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1.
Environ Manage ; 64(6): 772-782, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31748948

RESUMO

During the last decade, China's agro-food production has increased rapidly and been accompanied by the challenge of increasing greenhouse gas (GHG) emissions and other environmental pollutants from fertilizers, pesticides, and intensive energy use. Understanding the energy use and environmental impacts of crop production will help identify environmentally damaging hotspots of agro-production, allowing environmental impacts to be assessed and crop management strategies optimized. Conventional farming has been widely employed in wolfberry (Lycium barbarum) cultivation in China, which is an important cash tree crop not only for the rural economy but also from an ecological standpoint. Energy use and global warming potential (GWP) were investigated in a wolfberry production system in the Yellow River irrigated Jingtai region of Gansu. In total, 52 household farms were randomly selected to conduct the investigation using questionnaires. Total energy input and output were 321,800.73 and 166,888.80 MJ ha-1, respectively, in the production system. The highest share of energy inputs was found to be electricity consumption for lifting irrigation water, accounting for 68.52%, followed by chemical fertilizer application (11.37%). Energy use efficiency was 0.52 when considering both fruit and pruned wood. Nonrenewable energy use (88.52%) was far larger than the renewable energy input. The share of GWP of different inputs were 64.52% electricity, 27.72% nitrogen (N) fertilizer, 5.07% phosphate, 2.32% diesel, and 0.37% potassium, respectively. The highest share was related to electricity consumption for irrigation, followed by N fertilizer use. Total GWP in the wolfberry planting system was 26,018.64 kg CO2 eq ha-1 and the share of CO2, N2O, and CH4 were 99.47%, 0.48%, and negligible respectively with CO2 being dominant. Pathways for reducing energy use and GHG emission mitigation include: conversion to low carbon farming to establish a sustainable and cleaner production system with options of raising water use efficiency by adopting a seasonal gradient water pricing system and advanced irrigation techniques; reducing synthetic fertilizer use; and policy support: smallholder farmland transfer (concentration) for scale production, credit (small- and low-interest credit) and tax breaks.


Assuntos
Aquecimento Global , Lycium , Agricultura , Carbono , China , Fertilizantes , Efeito Estufa , Metano , Óxido Nitroso
2.
J Cell Biochem ; 120(11): 18937-18945, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31237019

RESUMO

OBJECTIVES: Current methods for diagnosing lung cancer (LC) have varying degrees of risks and complications. MicroRNA (miRNA) is a small molecule noncoding RNA with gene regulation functions. Many studies have shown that miRNA can be used for the diagnosis of LC, but there are differences in diagnostic accuracy. Therefore, we aim to systematically review and meta-analyze published articles to comprehensively evaluate the diagnostic value of miRNA for LC. MATERIALS AND METHODS: We searched the PubMed, Embase, and Cochrane databases, and calculated the area under the curve (AUC) by plotting the summary receiver operator characteristic curve using the sensitivity and specificity of each included study. The AUC was calculated and the likelihood ratio was plotted to assess the diagnostic accuracy of miRNA. We used QUADAS-2 in Review Manager 5.3 to evaluate the quality of all the articles. The other analyses were performed using the STATA 12.0 software. RESULTS: We included a total of 29 articles, 98 studies, and the qualities of all the articles were satisfactory. The overall pooled parameters calculated from all studies were as follows: sensitivity = 0.77, specificity = 0.83, positive likelihood ratio (PLR) = 4.6, negative likelihood ratio (NLR) = 0.28, and AUC = 0.87 for miRNA diagnosis. It had significant advantages over other biomarkers. Subgroup analysis showed that when combined four or more miRNA for the diagnosis of LC, the parameters were as follows: sensitivity = 0.90, specificity = 0.93, PLR = 13.2, NLR = 0.11, and AUC = 0.97. CONCLUSION: Four or more miRNA combination could be used for the diagnosis of LC. Besides this, we also found that miRNA showed a greater advantage in distinguishing LC from benign lung diseases than distinguishing between LC and normal people. Our findings provided a new way of thinking about the clinical diagnosis of LC from a nonmorphological aspect.

