Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.521
Filtrar
1.
Nat Commun ; 11(1): 4931, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004795

RESUMO

Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics.


Assuntos
Antígenos de Neoplasias/ultraestrutura , Proteínas de Neoplasias/ultraestrutura , Neoplasias/tratamento farmacológico , Ubiquitina-Proteína Ligases/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Motivos de Aminoácidos , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Mutagênese , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Estudo de Prova de Conceito , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Domínios Proteicos/genética , Mapeamento de Interação de Proteínas , Relação Estrutura-Atividade , Especificidade por Substrato/efeitos dos fármacos , Especificidade por Substrato/genética , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genética
2.
Nat Commun ; 11(1): 3819, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732875

RESUMO

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.


Assuntos
Neoplasias da Mama/terapia , Imunoterapia/métodos , Niacinamida/administração & dosagem , Receptor ErbB-2/imunologia , 9,10-Dimetil-1,2-benzantraceno , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Progressão da Doença , Feminino , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/prevenção & controle , Acetato de Medroxiprogesterona , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor ErbB-2/metabolismo , Análise de Sobrevida
3.
Life Sci ; 258: 118186, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768586

RESUMO

Antioxidants are essential in preventing the formation and suppressing the activities of reactive nitrogen and oxygen species. The aim of this study was to review the role of antioxidants in cancer development or prevention. Antioxidants are believed to prevent and treat various types of malignancies. Currently, natural antioxidant compounds have been generally consumed to prevent and treat cancers. Certainly, phenolic compounds extracted from medicinal plants have opened a new prospect with respect to the prevention and treatment of cancers due to having antioxidant characteristics. However, some recently published studies have revealed that antioxidant compounds do not indicate absolute anti-tumor properties. Some antioxidants are helpful in cancer initiation and progression. Taken together, antioxidants demonstrate a two-faced nature toward cancer. However, it is required to conduct further cell culture and in vivo studies to confirm the exact role of antioxidants and then use them for efficient cancer treatments.


Assuntos
Antioxidantes/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Metástase Neoplásica , Neoplasias/patologia
4.
Int J Nanomedicine ; 15: 4063-4078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606664

RESUMO

Background: Among various theories for the origin of cancer, the "stemness phenotype model" suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-ßcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-ßcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs. Materials and Methods: We prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-ßcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay. Results: We found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction. Conclusion: Our study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.


Assuntos
Neoplasias da Mama/patologia , Carcinogênese/patologia , Ouro/química , Nanopartículas Metálicas/química , Células-Tronco Neoplásicas/patologia , Coroa de Proteína/química , Vorinostat/farmacologia , Proteínas Wnt/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Células MCF-7 , Nanosferas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Espectrofotometria Ultravioleta , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
5.
Toxicol Appl Pharmacol ; 401: 115109, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544403

RESUMO

Bladder cancer (BCa) is the fourth leading cause of cancer deaths worldwide due to its aggressiveness and resistance against therapies. Intricate interactions between cancer cells and the tumor microenvironment (TME) are essential for both disease progression and regression. Thus, interrupting molecular communications within the TME could potentially provide improved therapeutic efficacies. M2-polarized tumor-associated macrophages (M2 TAMs) were shown to contribute to BCa progression and drug resistance. We attempted to provide evidence for ovatodiolide (OV) as a potential therapeutic agent that targets both TME and BCa cells. First, tumor-suppressing functions of OV were determined by cell viability, colony, and tumor-sphere formation assays using a coculture system composed of M2 TAMs/BCa cells. Subsequently, we demonstrated that extracellular vesicles (EVs) isolated from M2 TAMs containing oncomiR-21 and mRNAs, including Akt, STAT3, mTOR, and ß-catenin, promoted cisplatin (CDDP) resistance, migration, and tumor-sphere generation in BCa cells, through increasing CDK6, mTOR, STAT3, and ß-catenin expression. OV treatment also prevented M2 polarization and reduced EV cargos from M2 TAMs. Finally, in vivo data demonstrated that OV treatment overcame CDDP resistance. OV only and the OV + CDDP combination both resulted in significant reductions in mTOR, ß-catenin, CDK6, and miR-21 expression in tumor samples and EVs isolated from serum. Collectively, we demonstrated that M2 TAMs induced malignant properties in BCa cells, in part via oncogenic EVs. OV treatment prevented M2 TAM polarization, reduced EV cargos derived from M2 TAMs, and suppressed ß-catenin/mTOR/CDK6 signaling. These findings provide preclinical evidence for OV as a single or adjuvant agent for treating drug-resistant BCa.


