RESUMO
Ascorbate acts as a prooxidant when administered parenterally at high supraphysiological doses, which results in the generation of hydrogen peroxide in dependence on oxygen. Most cancer cells are susceptible to the emerging reactive oxygen species (ROS). Accordingly, we evaluated high-dose ascorbate for the treatment of the B16F10 melanoma model. To investigate the effects of ascorbate on the B16F10 cell line in vitro, viability, cellular impedance, and ROS production were analyzed. In vivo, C57BL/6NCrl mice were subcutaneously injected into the right flank with B16F10 cells and tumor-bearing mice were treated intraperitoneally with ascorbate (3 g/kg bodyweight), immunotherapy (anti-programmed cell death protein 1 (PD1) antibody J43; 2 mg/kg bodyweight), or both treatments combined. The efficacy and toxicity were analyzed by measuring the respective tumor sizes and mouse weights accompanied by histological analysis of the protein levels of proliferating cell nuclear antigen (Pcna), glucose transporter 1 (Glut-1), and CD3. Treatment of B16F10 melanoma-carrying mice with high-dose ascorbate yielded plasma levels in the pharmacologically effective range, and ascorbate showed efficacy as a monotherapy and when combined with PD1 inhibition. Our data suggest the applicability of ascorbate as an additional therapeutic agent that can be safely combined with immunotherapy and has the potential to potentiate anti-PD1-based immune checkpoint blockades.
Assuntos
Antineoplásicos , Melanoma , Animais , Camundongos , Espécies Reativas de Oxigênio , Camundongos Endogâmicos C57BL , Melanoma/tratamento farmacológico , Antineoplásicos/farmacologia , Melanoma Maligno CutâneoRESUMO
High-dose ascorbate paradoxically acts as a pro-oxidant causing the formation of hydrogen peroxide in an oxygen dependent manner. Tumor cells (in particular melanoma cells) show an increased vulnerability to ascorbate induced reactive oxygen species (ROS). Therefore, high-dose ascorbate is a promising pharmacological approach to treating refractory melanomas, e.g., with secondary resistance to targeted BRAF inhibitor therapy. BRAF mutated melanoma cells were treated with ascorbate alone or in combination with the BRAF inhibitor vemurafenib. Viability, cell cycle, ROS production, and the protein levels of phospho-ERK1/2, GLUT-1 and HIF-1α were analyzed. To investigate the treatment in vivo, C57BL/6NCrl mice were subcutaneously injected with D4M.3A (BrafV600E) melanoma cells and treated with intraperitoneal injections of ascorbate with or without vemurafenib. BRAF mutated melanoma cell lines either sensitive or resistant to vemurafenib were susceptible to the induction of cell death by pharmacological ascorbate. Treatment of BrafV600E melanoma bearing mice with ascorbate resulted in plasma levels in the pharmacologically active range and significantly improved the therapeutic effect of vemurafenib. We conclude that intravenous high-dose ascorbate will be beneficial for melanoma patients by interfering with the tumor's energy metabolism and can be safely combined with standard melanoma therapies such as BRAF inhibitors without pharmacological interference.
Assuntos
Antineoplásicos , Melanoma , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Espécies Reativas de Oxigênio/uso terapêutico , Vemurafenib/farmacologia , Vemurafenib/uso terapêuticoRESUMO
A chronic low-grade inflammation, originating in the adipose tissue, is considered a driver of obesity-associated insulin resistance. Macrophage composition in white adipose tissue is believed to contribute to the pathogenesis of metabolic diseases, but a detailed characterization of pro- and anti-inflammatory adipose tissue macrophages (ATMs) in human obesity and how they are distributed in visceral- and subcutaneous adipose depots is lacking. In this study, we performed a surface proteome screening of pro- and anti-inflammatory ATMs in both subcutaneous- (SAT) and visceral adipose tissue (VAT) and evaluated their relationship with systemic insulin resistance. From the proteomics screen we found novel surface proteins specific to M1-like- and M2-like macrophages, and we identified depot-specific immunophenotypes in SAT and VAT. Furthermore, we found that insulin resistance, assessed by HOMA-IR, was positively associated with a relative increase in pro-inflammatory M1-like macrophages in both SAT and VAT.