3.
Chem Biodivers ; 15(3): e1700513, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29333734

RESUMO

A series of novel quinazolinone derivatives containing a substituted amino moiety were synthesized, evaluated for their cytotoxic and antibacterial activities. The results of MTT assay showed that all synthesized target compounds 5A - 5O showed potent cytotoxicity against SGC-7901 (IC50 , 0.72 - 1.41 µm). Moreover, the compounds 5D, 5I, and 5K showed better selectivity as compared with positive controls pemetrexed and MTX due to weak cytotoxicity against normal tissue cell line HUVSMC. Among synthesized compounds, the compounds 5E, 5J, 5L, and 5N showed broad-spectrum cytotoxic activities against at least four cancer cell lines at a micromolar level. The results of antibacteria evaluation revealed that all synthesized compounds showed good to moderate antibacterial activities against Gram-negative bacteria Escherichia coli. Among them, the MIC values of the compounds 5C, 5F, and 5M were 0.31 µg/mL.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Quinazolinonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
4.
Chem Biodivers ; 14(2)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27696660

RESUMO

A series of 3-(substituted aroyl)-4-(3,4,5-trimethoxyphenyl)-1H-pyrrole derivatives were synthesized and determined for their anticancer activity against eleven cancer cell lines and two normal tissue cell lines using MTT assay. Among the synthesized compounds, compound 3f was the most potent compound against A375, CT-26, HeLa, MGC80-3, NCI-H460 and SGC-7901 cells (IC50  = 8.2 - 31.7 µm); 3g, 3n and 3a were the most potent compounds against CHO (IC50  = 8.2 µm), HCT-15 (IC50  = 21 µm) and MCF-7 cells (IC50  = 18.7 µm), respectively. Importantly, all the target compounds showed no cytotoxicity towards the normal tissue cell (IC50  > 100 µm). Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Neoplasias/tratamento farmacológico , Pirróis/síntese química , Pirróis/farmacologia , Antineoplásicos/química , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Estrutura Molecular , Neoplasias/patologia , Relação Estrutura-Atividade
5.
Anticancer Agents Med Chem ; 17(6): 821-831, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27671311

RESUMO

BACKGROUND: Cancer is considered a major public health problem worldwide. OBJECTIVE: The aim of this paper is to design and synthesis of novel anticancer agents with potent anticancer activity and minimum side effects. METHOD: A series of pyrrole derivatives were synthesized, their anti-cancer activity against nine cancer cell lines and two non-cancer cell lines were evaluated by MTT assay, and their cell cycle progression were determined by flow cytometry analysis. RESULTS: The study of the structure-activity relationships revealed that the introduction of the electron-donation groups at the 4th position of the pyrrole ring increased the anti-cancer activity. Among the synthesized compounds, specially the compounds bearing 3,4-dimethoxy phenyl at the 4th position of the pyrrole ring showed potent anti-cancer activity, cpd 19 was the most potent against MGC 80-3, HCT-116 and CHO cell lines (IC50s = 1.0-1.7 µM), cpd 21 was the most potent against HepG2, DU145 and CT-26 cell lines (IC50s = 0.5-0.9 µM), and cpd 15 was the most potent against A549 (IC50 = 3.6 µM). Moreover, these potent compounds showed weak cytotoxicity against HUVEC and NIH/3T3. Thus, the cpds 15, 19 and 21 show potential anti-cancer for further investigation. Furthermore, the flow cytometry analysis revealed that cpd 21 arrested the CT-26 cells at S phase, and induced the cell apoptosis. CONCLUSION: Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Animais , Antineoplásicos/química , Células CHO , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Pirróis/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
6.
ACS Med Chem Lett ; 7(3): 324-9, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26985323

RESUMO

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

7.
J Environ Manage ; 157: 303-10, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25925391

RESUMO

The largest global source of anthropogenic CO2 emissions comes from the burning of fossil fuel and approximately 30% of total net emissions come from land use and land use change. Forestation and reforestation are regarded worldwide as effective options of sequestering carbon to mitigate climate change with relatively low costs compared with industrial greenhouse gas (GHG) emission reduction efforts. Cash trees with a steady augmentation in size are recognized as a multiple-beneficial solution to climate change in China. The reporting of C changes and GHG emissions for sustainable land management (SLM) practices such as afforestation is required for a variety of reasons, such as devising land management options and making policy. The Carbon Benefit Project (CBP) Simple Assessment Tool was employed to estimate changes in soil organic carbon (SOC) stocks and GHG emissions for wolfberry (Lycium barbarum L.) planting on secondary salinized land over a 10 year period (2004-2014) in the Jingtai oasis in Gansu with salinized barren land as baseline scenario. Results show that wolfberry plantation, an intensively managed ecosystem, served as a carbon sink with a large potential for climate change mitigation, a restorative practice for saline land and income stream generator for farmers in soil salinized regions in Gansu province. However, an increase in wolfberry production, driven by economic demands, would bring environmental pressures associated with the use of N fertilizer and irrigation. With an understanding of all of the components of an ecosystem and their interconnections using the Drivers-Pressures-State-Impact-Response (DPSIR) framework there comes a need for strategies to respond to them such as capacity building, judicious irrigation and institutional strengthening. Cost benefit analysis (CBA) suggests that wolfberry cultivation was economically profitable and socially beneficial and thus well-accepted locally in the context of carbon sequestration. This study has important implications for Gansu as it helps to understand the role cash trees can play in carbon emission reductions. Such information is necessary in devising management options for sustainable land management (SLM).


Assuntos
Carbono/química , Lycium , Poluentes do Solo/química , Solo/química , Sequestro de Carbono , China , Conservação dos Recursos Naturais/economia , Análise Custo-Benefício , Humanos , Modelos Teóricos
8.
PLoS One ; 9(10): e108371, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25289887

RESUMO

Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias/metabolismo , Compostos de Piridínio/farmacologia , Proteína bcl-X/metabolismo , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Compostos de Epóxi/farmacologia , Feminino , Dosagem de Genes , Humanos , Masculino , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Neoplasias/genética , Fenantrenos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X/genética
9.
ACS Med Chem Lett ; 5(5): 572-5, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900882

RESUMO

Introduction of an aliphatic side chain to a key position of a novel piperidine-based HDM2 inhibitor scaffold resulted in significant potency gains, enabling further series progression.

10.
Bioorg Med Chem Lett ; 24(8): 1983-6, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24656661

RESUMO

The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.


Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Bioensaio , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismo
11.
Bioorg Med Chem Lett ; 24(4): 1026-30, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24486134

RESUMO

Novel small molecule HDM2 inhibitor, substituted piperidine, was identified. Initial SAR study indicated potential for several position optimizations. Additional potency enhancement was achieved by introducing a sidechain off the aromatic ring. DMPK study of one of the active compounds has shown a moderate oral PK and reasonable bioavailability.


Assuntos
Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade
12.
Mol Cancer Ther ; 9(8): 2344-53, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20663931

RESUMO

Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Compostos de Piridínio/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Flavonoides/química , Flavonoides/farmacologia , Humanos , Fosforilação/efeitos dos fármacos , Piperidinas/efeitos adversos , Piperidinas/química , Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/química , Compostos de Piridínio/efeitos adversos , Compostos de Piridínio/química , Proteína do Retinoblastoma/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Mol Cancer Ther ; 9(2): 410-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20124453

RESUMO

The insulin-like growth factor-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) have been implicated in the growth, survival, and metastasis of a broad range of malignancies including pediatric tumors. Blocking the IGF-IR action is a potential cancer treatment. A fully human neutralizing monoclonal antibody, SCH 717454 (19D12, robatumumab), specific to IGF-IR, has shown potent antitumor effects in ovarian cancer in vitro and in vivo. In this study, SCH 717454 was evaluated in several pediatric solid tumors including neuroblastoma, osteosarcoma, and rhabdomyosarcoma. SCH 717454 is shown here to downregulate IGF-IR as well as inhibit IGF-IR and insulin receptor substrate-1 phosphorylation in pediatric tumor cells. IGF-IR and insulin receptor substrate-1 phosphorylation in the tumor cells. In vivo, SCH 717454 exhibits activity as a single agent and significantly inhibited growth of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor xenografts. Combination of SCH 717454 with cisplatin or cyclophosphamide enhanced both the degree and the duration of the in vivo antitumor activity compared with single-agent treatments. Furthermore, SCH 717454 treatment markedly reduced Ki-67 expression and blood vessel formation in tumor xenografts, showing that the in vivo activity is derived from its inhibition of tumor cell proliferation and angiogenesis activity.


Assuntos
Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor IGF Tipo 1/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Fator de Crescimento Insulin-Like I/imunologia , Antígeno Ki-67/biossíntese , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neovascularização Patológica , Fosforilação
14.
ACS Med Chem Lett ; 1(5): 204-8, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900195

RESUMO

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.

16.
J Cell Biochem ; 99(5): 1267-74, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16775842

RESUMO

Centrosome amplification has been proposed to contribute to the development of aneuploidy and genome instability. Here, we show that Ataxia-Telangiectasia Mutated (ATM) is localized to the centrosome and co-purified with gamma-tubulin. The importance of ATM in centrosome duplication is demonstrated in Atm-deficient primary mouse embryonic fibroblasts that display centrosome amplification. Interestingly, centrosome amplification was not observed in tumor cell lines derived from Atm and p21 double deficient mouse. Our results also indicate that both p53 and p21 operate in the same pathway as ATM in regulating centrosome biogenesis. Finally, a potential role of ATM in spindle checkpoint regulation is demonstrated by which ATM protein is activated by mitotic stress. These results suggest a role of ATM in spindle checkpoint regulation and indicate that ATM suppresses genome instability and cellular transformation by regulating centrosome biogenesis.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Centrossomo/metabolismo , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Mitose , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas de Ligação a DNA/genética , Ativação Enzimática , Fibroblastos/citologia , Fibroblastos/fisiologia , Instabilidade Genômica , Camundongos , Camundongos Knockout , Micronúcleos com Defeito Cromossômico , Proteínas Serina-Treonina Quinases/genética , Fuso Acromático/metabolismo , Proteínas Supressoras de Tumor/genética
17.
Carcinogenesis ; 27(4): 848-55, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16400190

RESUMO

Ataxia-telangiectasia (A-T), which is due to mutations in the ATM gene, is a rare autosomal recessive genomic instability syndrome characterized by radiosensitivity and predisposition to cancer. Epidemiological studies have suggested that relatives of A-T patients (A-T carriers) have increased risks of developing breast cancer. We propose that increased breast cancer risks in A-T carriers may be due to exposure to various environmental carcinogens and/or dietary consumption. To test this hypothesis, we treated a congenic strain of Atm+/- mice with DMBA (7,12-dimethylbenz(alpha)anthracene), a mammary carcinogen, and observed mammary tumor incidence. It was found that Atm+/- mice have a 2-fold increase, as well as early onset, in mammary tumor incidence relative to wild-type mice (P<0.005). The increased mammary tumor development is correlated with a 3-fold increase in the development of mammary dysplasia in Atm+/- compared with wild-type mice (P<0.05). We also found that Ras signaling pathway was not activated in DMBA-induced mammary tumors irrespective of the Atm status. At the cellular level, Atm-haploinsufficiency confers increased cellular stress manifested by an increased p53 expression and a slightly enhanced survival of mammary epithelial cells in response to radiation. Our results demonstrate that Atm heterozygotes are predisposed to mammary tumor development and support the hypothesis that exposure to environmental carcinogens contributes to the increased rate of breast cancer development in A-T carriers. Given that 1% of the general population are ATM heterozygotes (A-T carriers), this study has great implications in breast cancer development in this population.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/prevenção & controle , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , 9,10-Dimetil-1,2-benzantraceno/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Carcinógenos/farmacologia , Poluentes Ambientais/farmacologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Camundongos , Fatores de Risco , Transdução de Sinais , Análise de Sobrevida
18.
Mol Carcinog ; 44(4): 252-61, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16273555

RESUMO

Acute promyelocytic leukemia (APL) is invariably associated with chromosomal translocation to retinoic acid receptor alpha (RARalpha) locus. In a vast majority of cases, RARalpha translocates to and fuses with the promyelocytic leukemia (PML) gene. It was thought that the fusion protein PML-RARalpha acts as a double dominant negative mutant to inhibit the PML and RARalpha signaling. In an attempt to study the physiological role of retinoic acid in mammary gland development, we created a transgenic model system expressing a dominant negative RARalpha under the regulation of murine mammary tumor viral promoter. We found that the transgene was also targeted to the lymphoid system in addition to mammary gland. Here we showed that dominant negative RARalpha induced acute lymphoblastic leukemia and lymphoma development in the transgenic mice. Retinoic acid blocked tumor development ex vivo through induction of apoptosis. Thus, our results suggested that disruption of RARalpha signaling was the first essential step in the development of APL in vivo.


Assuntos
Regulação da Expressão Gênica/fisiologia , Genes Dominantes , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Receptores do Ácido Retinoico/genética , Doença Aguda , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Masculino , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Transgênicos , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Taxa de Sobrevida , Tretinoína/farmacologia , Células Tumorais Cultivadas
19.
Dev Dyn ; 234(4): 892-9, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16217742

RESUMO

Retinoic acid (RA), a bioactive chemical compound synthesized from dietary derived vitamin A, has been successfully used as a chemopreventive and chemotherapeutic agent through the regulation of cell proliferation, differentiation, and apoptosis acting via the retinoic acid receptors. Despite two decades of research on the function of retinoic acid, the physiological role of RA in mammary gland development is still not well characterized. In this report, we demonstrate that RA is required for proper morphogenesis of mouse mammary gland in a novel transgenic mouse model system. It was found that inhibition of RA signaling in vivo leads to excessive mammary ductal morphogenesis through upregulation of cyclin D1 and MMP-3 expression. Furthermore, we show that the transgene-induced excessive branching morphogenesis could be reversed by treatment with RA, demonstrating the direct physiological effect of RA signaling in vivo. In addition, we demonstrate that excessive branching morphogenesis in the transgenic mammary gland are cell-autonomous and do not require stromal signals within the transgenic mammary gland. Finally, we provide evidence suggesting that retinoic acid signaling is required for appropriate mammary gland differentiation. Collectively, our data indicate for the first time that retinoic acid signaling is required to maintain the homeostasis of mammary gland morphogenesis.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Glândulas Mamárias Animais/embriologia , Morfogênese/fisiologia , Transdução de Sinais/fisiologia , Tretinoína/metabolismo , Animais , Proliferação de Células , Ciclina D1/metabolismo , Imuno-Histoquímica , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Morfogênese/efeitos dos fármacos , Receptores do Ácido Retinoico/metabolismo , Tretinoína/farmacologia , Tretinoína/fisiologia
20.
Cancer Res ; 65(19): 8747-53, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16204044

RESUMO

The DNA damage checkpoint protein kinase mutated in ataxia telangiectasia (ATM) is involved in sensing and transducing DNA damage signals by phosphorylating and activating downstream target proteins that are implicated in the regulation of cell cycle progression and DNA repair. Atm-/- cells are defective in cellular proliferation mediated by the Arf/p53/p21 pathway. In this report, we show that increased expression of p21 (also known as Waf1 or CDKN1a) in Atm-/- cells serves as a cellular defense mechanism to suppress further chromosomal instability (CIN) and tumor development because Atm-/- p21-/- mice are predisposed to carcinomas and sarcomas with intratumoral heterogeneity. It was found that Atm-deficient cells are defective in metaphase-anaphase transition leading to abnormal karyokinesis. Moreover, Atm-/- p21-/- primary embryonic fibroblasts exhibit increased CIN compared with either Atm-/- or p21-/- cells. The increased CIN is manifested at the cellular level by increased chromatid breaks and elevated aneuploid genome in Atm-/- p21-/- cells. Finally, we showed that the role of p21 in a CIN background induced by loss of Atm is to suppress numerical CIN but not structural CIN. Our data suggest that the development of aneuploidy precedes tumor formation and implicates p21 as a major tumor suppressor in a genome instability background.


Assuntos
Aneuploidia , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteínas de Ligação a DNA/genética , Neoplasias Experimentais/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Transformação Celular Neoplásica/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Proteínas de Ligação a DNA/deficiência , Feminino , Genes Supressores de Tumor , Cariotipagem , Masculino , Camundongos , Camundongos Knockout , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Supressoras de Tumor/deficiência
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