Assuntos
Quinase 6 Dependente de Ciclina/metabolismo , Diterpenos/uso terapêutico , MicroRNAs/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , beta Catenina/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Exossomos/patologia , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/antagonistas & inibidores , Plantas Medicinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , beta Catenina/antagonistas & inibidores
6.
PLoS One ; 15(6): e0234643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555717

RESUMO

BACKGROUND: Photoimmunotherapy (PIT) employs the use of a near-infrared (NIR) laser to activate an antibody conjugated to a NIR-activatable dye to induce cancer cell death. PIT has shown to be effective in a number of studies, however, there are no data on its use in colorectal cancer in an orthotopic model. METHODS: Humanized anti-CEA antibody (M5A) was conjugated to NIR-activatable IRDye700DX (M5A-700). PIT was validated in vitro with a colon cancer cell-line, using a laser intensity of either 4 J/cm2, 8 J/cm2, or 16 J/cm2. Orthotopic colon cancer mouse models were established by surgical implantation of LS174T tumor fragments onto the cecum. M5A-700 was administered and PIT was performed 24 hours later using a 690 nm laser. Repeat PIT was performed after 7 days in one group. Control mice received laser treatment only. RESULTS: In vitro PIT demonstrated tumor cell death in a laser intensity dose-dependent fashion. In orthotopic models, control mice demonstrated persistent tumor growth. Mice that underwent PIT one time had tumor growth arrested for one week, after which re-growth occurred. The group that received repeated PIT exposure had persistent inhibition of tumor growth. CONCLUSION: PIT arrests tumor growth in colon cancer orthotopic nude-mouse models. Repeated PIT arrests colon cancer growth for a longer period of time. PIT may be a useful therapy in the future as an adjunct to surgical resection or as primary therapy to suppress tumor progression.


Assuntos
Neoplasias Colorretais/terapia , Imunoconjugados/farmacologia , Imunoterapia/métodos , Indóis/uso terapêutico , Compostos de Organossilício/uso terapêutico , Fototerapia/métodos , Receptores de Superfície Celular/imunologia , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Fármacos Fotossensibilizantes/uso terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Toxicol Appl Pharmacol ; 401: 115102, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512071

RESUMO

PURPOSE: Cadmium (Cd) is reported to be associated with carcinogenesis. The molecular mechanisms associated with Cd-induced prostate cancer (PCa) remain elusive. MATERIALS AND METHODS: RWPE1, PWR1E and DU 145 cells were used. RT2 Profiler Array, real-time-quantitative-PCR, immunofluorescence, cell cycle, apoptosis, proliferation and colony formation assays along with Gene Set Enrichment Analysis (GSEA) were performed. RESULT: Chronic Cd exposure of non-malignant RWPE1 and PWR1E cells promoted cell survival, proliferation and colony formation with inhibition of apoptosis. Even a two-week Cd exposure of PCa cell line (DU 145) significantly increased the proliferation and decreased apoptosis. RT2 profiler array of 84 genes involved in the Erk/MAPK pathway revealed induction of gene expression in Cd-RWPE1 cells compared to RWPE1. This was confirmed by individual TaqMan gene expression analysis in both Cd-RWPE1 and Cd-PWR1E cell lines. GSEA showed an enrichment of the Erk/MAPK pathway along with other pathways such as KEGG-ERBB, KEGG-Cell Cycle, KEGG-VEGF, KEGG-Pathways in cancer and KEGG-prostate cancer pathway. We randomly selected upregulated genes from Erk/MAPK pathway and performed profile analysis in a PCa data set from the TCGA/GDC data base. We observed upregulation of these genes in PCa compared to normal samples. An increase in phosphorylation of the Erk1/2 and Mek1/2 was observed in Cd-RWPE1 and Cd-PWR1E cells compared to parental cells, confirming that Cd-exposure induces activation of the Erk/MAPK pathway. CONCLUSION: This study demonstrates that Erk/MAPK signaling is a major pathway involved in Cd-induced malignant transformation of normal prostate cells. Understanding these dominant oncogenic pathways may help develop optimal therapeutic strategies for PCa.