Assuntos
Resistência à Insulina , Tecido Adiposo/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Obesidade/complicaçõesRESUMO
Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5-50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity.
RESUMO
Resveratrol, a natural plant phytoalexin, is produced in response to fungal infection or- UV irradiation. It exists as an isomeric pair with cis- and trans-conformation. Whereas multiple physiological effects of the trans-form, including a pronounced anti-tumoral activity, are nowadays elucidated, much less knowledge exists concerning the cis-isomer. In our work, we analyzed the antiproliferative and cytotoxic properties of cis-resveratrol in four different human tumor entities in direct comparison to trans-resveratrol. We used human cell lines as tumor models for hepatocellular carcinoma (HCC; HepG2, Hep3B), colon carcinoma (HCT-116, HCT-116/p53(-/-)), pancreatic carcinoma (Capan-2, MiaPaCa-2), and renal cell carcinoma (A498, SN12C). Increased cytotoxicity in all investigated tumor cells was observed for the trans-isomer. To verify possible effects of the tumor suppressor p53 on resveratrol-induced cell death, we used wild type and p53-deleted or -mutated cell lines for every tested tumor entity. Applying viability and cytotoxicity assays, we demonstrated a differential, dose-dependent sensitivity towards cis- or trans-resveratrol among the respective tumor types.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Resveratrol , Proteína Supressora de Tumor p53 , Antineoplásicos , Apoptose/efeitos dos fármacos , HumanosRESUMO
Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
Assuntos
Adipócitos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Células 3T3-L1 , Sistema y+ de Transporte de Aminoácidos/genética , Animais , Western Blotting , Diabetes Mellitus Tipo 2/metabolismo , Genótipo , Glutationa/metabolismo , Humanos , Resistência à Insulina/fisiologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de RNA , Peixe-ZebraRESUMO
BACKGROUND/AIMS: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). METHODS: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. RESULTS: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. CONCLUSION: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities.
Assuntos
Apoptose/efeitos dos fármacos , Flavanonas/farmacologia , Flavonoides/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Humulus/química , Acetilação/efeitos dos fármacos , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavanonas/química , Flavanonas/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/isolamento & purificação , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Humulus/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Despite recent progress in melanoma therapy via inhibition of activated oncogenes or immune stimulation, most stage IV melanoma patients still have limited survival times. Existing therapeutic approaches eventually fail to prevent further invasion and metastasis, which is driven by a morphological process termed epithelial-mesenchymal transition (EMT). We previously demonstrated that inhibition of EMT in melanoma cells via antagonizing the bone morphogenetic protein (BMP)-pathway abrogated EMT and neural crest migration of melanoma cells in chick embryos. Here, we show that BMP-2 is highly expressed in invasive melanoma cells and is elevated in the serum of stage IV melanoma patients compared to stage IB-IIC patients and healthy controls. Highly BMP-2-expressing melanoma cells display enhanced invasion in the rhombencephalon of the chick embryo. In addition to driving neural crest migration in the zebrafish embryo, the agonists BMP-2, BMP-7 and nodal induce EMT/invasion in radial growth phase melanoma cells and in human melanocytes in skin reconstructs. Blocking either BMP or nodal signaling by antagonists (noggin, lefty), or the Alk4/5/7-receptor inhibitor SB431542, decreases EMT and invasion of melanoma cells in human epidermal skin reconstructs. Together, our data suggest that inhibition of EMT-inducing pathways in melanoma might be a therapeutic approach to attenuate melanoma cell invasiveness.
