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986964

RESUMO

Poly(ADP-ribosyl)ation is a rapid and transient post-translational protein modification that was described first in mammalian cells. Activated by the sensing of DNA strand breaks, poly(ADP-ribose)polymerase1 (PARP1) transfers ADP-ribose units onto itself and other target proteins using NAD⁺ as a substrate. Subsequently, DNA damage responses and other cellular responses are initiated. In plants, poly(ADP-ribose) polymerases (PARPs) have also been implicated in responses to DNA damage. The Arabidopsis genome contains three canonical PARP genes, the nomenclature of which has been uncoordinated in the past. Albeit assumptions concerning the function and roles of PARP proteins in planta have often been inferred from homology and structural conservation between plant PARPs and their mammalian counterparts, plant-specific roles have become apparent. In particular, PARPs have been linked to stress responses of plants. A negative role under abiotic stress has been inferred from studies in which a genetic or, more commonly, pharmacological inhibition of PARP activity improved the performance of stressed plants; in response to pathogen-associated molecular patterns, a positive role has been suggested. However, reports have been inconsistent, and the effects of PARP inhibitors appear to be more robust than the genetic abolition of PARP gene expression, indicating the presence of alternative targets of those drugs. Collectively, recent evidence suggests a conditionality of stress-related phenotypes of parp mutants and calls for a reconsideration of PARP inhibitor studies on plants. This review critically summarizes our current understanding of poly(ADP-ribosylation) and PARP proteins in plants, highlighting similarities and differences to human PARPs, areas of controversy, and requirements for future studies.


Assuntos
Plantas/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Dano ao DNA , Genoma de Planta , Humanos , Poli Adenosina Difosfato Ribose/metabolismo , Estresse Fisiológico
18.
Med Sci Monit ; 25: 2599-2608, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30964854

RESUMO

BACKGROUND Mantle cell lymphoma (MCL) is a high-grade B-cell lymphoma with poor prognosis. Fludarabine is used alone or in combination for relapsed and advanced-stage MCL. The expression of the signal transducer and activator of transcription 5B (STAT5B) gene is associated with tumorigenesis in solid tumors, but its role in MCL remains unknown. The aims of this study were to investigate the role of STAT5B in GRANTA-519 human mantle cell lymphoma cells and drug resistance. MATERIAL AND METHODS GRANTA-519 human mantle cell lymphoma cells were cultured with and without 10 µM fludarabine dephosphorylated 9-ß-D-arabinofuranosyl-2-fluoroadenine, (2-F-araA) or 10 µM 4-hydroperoxycyclophosphamide (4-HC). The MTT assay assessed cell proliferation. Flow cytometry was used to investigate the cell cycle in MCL cells treated with the specific inhibitor of the Akt pathway, LY294002, and assessed cell cycle and cell apoptosis. Western blot was used to detect the expression levels of p-Akt/Akt and STAT5B/p-STAT5B. The gene expression profiles of lymph node (LN)-derived MCL cells were compared with peripheral blood (PB)-derived lymphocytes using bioinformatics and hierarchical cluster analysis. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to determine the expression of the marker of proliferation Ki-67 (MKI67) gene. RESULTS STAT5B was significantly upregulated in LN-derived MCL cells compared with PB lymphocytes. Increased expression of STAT5B was associated with increased MCL cell proliferation and reduced cell apoptosis and was associated with drug resistance and activation of Akt. CONCLUSIONS STAT5B promoted cell proliferation and drug resistance in human MCL cells by activating the Akt signaling pathway.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT5/genética , Transdução de Sinais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/patologia , Linfócitos/metabolismo , Linfoma de Célula do Manto/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT5/metabolismo
19.
Mol Med Rep ; 19(5): 4019-4026, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942438

RESUMO

The role of ginsenoside in the prevention of cancer has been well established. Ginsenoside Rg5 is one of the main components isolated from red ginseng, which has been demonstrated to have anti­tumor effects by inhibiting cell proliferation and causing DNA damage. However, the role of ginsenoside Rg5 and its molecular mechanisms remain unclear in human esophageal cancer. In the present study, Rg5 was investigated as a novel drug for the chemotherapy of esophageal cancer in in vitro experiments. Esophageal cancer Eca109 cells were exposed to various concentrations of ginsenoside Rg5 (0­32 µΜ) for 24 h. Subsequent cell proliferation assays demonstrated that treatment with ginsenoside Rg5 resulted in the dose­dependent inhibition of proliferation, while a significant increase in apoptotic rate and increased activities of caspase­3, ­8 and ­9 were observed. In addition, the mitochondrial membrane potential was decreased and the cytoplasmic free calcium level increased following treatment with ginsenoside Rg5. Furthermore, the expression of B­cell lymphoma 2 and phosphorylated­protein kinase B (p­Akt) decreased. The specific phosphoinositide­3 kinase (PI3K) inhibitor LY294002 promoted this effect, while insulin­like growth factor­1, a specific PI3K activator, inhibited this action. Taken together, the results suggested that ginsenoside Rg5 may have a tumor­suppressive effect on esophageal cancer by promoting apoptosis and may be associated with the downregulation of the PI3K/Akt signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Ginsenosídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Cálcio/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Cromonas/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
20.
Neurochem Res ; 44(7): 1715-1725, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31011879

RESUMO

This study investigated the efficacy of quercetin (QCT) in combination with sodium butyrate (NaB) in enhancing apoptosis in rat C6 and human T98G glioblastoma cells though blockage of autophagy under nutrient-starvation. The most synergistic doses of the drugs were determined to be 25 µM QCT and 1 mM NaB in both cell lines. After QCT and QCT + NaB treatments, autophagy quantification with acridine orange staining showed a drastic decrease in protective autophagy in the cells under nutrient-starvation. Decrease in autophagy was correlated with decreases in expression of Beclin-1 and LC3B II. Combination treatment increased the morphological signs of apoptosis including membrane blebbing, nuclear fragmentation, and chromatin condensation. Annexin V staining was also performed for detection and quantification of increases in apoptosis. Western blotting results showed that combination of QCT and NaB increased apoptosis by decreasing anti-apoptotic Bcl-2 and increasing pro-apoptotic Bax, decreasing survivin, activating caspase-3, and degrading poly (ADP-ribose) polymerase (PARP). This study demonstrated the therapeutic potentials of a novel combination therapy in inhibiting protective autophagy to enhance apoptosis in rat C6 and human T98G glioblastoma cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Ácido Butírico/farmacologia , Quercetina/farmacologia , Animais , Proteína Beclina-1/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Glioblastoma/patologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína X Associada a bcl-2/metabolismo
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