Assuntos
Cádmio/toxicidade , Sistema de Sinalização das MAP Quinases/fisiologia , Próstata/efeitos dos fármacos , Próstata/enzimologia , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/enzimologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Próstata/patologia , Neoplasias da Próstata/patologia
8.
J Cancer Res Clin Oncol ; 146(8): 1893-1922, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32583237

RESUMO

PURPOSE: Melatonin is an amphipathic indolamine molecule ubiquitously present in all organisms ranging from cyanobacteria to humans. The pineal gland is the site of melatonin synthesis and secretion under the influence of the retinohypothalamic tract. Some extrapineal tissues (skin, lens, gastrointestinal tract, testis, ovary, lymphocytes, and astrocytes) also enable to produce melatonin. Physiologically, melatonin regulates various functions like circadian rhythm, sleep-wake cycle, gonadal activity, redox homeostasis, neuroprotection, immune-modulation, and anticancer effects in the body. Inappropriate melatonin secretion advances the aging process, tumorigenesis, visceral adiposity, etc. METHODS: For the preparation of this review, I had reviewed the literature on the multidimensional activities of melatonin from the NCBI website database PubMed, Springer Nature, Science Direct (Elsevier), Wiley Online ResearchGate, and Google Scholar databases to search relevant articles. Specifically, I focused on the roles and mechanisms of action of melatonin in cancer prevention. RESULTS: The actions of melatonin are primarily mediated by G-protein coupled MT1 and MT2 receptors; however, several intracellular protein and nuclear receptors can modulate the activity. Normal levels of the melatonin protect the cells from adverse effects including carcinogenesis. Therapeutically, melatonin has chronomedicinal value; it also shows a remarkable anticancer property. The oncostatic action of melatonin is multidimensional, associated with the advancement of apoptosis, the arrest of the cell cycle, inhibition of metastasis, and antioxidant activity. CONCLUSION: The present review has emphasized the mechanism of the anti-neoplastic activity of melatonin that increases the possibilities of the new approaches in cancer therapy.


Assuntos
Melatonina/metabolismo , Melatonina/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Progressão da Doença , Humanos , Melatonina/administração & dosagem , Neoplasias/metabolismo , Neoplasias/patologia , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo
9.
J Environ Pathol Toxicol Oncol ; 39(1): 77-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479014

RESUMO

Helicobacter pylori causes a Gram-negative bacterial infection that can increase the risk of gastric cancer. Consequently, meticulous prevention of an H. pylori infection is significant for averting gastric cancer in humans. Nobiletin, an important dietary polymethoxylated flavonoid in citrus fruits, possesses multidimensional pharmaceutical properties, including its ability to act as an anticancer, anti-inflammatory, antioxidative, cardiovascularly defensive, neuroprotective, and antimetabolic agent. Our study evaluates the role of nobiletin in inflammation-mediated gastric carcinogenic signaling of H. pylori-arbitrated coculture in the human gastric epithelial (GES)-1 cell line. Our results show that the culture system of H. pylori-tainted GES-1 cells demonstrates maximum fabrication of reactive oxygen species (ROS), mediating DNA injury and augmenting nuclear fragmentations. Treatment with nobiletin reduces ROS levels and apoptotic morphological changes by dual staining and decreases levels of lipid peroxides and glutathione content in H. pylori-infected GES-1 cells. Phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/phosphatase and tensin homolog signaling have been implicated to affect cell endurance, inflammation, proliferation, and carcinogenic activity in gastric GES-1 cells. We find that nobiletin strongly impedes tumor necrosis factor-α, interleukin-6, cyclooxygenase-2, PI3K, AKT, and mitogen-activated protein kinase molecules, including p38, extracellular receptor kinase 1, and c-Jun amino-terminal expression in H. pylori-infected GES-1 cells. We conclude that nobiletin potentially impedes H. pylori infection and its related activation, likely preventing H. pylori infection-mediated gastric cancer.