RESUMO
Cutaneous melanoma represents one of the most aggressive human tumor entities possessing a high tendency to metastasize. Cancer cells frequently exploit a highly conserved developmental program, the epithelial-to-mesenchymal transition (EMT), to gain migratory and invasive properties promoting their metastatic spread. Cytoplasmic localization of the oncogenic transcription and translation factor Y-box binding protein 1 (YB-1) is a powerful inducer of EMT in breast carcinoma cells. Interestingly, EMT-like processes have also been observed in cutaneous melanoma despite its neural crest origin. Here, increased expression of YB-1 negatively affects patient survival in malignant melanoma and promotes melanoma cell tumorigenicity both in vitro and in vivo Intriguingly, this effect seems to be mainly mediated by cytoplasmic YB-1 that does not exhibit phosphorylation at serine-102 (S102). Moreover, S102 unphosphorylated YB-1 enhances the migratory and invasive potential of human melanoma cells in two-dimensional (2D) and three-dimensional (3D) culture systems and facilitates acquisition of a mesenchymal-like invasive phenotype in the chick embryo model. Collectively, these data demonstrate that the cytoplasmic activity of YB-1 stimulates tumorigenicity and metastatic potential of melanoma cells by promoting EMT-like properties.Implications: This study reveals for the first time that YB-1 efficiently drives tumorigenicity and invasiveness of melanoma cells in its S102 unphosphorylated cytoplasmic state and that YB-1 expression represents a negative prognostic factor in primary melanoma patients. Mol Cancer Res; 16(7); 1149-60. ©2018 AACR.
Assuntos
Carcinogênese/genética , Transição Epitelial-Mesenquimal/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Proteína 1 de Ligação a Y-Box/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Embrião de Galinha , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/patologia , Camundongos , Invasividade Neoplásica/genética , Neoplasias Cutâneas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Melanoma Maligno CutâneoRESUMO
BACKGROUND: During embryonic development Wnt family members and bone morphogenetic proteins (BMPs) cooperatively induce epithelial-mesenchymal transition (EMT) in the neural crest. Wnt and BMPs are reactivated during malignant transformation in melanoma. We previously demonstrated that the BMP-antagonist noggin blocked the EMT phenotype of melanoma cells in the neural crest and malignant invasion of melanoma cells in the chick embryo; vice-versa, malignant invasion was induced in human melanocytes in vivo by pre-treatment with BMP-2. RESULTS: Although there are conflicting results in the literature about the role of ß-catenin for invasion of melanoma cells, we found Wnt/ß-catenin signaling to be analogously important for the EMT-like phenotype of human metastatic melanoma cells in the neural crest and during invasion: ß-catenin was frequently expressed at the invasive front of human primary melanomas and Wnt3a expression was inversely correlated with survival of melanoma patients. Accordingly, cytoplasmic ß-catenin levels were increased during invasion of melanoma cells in the rhombencephalon of the chick embryo. Fibroblast derived Wnt3a reduced melanoma cell adhesion and enhanced migration, while the ß-catenin inhibitor PKF115-584 increased adhesion and reduced migration in vitro and in the chick embryonic neural crest environment in vivo. Similarly, knockdown of ß-catenin impaired intradermal melanoma cell invasion and PKF115-584 efficiently reduced liver metastasis in a chick chorioallantoic membrane model. Our observations were accompanied by specific alterations in gene expression which are linked to overall survival of melanoma patients. CONCLUSION: We present a novel role for Wnt-signaling in neural crest like melanoma cell invasion and metastasis, stressing the crucial role of embryonic EMT-inducing neural crest signaling for the spreading of malignant melanoma.
