RESUMO
Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
Assuntos
Senescência Celular , Metilação de DNA , Epigênese Genética , Fibroblastos/enzimologia , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Interleucina-1alfa/metabolismo , 9,10-Dimetil-1,2-benzantraceno , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Feminino , Células HEK293 , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Humanos , Interleucina-1alfa/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Microscopia de Fluorescência , Papiloma/induzido quimicamente , Papiloma/genética , Papiloma/metabolismo , Papiloma/patologia , Fenótipo , Via Secretória , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Acetato de TetradecanoilforbolRESUMO
Fibropapillomatosis (FP) poses a significant threat to the conservation of green sea turtles (Chelonia mydas). Polycyclic aromatic hydrocarbons-PAHs are considered mutagenic, carcinogenic and toxic, and can act as cofactor of this disease. In order to evaluate possible differences between green sea turtles with and without FP, we monitored 15 PAHs in liver samples of 44 specimens (24 with FP) captured in Brazil. We detected eight PAHs and quantified phenanthrene in all green sea turtles with FP. Specimens without FP presented lower values than the tumored ones (1.48â¯ngâ¯g-1 and 17.35â¯ngâ¯g-1, respectively; pâ¯<â¯0.0001). There were no significant differences between tumored and non-tumored specimens, among studied areas, or Southwest Atlantic Fibropapillomatosis Score. Even though we found higher concentrations in the liver samples of green sea turtles with FP, further studies are necessary to confirm if these pollutants are involved in the pathogenesis of the disease.
Assuntos
Fígado/química , Papiloma/veterinária , Hidrocarbonetos Policíclicos Aromáticos/análise , Tartarugas , Animais , Brasil , Estudos de Casos e Controles , Papiloma/induzido quimicamente , Fenantrenos/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidadeRESUMO
Chronic inflammation affects most stages of tumorigenesis, including initiation, promotion, malignant differentiation, invasion and metastasis. Inflammasomes have been described as involved with persistent inflammation and are known to exert both pro and antitumour effects. We evaluated the influence of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase (CASP)-1 in the antitumor immune response using a multistage model of squamous cell carcinoma (SCC) development. Absence of ASC and CASP-1 resulted in an earlier incidence and increased number of papilloma. Loss of inflammassome function in mice resulted in decreased presence of natural killer (NK), dendritic (DC), CD4(+), CD8(+) and CD45RB(+) T cells in the tumor lesions as well as in lymph nodes (LN) compared with WT mice. Increased percentage of CD4(+)CD25(+)Foxp3(+) T cells was associated with association with inflammasome loss of function. Moreover, significant differences were also found with neutrophils and macrophage infiltrating the lesions. Myeloperoxidase (MPO), but not elastase (ELA), activity oscillated among the groups during the SCC development. Levels of proinflammatory cytokines IL-1ß, IL-18, Tumor Necrosis Factor (TNF)-α and Interferon (IFN)-γ were decreased in the tumor microenvironment in the absence of inflammasome proteins. These observations suggest a link between inflammasome function and SCC tumorigenesis, indicating an important role for inflammasome activation in the control of SCC development.
Assuntos
Carcinoma de Células Escamosas/imunologia , Inflamassomos/fisiologia , Papiloma/imunologia , Neoplasias Cutâneas/imunologia , 9,10-Dimetil-1,2-benzantraceno , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Feminino , Linfonodos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Papiloma/induzido quimicamenteRESUMO
Euphorbia milii (Euphorbiaceae) is a decorative plant used in gardens and living fences. In China, it has also been employed in herbal remedies for hepatitis and abdominal edema. Since E. milii latex--lyophilized or in natura--proved to be a potent plant molluscicide, its toxicity to non-target organisms has been comprehensively studied. Concerns on a possible tumor promoting activity have discouraged its use as a locally-available alternative molluscicide in schistosomiasis control programs. Two in vitro assays (inhibition of metabolic cooperation in V79 cells and Epstein-Barr virus induction in Raji cells) had suggested that E. milii latex contained tumor-promoting substances. This study was undertaken to verify whether the latex acts as a tumor promoter in vivo as well. A single dose of the initiating agent DMBA (400 nmol) was applied on the back skin of male and female DBA/2 mice. Testing for tumor promoting activity began 10 days after initiation. Tetradecanoyl phorbol acetate (TPA) (5 nmol, positive control), lyophilized latex (20, 60 and 200 microg per mouse) or acetone (vehicle control) were applied on mouse back skin twice a week for 20 weeks. In TPA-treated mice, papillomas were firstly noted during the 11th week, and by the 17th week all animals exhibited skin tumors. No tumors developed in mice treated with the solvent alone and in those exposed to latex. Findings from the present study therefore indicated that E. milii crude latex does not act as a tumor promoting agent on the mouse back skin assay.