Assuntos
Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Flavonas/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Epiteliais , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Inflamação/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Gástricas/microbiologia
10.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188380, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32461135

RESUMO

Cellular communication through gap junctions and hemichannels formed by connexins and through channels made by pannexins allows for metabolic cooperation and control of cellular activity and signalling. These channel proteins have been described to be tumour suppressors that regulate features such as cell death, proliferation and differentiation. However, they display cancer type-dependent and stage-dependent functions and may facilitate tumour progression through junctional and non-junctional pathways. The accumulated knowledge and emerging strategies to target connexins and pannexins are providing novel clinical opportunities for the treatment of cancer. Here, we provide an updated overview of the role of connexins and pannexins in malignant melanoma. We discuss how targeting of these channel proteins may be used to potentiate antitumour effects in therapeutic settings, including through improved immune-mediated tumour elimination.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Conexinas/metabolismo , Melanoma/secundário , Neoplasias Cutâneas/patologia , Pele/patologia , Animais , Antineoplásicos Imunológicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Carcinogênese/patologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Conexinas/agonistas , Conexinas/antagonistas & inibidores , Modelos Animais de Doenças , Progressão da Doença , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/patologia , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/mortalidade , Microbiota/imunologia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Estadiamento de Neoplasias , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Pele/citologia , Pele/microbiologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
11.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188379, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32439311

RESUMO

Breast cancer is the most ubiquitous type of neoplasms among women worldwide. Molecular aberrations associated with breast development and progressions have been extensively investigated in recent years. An AMP-activated kinase (AMPK) initially identified as a cellular energy sensor that plays a crucial role in cellular energy homeostasis. Intensive research over the last decade about the molecular mechanisms of AMPK has demonstrated that AMPK mediated diverse biological functions are achieved through phosphorylation and regulation of multiple downstream signaling molecules in normal tissue. Downregulation of AMPK activity or decreased level involved in the promotion of breast tumorigenesis, and thus activation of AMPK found to oppose tumor progression. In this review, we epitomize the recent advances in exploring the tumor suppressor function of AMPK pathways. Besides, we discuss the developments in the area of AMPK activator and its molecular mechanisms for breast cancer treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ativadores de Enzimas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Aspirina/farmacologia , Aspirina/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Neoplasias da Mama/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Progressão da Doença , Ativadores de Enzimas/farmacologia , Feminino , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Resultado do Tratamento
12.
Chem Biol Interact ; 325: 109131, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417163

RESUMO

We have previously demonstrated promotion of diethylnitrosamine (DEN) initiated liver tumorigenesis after feeding diets high in fat or ethanol (EtOH) to male mice. This was accompanied by hepatic induction of the proto-oncogene PIKE (Agap2). Switch of dietary protein from casein to soy protein isolate (SPI) significantly reduced tumor formation in these models. We have linked EtOH consumption in mice to microbial dysbiosis. Adoptive transfer studies demonstrate that microbiota from mice fed ethanol can induce hepatic steatosis in the absence of ethanol suggesting that microbiota or the microbial metabolome play key roles in development of fatty liver disease. Feeding SPI significantly changed gut bacteria in mice increasing alpha diversity (P < 0.05) and levels of Clostidiales spp. Feeding soy formula to piglets also resulted in significant changes in microbiota, the pattern of bile acid metabolites and in inhibition of the intestinal-hepatic FXR/FGF19-SHP pathway which has been linked to both steatosis and hepatocyte proliferation. Moreover, feeding SPI also resulted in induction of hepatic PPARα signaling and inhibition of PIKE mRNA expression coincident with inhibition of steatosis and cancer prevention. Feeding studies in the DEN model with differing dietary fats demonstrated tumor promotion specific to the saturated fat, cocoa butter relative to diets containing olive oil or corn oil associated with microbial dysbiosis including dramatic increases in Lachnospiraceae particularly from the genus Coprococcus. Immunohistochemical analysis demonstrated that tumors from EtOH-fed mice and patients with alcohol-associated HCC also expressed high levels of a novel cytochrome P450 enzyme CYP2W1. Additional adoptive transfer experiments and studies in knockout mice are required to determine the exact relationship between soy effects on the microbiota, expression of PIKE, CYP2W1, PPARα activation and prevention of tumorigenesis.