Assuntos
Movimento Celular , Transformação Celular Neoplásica/metabolismo , Melanoma/etiologia , Melanoma/metabolismo , Crista Neural/metabolismo , Fenótipo , Via de Sinalização Wnt , Animais , Biomarcadores , Adesão Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Embrião de Galinha , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Técnicas de Silenciamento de Genes , Humanos , Melanoma/mortalidade , Melanoma/patologia , Melanoma Experimental , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Crista Neural/patologia , Perileno/análogos & derivados , Perileno/farmacologia , RNA Interferente Pequeno/genética , Peixe-Zebra , beta Catenina/genética , beta Catenina/metabolismoRESUMO
SCOPE: Prenylated chalcones and flavonoids from hop (Humulus lupulus L.), such as 6-prenylnaringenin (6-PN) and 8-prenylnaringenin (8-PN), are investigated for their health beneficial and anticancer activities. We, thus, compare the oral bioavailability and safety of 6-PN and 8-PN in healthy young women and men, and investigated their effects on peripheral blood mononuclear cells (PBMC). METHODS AND RESULTS: A double-blind, placebo-controlled, crossover trial is conducted with 16 healthy volunteers (eight women, eight men) given a single oral dose of 500 mg 6-PN, 8-PN, or placebo in random order. Maximum total concentrations of 6-PN and 8-PN in plasma (Cmax ; 543 and 2834 nmol L-1 ) and their respective area under the plasma concentration-time curve (AUC; 3635 and 15801 nmol L-1 × h) are significantly (5.2- and 4.3-fold) higher for 8-PN than for 6-PN (p Ë 0.05). PBMC for ex vivo experiments are isolated from blood sampled before and 6 h after intake of 6-PN, 8-PN, or placebo. Despite the single-treatment regime and low blood concentrations, both 6-PN and 8-PN increase the survival of PBMC relative to control. CONCLUSION: 8-PN is significantly more bioavailable in healthy humans than its isomer 6-PN. Interestingly, 6-PN, despite being less bioavailable, is similarly effective as 8-PN in enhancing PBMC viability.
Assuntos
Anticarcinógenos/metabolismo , Flavanonas/metabolismo , Flavonoides/metabolismo , Humulus/química , Inflorescência/química , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/metabolismo , Anticarcinógenos/efeitos adversos , Anticarcinógenos/sangue , Anticarcinógenos/síntese química , Sobrevivência Celular , Células Cultivadas , Estudos Cross-Over , Método Duplo-Cego , Feminino , Flavanonas/efeitos adversos , Flavanonas/sangue , Flavanonas/urina , Flavonoides/efeitos adversos , Flavonoides/sangue , Flavonoides/urina , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/sangue , Fatores Imunológicos/metabolismo , Fatores Imunológicos/urina , Absorção Intestinal , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Valor Nutritivo , Eliminação Renal , Adulto JovemRESUMO
BACKGROUND/AIMS: Membrane-type matrix metalloproteinases (MT-MMPs) are expressed on the cell surface and hydrolyze extracellular matrix components and signaling molecules by which they influence cancer cell migration and metastasis. Two of the six known MT-MMPs are anchored to the plasma membrane via a GPI anchor, one of which is MT4-MMP. Only little is known about MT4-MMP expression, synthesis, regulation and degradation. METHODS: We analyzed several human cancer cell lines as well as tissue homogenates using Western blotting and quantitative PCR for the expression of MT4-MMP. Organelles of SK-Mel-28 cells were separated using continuous Iodixanol gradients. Glycosylation of the SK-Mel-28 protein was studied via glucosidases and site directed mutagenesis of the MT4-MMP cDNA prior to transfection. RESULTS: We found the MT4-MMP highly expressed in human melanoma cell lines as well as skin and melanoma tissue samples. Three forms of MT4-MMP with molecular masses of 45 kDa, 58 kDa and 69 kDa were detected. Further, we demonstrate that the 58 kDa form is the mature protein in the cell membrane, while the 69 kDa form is its precursor found in intracellular compartments. The 69 kDa forms are processed by furin cleavage in the Golgi apparatus. Moreover, we identified Asn318 as the single N-glycosylation site of MT4-MMP. CONCLUSION: We demonstrate the novel expression of MT4-MMP in melanocytic tissues and propose a precursor/product-relationship of the different forms of MT4-MMP in melanoma cells.
Assuntos
Metaloproteinases da Matriz Associadas à Membrana/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/patologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Estresse do Retículo Endoplasmático , Glicosilação , Complexo de Golgi/metabolismo , Humanos , Metaloproteinases da Matriz Associadas à Membrana/genética , Melanoma/metabolismo , Mutagênese Sítio-Dirigida , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/metabolismoRESUMO
Flavonoids are a large group of secondary plant metabolites present in the diet with numerous potentially health-beneficial biological activities. In addition to antioxidant, anti-inflammatory, cholesterol-lowering, and many other biological functions reported in the literature, flavonoids appear to inhibit cancer cell proliferation and stimulate immune function. Although the immunomodulatory potential of flavonoids has been intensively investigated, only little is known about their impact on natural killer (NK) cells. Enhancing NK cell activity, however, would have strong implications for a possible clinical use of flavonoids, especially in the treatment and prevention of diseases like cancer and viral infections. Therefore, the purpose of this review is to summarize the currently available information on NK cell modulation by flavonoids. Many of the structurally diverse flavonoids stimulate NK cell activity and have thus great potential as diet-derived immune-modulatory chemopreventive agents and may even serve as therapeutic compounds or lead structures for the development of novel drugs for the treatment of both malignant and viral diseases.