Assuntos
Carcinógenos , Cocarcinogênese , Euphorbia , Látex/toxicidade , Papiloma/induzido quimicamente , Neoplasias Cutâneas/induzido quimicamente , 9,10-Dimetil-1,2-benzantraceno , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Acetato de TetradecanoilforbolRESUMO
Gallic acid (1) and methyl gallate (2) were isolated from Juca, a Brazilian folk medicine, fruits of Caesalpinia ferrea MART (Leguminosae), decreased significantly the average number of papillomas per mouse in the experiment of the promoting effects of 12-O-tetra- decanoylphorbol-13-acetate (TPA) on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA).
Assuntos
Anticarcinógenos/farmacologia , Caesalpinia/química , Ácido Gálico/análogos & derivados , Medicina Tradicional , Extratos Vegetais/farmacologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/prevenção & controle , 9,10-Dimetil-1,2-benzantraceno/farmacologia , Animais , Anticarcinógenos/química , Brasil/etnologia , Feminino , Frutas/química , Ácido Gálico/isolamento & purificação , Ácido Gálico/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Papiloma/induzido quimicamente , Papiloma/prevenção & controle , Fitoterapia , Extratos Vegetais/química , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
The modulating effect of As (As2O3) in drinking water plus dietary fatty acids on benzo-a-pyrene (BP) induced forestomach tumorigenesis was assayed in mice fed with corn oil (CO), Olein (O), palmstearin (PS) and cod liver oil (CLO) enriched formulae, and a mixed-fat (S-stock) diet during 28 weeks. Neither pre-or neoplastic lesions were recorded in esophagus or forestomach of mice treated with As alone. CLO diet showed a protective effect. Indeed, multiple epidermal hyperplasia were significantly reduced compared to S group and a reduction in papillomas multiplicity with respect to S, CO and O groups was also observed. Mice fed on PS formula showed minor papillomas per mouse with respect to CO and O. These results indicate that As plus BP did not exhibit any synergistic effect on the development of epidermoid tumor lesions, whereas CLO diet exerted antipromoting activity . In spite of their common essential fatty acid deficiency (EFAD) condition, PS and O lots showed contradictory results. Hence, the dietary enrichment in 18:1 n-9 (O diet) per se, and not the EFAD state, may play a deleterious role. Corn diet showed no promoting activity on the epidermoid tumor development in this model.
Assuntos
Arsênio/toxicidade , Benzo(a)pireno/toxicidade , Carcinógenos/toxicidade , Gorduras na Dieta/metabolismo , Neoplasias Gástricas/induzido quimicamente , Animais , Arsênio/farmacocinética , Benzo(a)pireno/farmacocinética , Carcinógenos/farmacocinética , Modelos Animais de Doenças , Interações Medicamentosas , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/patologia , Ácidos Graxos/metabolismo , Feminino , Hiperplasia , Masculino , Camundongos , Papiloma/induzido quimicamente , Papiloma/patologia , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologiaRESUMO
Chemical investigation on polyphenol-rich fractions of Cowania mexicana and Coleogyne ramosissima (Rosaceae) which showed significant inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), has led to the characterization of 10 compounds including C-glucosidic ellagitannin monomers and dimers from the former plant, and 17 polyphenols including flavonoid glycosides from the latter. The effects of individual components and their analogues with related structures on the TPA-induced EBV-EA activation were then evaluated. Among the compounds isolated from C. mexicana, two C-glucosidic ellagitannins, alienanin B and stenophyllanin A and a nitrile glucoside (lithospermoside), and among the constituents from C. ramosissima, two flavonoid glycosides, isorhamnetin 3-0-beta-D-glucoside and narcissin were revealed to possess strong inhibitory effects on EVB-EA activation, the potencies of which were either comparable to or stronger than that of a green tea polyphenol, (-)-epigallocatechin gallate. These polyphenols except for nitrile glucoside, which was not tested owing to an insufficient amount, were also found to exhibit anti-tumor promoting activity in two-stage mouse skin carcinogenesis using 7,12-dimethylbenz[a]anthracene (DMBA) and TPA.
Assuntos
Antineoplásicos/farmacologia , Flavonoides , Papiloma/tratamento farmacológico , Fenóis/farmacologia , Polímeros/farmacologia , Rosales/química , Neoplasias Cutâneas/tratamento farmacológico , Ativação Viral/efeitos dos fármacos , 9,10-Dimetil-1,2-benzantraceno , Animais , Antígenos Virais/efeitos dos fármacos , Antineoplásicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/crescimento & desenvolvimento , Humanos , Camundongos , Camundongos Endogâmicos ICR , Papiloma/induzido quimicamente , Fenóis/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Plantas Medicinais , Polímeros/isolamento & purificação , Polifenóis , Neoplasias Cutâneas/induzido quimicamente , Organismos Livres de Patógenos Específicos , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol , Células Tumorais CultivadasRESUMO
The different potential of initiated and non-initiated urinary bladder mucosa (UBM) to develop neoplasia was quantitatively evaluated in the male Wistar rat. Initiation of carcinogenesis was accomplished with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Stimuli for cell proliferation and apoptosis were obtained by exposure followed by withdrawal of 3% Uracil in the diet. The proliferation index (PI) was estimated in UBM immunostained for the proliferating nuclear cell antigen (PCNA). The apoptotic index (AI) and the density of papillary/nodular hyperplasia (PNH) were estimated in hematoxilin-eosin stained sections. PNH was the main proliferative response to the mechanical irritation by uracil, irrespective of previous initiation with BBN. Uracil exposure induced higher PI and PNH density in the initiated rats. After uracil withdrawal, there was a significant increase of the AI in both uracil-treated groups, which correlated well to the respective PNH density. However, at the end of the experiment, PNH incidence and density were significantly higher in the BBN-initiated mucosa, which also presented 18% incidence of papillomas and 27% of carcinomas. Therefore, under prolonged uracil calculi trauma, the UBM of BBN-initiated Wistar rats gives rise to epithelial proliferative lesions that progress to neoplasia through acquired resistance to apoptosis.
Assuntos
Butilidroxibutilnitrosamina/toxicidade , Carcinógenos/toxicidade , Papiloma/patologia , Uracila/toxicidade , Cálculos da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Animais , Apoptose , Divisão Celular/efeitos dos fármacos , Hiperplasia , Masculino , Mucosa/efeitos dos fármacos , Mucosa/patologia , Papiloma/induzido quimicamente , Antígeno Nuclear de Célula em Proliferação/análise , Ratos , Ratos Wistar , Bexiga Urinária/efeitos dos fármacos , Cálculos da Bexiga Urinária/induzido quimicamente , Cálculos da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/induzido quimicamenteRESUMO
The modulating effect of dietary polyunsaturated fatty acids (PUFAs) on benzo(a)pyrene-induced forestomach tumorigenesis was assayed in mice fed with corn oil (CO), olein (O), Zizyphus mistol seed oil (MO), cod liver oil (CLO), and mixed fat (Stock diet). The fatty acid composition of liver lipids correlated well with the fatty acid composition of each diet. Only mice fed the O diet showed biochemical and clinical evidences of essential fatty acid deficiency (EFAD). Only 3 animals developed well-differentiated invading squamous cell carcinomas in the O group. The papilloma incidence was reduced in MO and CLO with respect to the O group. Forestomach papillomatosis was increased in mice fed an n-9 enriched diet in comparison to stock and CO groups. In comparison with stock mice, the frequency of multiple epidermoidal hyperplasia (MEH) was significantly decreased in the CLO group. Animals fed n-3 enriched diets (MO and CLO) showed significant antipromoting effect. These findings indicate that dietary fat can modulate tumorigenesis initiated in mouse forestomach by benzo(a)pyrene. In addition, the lack of action of an n-6 fatty acid-enriched diet in our experimental model suggests that the effect of PUFAs on tumorigenesis has target-tissue specificity. Mistol seed oil might be of potential value as a natural vegetable antipromoter nutrient.
Assuntos
Anticarcinógenos/uso terapêutico , Benzo(a)pireno , Carcinoma de Células Escamosas/prevenção & controle , Óleo de Fígado de Bacalhau/uso terapêutico , Gorduras na Dieta/uso terapêutico , Ácidos Graxos Insaturados/uso terapêutico , Papiloma/prevenção & controle , Óleos de Plantas/uso terapêutico , Lesões Pré-Cancerosas/prevenção & controle , Gastropatias/prevenção & controle , Neoplasias Gástricas/prevenção & controle , Animais , Anticarcinógenos/administração & dosagem , Carcinoma de Células Escamosas/induzido quimicamente , Óleo de Fígado de Bacalhau/administração & dosagem , Óleo de Milho/administração & dosagem , Óleo de Milho/uso terapêutico , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/toxicidade , Ácidos Graxos/análise , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Graxos Insaturados/administração & dosagem , Hiperplasia , Fígado/química , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Óleo de Palmeira , Papiloma/induzido quimicamente , Óleos de Plantas/administração & dosagem , Óleos de Plantas/toxicidade , Lesões Pré-Cancerosas/induzido quimicamente , Antro Pilórico/patologia , Gastropatias/induzido quimicamente , Neoplasias Gástricas/induzido quimicamenteRESUMO
Conventional studies on bracken fern (Pteridium aquilinum; PA) carcinogenicity have used high dietary concentrations (around 30%) and long-term exposure (up to 52-70 weeks) without consideration of the multistep character of the chemical carcinogenesis process. The present study evaluated specifically the promoting potential of 3-5% dietary crude PA in the rat urinary bladder mucosa in a 32-week-long initiation-promotion assay for chemical carcinogenesis. Initiation of urothelial carcinogenesis was accomplished with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Uracil (U) was provided through the diet in order to expand the population of initiated cells. Seven groups (G) of male Wistar rats were submitted to the following treatments: G1 = BBN (n = 8); G2 = U (n = 10); G3 = BBN-U (n = 9); G4 = BBN-PA-U-PA (n = 16); G5 = PA (n = 8); G6 = BBN-PA (n = 10); G7 = PA-U-PA (n = 12). At the end of the experiment rats presenting epithelial papillary or nodular hyperplasia (PNH), papillomas (PAP), or simultaneous PNH plus PAP numbered, respectively G1: 2-0-1; G2: 0-0-0; G3: 3-0-2; G4: 4-3-2; G5: 1-0-1; G6: 8-0-0; and G7: 0-0-0, with no significant differences in the incidence of lesions among the groups. More frequent and more severe lesions occurred in BBN-initiated animals, predominantly in those also exposed to uracil (G3 and G4). Low-dose crude bracken fern in the diet does not promote rat urinary bladder carcinogenesis after a 32-week period of exposure, even when the initiated urothelial cell population has been expanded through a mechanical stimulus.
Assuntos
Butilidroxibutilnitrosamina/toxicidade , Carcinógenos/toxicidade , Plantas Tóxicas , Uracila/toxicidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Animais , Masculino , Papiloma/induzido quimicamente , Ratos , Ratos WistarRESUMO
The ability of a biomimetic superoxide dismutase agent, copper(II)(3,5-diisopropylsalicylate)2 (CuDIPS), to modulate benzoyl peroxide (BzPo)-induced tumor promotion and progression in mouse skin multistage carcinogenesis was evaluated. The results showed a significant inhibition of tumor incidence by CuDIPS pretreatment during promotion-progression. Different types of tumors were developed: papillomas, keratoacanthomas and squamous cell carcinomas. There was a significant increase in the keratoacanthoma-papilloma ratio when the period of treatment with BzPo was prolonged, which was inhibited by CuDIPS pretreatment. CuDIPS induced a significant inhibition of malignant conversion. Our results suggest that reactive oxygen species could be important in BzPo-induced promotion and progression.