Assuntos
Família 2 do Citocromo P450/metabolismo , Microbioma Gastrointestinal , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/prevenção & controle , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Proteínas de Soja/farmacologia , Animais , Carcinogênese/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
13.
Nat Commun ; 11(1): 1802, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286276

RESUMO

Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.


Assuntos
Colite/complicações , Colite/patologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Dano ao DNA , Helicobacter pylori/fisiologia , Estresse Oxidativo , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Colite/induzido quimicamente , Colite/microbiologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/efeitos dos fármacos , Sulfato de Dextrana , Modelos Animais de Doenças , Disbiose/complicações , Disbiose/patologia , Escherichia coli/metabolismo , Feminino , Guanosina/análogos & derivados , Guanosina/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/efeitos dos fármacos , Humanos , Inflamação/complicações , Inflamação/patologia , Interleucina-10/deficiência , Interleucina-10/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação/genética , Estresse Oxidativo/efeitos dos fármacos
14.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188365, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32325165

RESUMO

Transcriptional factors (TFs) play a central role in governing gene expression under physiological conditions including the processes of embryonic development, metabolic homeostasis and response to extracellular stimuli. Conceivably, the aberrant dysregulations of TFs would dominantly result in various human disorders including tumorigenesis, diabetes and neurodegenerative diseases. Serving as the most evolutionarily reserved TFs, Fox family TFs have been explored to exert distinct biological functions in neoplastic development, by manipulating diverse gene expression. Recently, among the Fox family members, the pilot roles of FoxAs attract more attention due to their functions as both pioneer factor and transcriptional factor in human tumorigenesis, particularly in the sex-dimorphism tumors. Therefore, the pathological roles of FoxAs in tumorigenesis have been well-explored in modulating inflammation, immune response and metabolic homeostasis. In this review, we comprehensively summarize the impressive progression of FoxA functional annotation, clinical relevance, upstream regulators and downstream effectors, as well as valuable animal models, and highlight the potential strategies to target FoxAs for cancer therapies.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fatores Nucleares de Hepatócito/metabolismo , Neoplasias/genética , Animais , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Intervalo Livre de Doença , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores Nucleares de Hepatócito/antagonistas & inibidores , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
15.
PLoS One ; 15(4): e0227592, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343689

RESUMO

BMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation. Our screen identified NUMA1-mutations as the most significant inducer of PTC-318 cell death resistance. Independent validations on NUMA1-proficient HAP1 and non-small cell lung cancer cell lines exposed to BMI1 inhibition by PTC-318 or BMI1 knockdown resulted in cell death following mitotic arrest. Interestingly, cells with CRISPR-Cas9 derived NUMA1 knockout also showed a mitotic arrest phenotype following BMI1 inhibition but, contrary to cells with wildtype NUMA1, these cells were resistant to BMI1-dependent cell death. The current study brings new insights to BMI1 inhibition-induced mitotic lethality in cancer cells and presents a previously unknown role of NUMA1 in this process.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Complexo Repressor Polycomb 1/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Sistemas CRISPR-Cas/genética , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , RNA Interferente Pequeno/metabolismo
16.
Curr Pharm Biotechnol ; 21(11): 1119-1128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32297576

RESUMO

BACKGROUND: Semaphorin 3F (SEMA3F) plays a substantial role in carcinogenesis, because of its role in inducing angiogenesis, and creating a microenvironment for the developing tumor. OBJECTIVE: The purpose of this work was to assess the impact of cisplatin, depending on the concentration and exposure time on the expression pattern of SEMA3F in an endometrial cancer cell line. MATERIALS AND METHODS: Cultures of the Ishikawa endometrial cancer cells were incubated with cisplatin with the following concentrations: 2.5µM; 5µM; and 10µM and for the following periods of time: 12; 24; and 48 hours. Cells not incubated with the drug constituted the control in the experiment. To determine the effect of cisplatin on the expression of SEMA3F, the real-time quantitative reverse transcription reaction (RtqPCR; mRNA) was used, as well as the ELISA assay (protein). The statistical analysis was done with the admission of p<0.05. RESULTS: The silencing of SEMA3F expression on the transcriptome and proteome levels in a culture unexposed to the effects of cisplatin in comparison to endometrial cancer cells under the influence of cisplatin (p<0.05) were noted. Along with an increase in the concentration of the drug used, the number of copies of the gene transcript, during the shortest incubation period had a gradual increase. Only for the highest concentration of the drug, substantial statistical differences in the expression of the SEMA3F protein between 24 and 48 hour incubation periods (p<0.05) were determined. CONCLUSION: Using cisplatin in an endometrial cancer cell culture results in an increased expression of SEMA3F, which advantageously affects the normalization of the neoplastic angiogenic process and lowers the proliferation of the cells making up the mass of the tumor.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Cisplatino/farmacologia , Neoplasias do Endométrio/metabolismo , Proteínas de Membrana/biossíntese , Proteínas do Tecido Nervoso/biossíntese , RNA Mensageiro/biossíntese , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Inativação Gênica , Humanos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , Microambiente Tumoral/efeitos dos fármacos
17.
Mutat Res ; 850-851: 503136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32247553

RESUMO

Tumorigenesis induced by oxidative stress is thought to be initiated by mutagenesis, but via an indirect mechanism. The dose-response curves for agents that act by this route usually show a threshold, for unknown reasons. To gain insight into these phenomena, we have analyzed the dose response for mutagenesis induced by the oral administration of potassium bromate, a typical oxidative-stress-generating agent, to gpt delta mice. The agent was given orally for 90 d to either Nrf2+ or Nrf2-knockout (KO) mice and mutants induced in the small intestine were analyzed. In Nrf2+mice, the mutant frequency was significantly greater than in the vehicle controls at a dose of 0.6 g/L but not at 0.2 g/L, indicating that a practical threshold for mutagenesis lies between these doses. At 0.6 g/L, the frequencies of G-to-T transversions (landmark mutations for oxidative stress) and G-to-A transitions were significantly elevated. In Nrf2-KO mice, too, the total mutant frequency was increased only at 0.6 g/L. G-to-T transversions are likely to have driven tumorigenesis in the small intestine. A site-specific G-to-T transversion at guanine (nucleotide 406) in a 5'-TGAA-3' sequence in gpt, and our primer extension reaction showed that formation of the oxidative DNA base modification 8-oxo-deoxyguanosine (8-oxo-dG) at nucleotide 406 was significantly increased at doses of 0.6 and 2 g/L in the gpt delta mice. In the Apc oncogene, guanine residues in the same or similar sequences (TGAA or AGAA) are highly substituted by thymine (G-to-T transversions) in potassium bromate-induced tumors. We propose that formation of 8-oxo-dG in the T(A)GAA sequence is an initiating event in tumor formation in the small intestine in response to oxidative stress.