Assuntos
Anticarcinógenos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Fatores Imunológicos/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Animais , Dieta , Flavonoides/farmacocinética , Humanos , Células Matadoras Naturais/imunologia , Viroses/tratamento farmacológico , Viroses/imunologiaRESUMO
Prenylated chalcones and flavonoids gained increasing attention not only in nutrition but also in cancer prevention because of their biological and molecular activities in humans, which have been extensively investigated in vitro or in preclinical studies. These naturally occurring compounds exhibit antioxidant effects, modulate metabolism of carcinogens by inhibition of distinct phase 1 metabolic enzymes and activation of phase 2 detoxifying enzymes, and display antiinflammatory properties. In particular, their potential to prevent proliferation of tumor cells is noteworthy. Some representatives of this subclass of secondary plant compounds exert pronounced anti-tumor-initiating capacities and directly inhibit growth of cancer cells, whereas their toxic effects on healthy tissues are remarkably low. These promising pharmacologic characteristics are countered by low ingestion, low bioavailability, and little knowledge of their metabolism. This review focuses on the great potential of these plant- and nutrient-derived compounds for cancer prevention and therapy. Provided here is a comprehensive summary of the current knowledge and inherent modes of action, focusing on the prenylated chalcones xanthohumol, desmethylxanthohumol, and xanthogalenol, as well as the prenylated flavonoids isoxanthohumol, 6-prenylnaringenin, 8-prenylnaringenin, 6-geranylnaringenin, 8-geranylnaringenin, and pomiferin.
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Chalconas/administração & dosagem , Flavonoides/administração & dosagem , Neoplasias/dietoterapia , Neoplasias/prevenção & controle , Cerveja/análise , Chalconas/química , Chalconas/classificação , Suplementos Nutricionais/classificação , Feminino , Flavonoides/química , Flavonoides/classificação , Humanos , Humulus/química , Masculino , PrenilaçãoRESUMO
Natural killer (NK) cells as part of the innate immune system represent the first line of defence against (virus-) infected and malignantly transformed cells. The emerging field of nutritional immunology focuses on compounds featuring immune-modulating activities in particular on NK cells, which e.g. can be exploited for cancer prevention and treatment. The plant-based nutrition resveratrol is a ternary hydroxylated stilbene, which is present in many foods and beverages, respectively. In humans it comprises a large variety of distinct biological activities. Interestingly, resveratrol strongly modulates the immune response including the activity of NK cells. This review will give an overview on NK cell functions and summarize the resveratrol-mediated modulation thereof.
Assuntos
Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Fenômenos Fisiológicos da Nutrição/imunologia , Estilbenos/farmacologia , Antineoplásicos Fitogênicos , Dieta , Humanos , Neoplasias/imunologia , Plantas Comestíveis/química , Resveratrol , Estilbenos/administração & dosagem , Estilbenos/farmacocinéticaAssuntos
Injeções Epidurais/efeitos adversos , Laringoscopia/tendências , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Síndrome do Desconforto Respiratório/mortalidade , Doenças da Coluna Vertebral/etiologia , Doenças da Coluna Vertebral/prevenção & controle , Biomarcadores/sangue , Cuidados Críticos/tendências , Humanos , Internacionalidade , Respiração Artificial/tendências , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/diagnóstico , Análise de SobrevidaRESUMO
BACKGROUND: DNA methylation at CpG dinucleotides is modified in tumorigenesis with potential impact on transcriptional activity. METHODS: We used the Illumina 450 K platform to evaluate DNA methylation patterns of 50 metastatic melanoma tumors, with matched gene expression data. RESULTS: We identified three different methylation groups and validated the groups in independent data from The Cancer Genome Atlas. One group displayed hypermethylation of a developmental promoter set, genome-wide demethylation, increased proliferation and activity of the SWI/SNF complex. A second group had a methylation pattern resembling stromal and leukocyte cells, over-expressed an immune signature and had improved survival rates in metastatic tumors (p < 0.05). A third group had intermediate methylation levels and expressed both proliferative and immune signatures. The methylation groups corresponded to some degree with previously identified gene expression phenotypes. CONCLUSIONS: Melanoma consists of divergent methylation groups that are distinguished by promoter methylation, proliferation and content of immunological cells.
Assuntos
Metilação de DNA , Perfilação da Expressão Gênica , Melanoma/imunologia , Melanoma/patologia , Proliferação de Células , Ilhas de CpG/genética , Feminino , Genômica , Humanos , Masculino , Melanoma/genética , Metástase Neoplásica , Regiões Promotoras Genéticas/genéticaRESUMO
Aberrant epigenetic modifications are described in an increasing number of pathological conditions, including neurodegenerative diseases, cardiovascular diseases, diabetes mellitus type 2, obesity and cancer. The general reversibility of epigenetic changes makes them an attractive and promising target e.g. in the treatment of cancer. Thus, a growing number of epigenetically active compounds are currently tested in clinical trials for their therapeutic potential. Interestingly, many phytochemicals present in plant foods, particularly flavonoids, are suggested to be able to alter epigenetic cellular mechanisms. Flavonoids are natural phenol compounds that form a large group of secondary plant metabolites with interesting biological activities. They can be categorized into six major subclasses, which display diverse properties affecting the two best characterized epigenetic mechanisms: modulation of the DNA methylation status and histone acetylation. High dietary flavonoid intake has strongly been suggested to reduce the risk of numerous cancer entities in a large body of epidemiological studies. Established health-promoting effects of diets rich in fruit and vegetables are faced by efforts to use purified flavonoids as supplements or pharmaceuticals, whereupon data on the latter applications remain controversial. The purpose of this review is to give an overview of current research on flavonoids to further elucidate their potential in cancer prevention and therapy, thereby focusing on their distinct epigenetic activities.
RESUMO
Intravenous application of high-dose ascorbate (vitamin C) has been used in complementary medicine since the 1970s to treat cancer patients. In recent years it became evident that high-dose ascorbate in the millimolar range bears selective cytotoxic effects on cancer cells in vitro and in vivo. This anticancer effect is dose dependent, catalyzed by serum components and mediated by reactive oxygen species and ascorbyl radicals, making ascorbate a pro-oxidative pro-drug that catalyzes hydrogen peroxide production in tissues instead of acting as a radical scavenger. It further depends on HIF-1 signaling and oxygen pressure, and shows a strong epigenetic signature (alteration of DNA-methylation and induction of tumor-suppressing microRNAs in cancer cells). The detailed understanding of ascorbate-induced antiproliferative molecular mechanisms warrants in-depth preclinical evaluation in cancer-bearing animal models for the optimization of an efficacious therapy regimen (e.g., combination with hyperbaric oxygen or O2-sensitizers) that subsequently need to be evaluated in clinical trials.
Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Fitoterapia , Células Tumorais Cultivadas/efeitos dos fármacos , Administração Oral , Animais , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Terapia Combinada , Terapias Complementares/legislação & jurisprudência , Relação Dose-Resposta a Droga , Aprovação de Drogas/legislação & jurisprudência , Epigênese Genética/efeitos dos fármacos , União Europeia , Humanos , Infusões Intravenosas , Melanoma/tratamento farmacológico , Melanoma/genética , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , Espécies Reativas de Oxigênio/metabolismo , Gestão de Riscos/legislação & jurisprudência , Resultado do TratamentoRESUMO
BACKGROUND: Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2'-desoxyuridine (5-FdU) results in N(4)-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2'-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. METHODS: In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. RESULTS: A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. CONCLUSION: The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation.