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1.
Carcinogenesis ; 36 Suppl 1: S160-83, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26106136

RESUMO

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.


Assuntos
Exposição Ambiental/efeitos adversos , Substâncias Perigosas/efeitos adversos , Microambiente Tumoral/efeitos dos fármacos , Animais , Carcinogênese/induzido quimicamente , Humanos , Neoplasias/induzido quimicamente
2.
Carcinogenesis ; 36 Suppl 1: S254-96, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26106142

RESUMO

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.


Assuntos
Carcinogênese/induzido quimicamente , Carcinógenos Ambientais/efeitos adversos , Exposição Ambiental/efeitos adversos , Substâncias Perigosas/efeitos adversos , Neoplasias/induzido quimicamente , Neoplasias/etiologia , Animais , Humanos
3.
PLoS One ; 7(7): e40926, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22815870

RESUMO

A novel role of the dihydroorotatedehydrogenase (DHODH) inhibitor leflunomide as a potential anti-melanoma therapy was recently reported (Nature 471:518-22, 2011). We previously reported that leflunomide strongly activates the transcriptional activity of the Aryl Hydrocarbon Receptor (AhR). We therefore tested whether the AhR regulates the anti-proliferative effects of leflunomide in melanoma. We first evaluated the expression of AhR in melanoma cells and found that AhR is highly expressed in A375 melanoma as well as in several other cancer cell types. To evaluate whether AhR plays a role in regulating the growth inhibitory effects of leflunomide in A375 cells, we generated a stable cell line from parental A375 cells expressing a doxycycline (DOX) inducible AhR shRNA. Using these cells in the absence or presence of DOX (normal AhR levels or AhR-knockdown, respectively) we found that the anti-proliferative effects of leflunomide, but not its metabolite A771726, were strongly dependent upon AhR expression. It has been well established that supplementation of cells with exogenous uridine completely rescues the anti-proliferative effects due to DHODH inhibition. Thus, we performed uridine rescue experiments in A375 cells to determine whether the anti-proliferative effects of leflunomide are solely due to DHODH inhibition as previously reported. Interestingly, saturating levels of uridine only modestly rescued A375 cells from the anti-proliferative effects of both leflunomide and A771726, indicating additional mechanism(s), apart from DHODH inhibition are responsible for the anti-proliferative effects of leflunomide in melanoma cells. Uridine also did not rescue MDA-MB-435S melanoma cell proliferation after leflunomide treatment. Our results reveal that the AhR is a molecular target of leflunomide and support the feasibility of the clinical application of leflunomide for treating melanoma. Furthermore, analysis of expression data from 967 cancer cell lines revealed that AhR is expressed in multiple different cancer types supporting the intriguing possibility of targeting the AhR for therapy in a number of cancers.


Assuntos
Isoxazóis/farmacologia , Melanoma/metabolismo , Melanoma/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Compostos de Anilina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crotonatos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Di-Hidro-Orotato Desidrogenase , Fluoresceínas/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Hidroxibutiratos/farmacologia , Leflunomida , Nitrilas , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Succinimidas/metabolismo , Toluidinas , Uridina/farmacologia
4.
Toxicol Sci ; 120(1): 42-58, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21163906

RESUMO

The objectives of this study were to determine the structural characteristics of perfluoroalkyl acids (PFAAs) that confer estrogen-like activity in vivo using juvenile rainbow trout (Oncorhynchus mykiss) as an animal model and to determine whether these chemicals interact directly with the estrogen receptor (ER) using in vitro and in silico species comparison approaches. Perfluorooctanoic (PFOA), perfluorononanoic (PFNA), perfluorodecanoic (PFDA), and perfluoroundecanoic (PFUnDA) acids were all potent inducers of the estrogen-responsive biomarker protein vitellogenin (Vtg) in vivo, although at fairly high dietary exposures. A structure-activity relationship for PFAAs was observed, where eight to ten fluorinated carbons and a carboxylic acid end group were optimal for maximal Vtg induction. These in vivo findings were corroborated by in vitro mechanistic assays for trout and human ER. All PFAAs tested weakly bound to trout liver ER with half maximal inhibitory concentration (IC(50)) values of 15.2-289 µM. Additionally, PFOA, PFNA, PFDA, PFUnDA, and perlfuorooctane sulfonate (PFOS) significantly enhanced human ERα-dependent transcriptional activation at concentrations ranging from 10-1000 nM. Finally, we employed an in silico computational model based upon the crystal structure for the human ERα ligand-binding domain complexed with E2 to structurally investigate binding of these putative ligands to human, mouse, and trout ERα. PFOA, PFNA, PFDA, and PFOS all efficiently docked with ERα from different species and formed a hydrogen bond at residue Arg394/398/407 (human/mouse/trout) in a manner similar to the environmental estrogens bisphenol A and nonylphenol. Overall, these data support the contention that several PFAAs are weak environmental xenoestrogens of potential concern.


Assuntos
Ácidos Acíclicos/toxicidade , Poluentes Ambientais/toxicidade , Estrogênios não Esteroides/toxicidade , Fluorocarbonos/toxicidade , Oncorhynchus mykiss/metabolismo , Receptores de Estrogênio/metabolismo , Ácidos Acíclicos/química , Animais , Ligação Competitiva , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Poluentes Ambientais/química , Ensaio de Imunoadsorção Enzimática , Receptor alfa de Estrogênio/metabolismo , Estrogênios não Esteroides/química , Fluorocarbonos/química , Humanos , Fígado/metabolismo , Estrutura Molecular , Ligação Proteica , Especificidade da Espécie , Relação Estrutura-Atividade , Vitelogeninas/sangue
5.
PLoS One ; 5(10)2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20957046

RESUMO

BACKGROUND: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity and biological activity of dioxins and related chemicals. The AhR influences a variety of processes involved in cellular growth and differentiation, and recent studies have suggested that the AhR is a potential target for immune-mediated diseases. METHODOLOGY/PRINCIPAL FINDINGS: During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory drug presently used in the clinic for the treatment of rheumatoid arthritis, was identified as an AhR agonist. We aimed to determine whether any biological activity of leflunomide could be attributed to a previously unappreciated interaction with the AhR. The currently established mechanism of action of leflunomide involves its metabolism to A771726, possibly by cytochrome P450 enzymes, followed by inhibition of de novo pyrimidine biosynthesis by A771726. Our results demonstrate that leflunomide, but not its metabolite A771726, caused nuclear translocation of AhR into the nucleus and increased expression of AhR-responsive reporter genes and endogenous AhR target genes in an AhR-dependent manner. In silico Molecular Docking studies employing AhR ligand binding domain revealed favorable binding energy for leflunomide, but not for A771726. Further, leflunomide, but not A771726, inhibited in vivo epimorphic regeneration in a zebrafish model of tissue regeneration in an AhR-dependent manner. However, suppression of lymphocyte proliferation by leflunomide or A771726 was not dependent on AhR. CONCLUSIONS: These data reveal that leflunomide, an anti-inflammatory drug, is an agonist of the AhR. Our findings link AhR activation by leflunomide to inhibition of fin regeneration in zebrafish. Identification of alternative AhR agonists is a critical step in evaluating the AhR as a therapeutic target for the treatment of immune disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Isoxazóis/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Animais , Sequência de Bases , Linhagem Celular , Citocromo P-450 CYP1A2/metabolismo , Primers do DNA , Imunofluorescência , Genes Reporter , Leflunomida , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Regeneração , Peixe-Zebra/genética , Peixe-Zebra/fisiologia
6.
J Med Chem ; 52(18): 5635-41, 2009 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-19719119

RESUMO

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor; the AhR Per-AhR/Arnt-Sim (PAS) domain binds ligands. We developed homology models of the AhR PAS domain to characterize previously observed intra- and interspecies differences in ligand binding using molecular docking. In silico structure-based virtual ligand screening using our model resulted in the identification of pinocembrin and 5-hydroxy-7-methoxyflavone, which promoted nuclear translocation and transcriptional activation of AhR and AhR-dependent induction of endogenous target genes.


Assuntos
Modelos Moleculares , Receptores de Hidrocarboneto Arílico/química , Receptores de Hidrocarboneto Arílico/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Camundongos , Dados de Sequência Molecular , Filogenia , Conformação Proteica , Estrutura Terciária de Proteína , Transporte Proteico , Receptores de Hidrocarboneto Arílico/genética , Ativação Transcricional/efeitos dos fármacos , Interface Usuário-Computador
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