Assuntos
Bromatos/toxicidade , Mutagênese/genética , Estresse Oxidativo/genética , Pentosiltransferases/genética , 8-Hidroxi-2'-Desoxiguanosina/genética , Administração Oral , Animais , Bromatos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , DNA/efeitos dos fármacos , DNA/genética , Relação Dose-Resposta a Droga , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Camundongos , Camundongos Knockout , Mutagênese/efeitos dos fármacos , Mutação , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos
18.
Chem Biol Interact ; 323: 109077, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32246921

RESUMO

7H-Dibenzo[c,g]carbazole (DBC), a local and systemic carcinogen in animal studies, is a common environmental pollutant. It generally co-occurs in a variety of organic complex mixtures derived from incomplete combustion of organic matter. Despite high lipophilicity, DBC is more water-soluble and faster metabolized than the homocyclic aromatics. Moreover, greater polarity, high bioaccumulation potential, and persistence in the environment may imply DBC's higher biological significance and impact on human health, even at lower concentrations. The biotransformation pathways of DBC are incompletely known and the ultimate carcinogenic metabolite(s) are not clearly identified as yet. Structure-biological studies suggest two ways of activation: at the ring carbon atoms and at the pyrrole nitrogen. It is supposed that the particular pathway of biotransformation might be connected with the tissue/organ specificity of DBC. Cytochrome P450 (CYP) family of enzymes plays a pivotal role in the metabolism of DBC; though, the one-electron activation and the aldo-keto reductase-catalyzed oxidation are also involved in metabolic activation. Additionally, DBC can be photoactivated even at physiologically relevant doses of UVA light due to the extended aromatic ring system resulting in strong genotoxicity and oxidative stress. The goal of this review is to summarize current knowledge on mechanisms of DBC activation and possible implications for toxicity, genotoxicity, and carcinogenicity.


Assuntos
Carbazóis/toxicidade , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Carbazóis/química , Carbazóis/metabolismo , Carcinogênese/induzido quimicamente , Carcinogênese/efeitos dos fármacos , Humanos , Luz , Oxirredução , Relação Estrutura-Atividade
19.
Chem Biol Interact ; 324: 109091, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32283069

RESUMO

Folate and alcohol are dietary factors affecting the risk of cancer development in humans. The interaction between folate status and alcohol consumption in carcinogenesis involves multiple mechanisms. Alcoholism is typically associated with folate deficiency due to reduced dietary folate intake. Heavy alcohol consumption also decreases folate absorption, enhances urinary folate excretion and inhibits enzymes pivotal for one-carbon metabolism. While folate metabolism is involved in several key biochemical pathways, aberrant DNA methylation, due to the deficiency of methyl donors, is considered as a common downstream target of the folate-mediated effects of ethanol. The negative effects of low intakes of nutrients that provide dietary methyl groups, with high intakes of alcohol are additive in general. For example, low methionine, low-folate diets coupled with alcohol consumption could increase the risk for colorectal cancer in men. To counteract the negative effects of alcohol consumption, increased intake of nutrients, such as folate, providing dietary methyl groups is generally recommended. Here mechanisms involving dietary folate and folate metabolism in cancer disease, as well as links between these mechanisms and alcohol effects, are discussed. These mechanisms include direct effects on folate pathways and indirect mediation by oxidative stress, hypoxia, and microRNAs.


Assuntos
Carcinogênese/efeitos dos fármacos , Etanol/farmacologia , Ácido Fólico/metabolismo , Neoplasias/etiologia , Animais , Dieta , Deficiência de Ácido Fólico/induzido quimicamente , Humanos , MicroRNAs/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fatores de Risco
20.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188353, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32112817

RESUMO

Glioma is the most common primary malignant tumor in the human brain. Although there are a variety of treatments, such as surgery, radiation and chemotherapy, glioma is still an incurable disease. Super-enhancers (SEs) are implicated in the control of tumor cell identity, and they promote oncogenic transcription, which supports tumor cells. Inhibition of the SE complex, which is required for the assembly and maintenance of SEs, may repress oncogenic transcription and impede tumor growth. In this review, we discuss the unique characteristics of SEs compared to typical enhancers, and we summarize the recent advances in the understanding of their properties and biological role in gene regulation. Additionally, we highlight that SE-driven lncRNAs, miRNAs and genes are involved in the malignant phenotype of glioma. Most importantly, the application of SE inhibitors in different cancer subtypes has introduced new directions in glioma treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/genética , Elementos Facilitadores Genéticos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , MicroRNAs/genética , Oncogenes/genética , RNA Longo não Codificante/genética , Transcrição Genética/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA