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1.
Environ Toxicol ; 34(9): 1025-1033, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31087429

RESUMO

Hepatocellular carcinoma is considered one of the most prevalent and lethal malignancies worldwide. Chemotherapy with cytotoxic agents showed a low response rate with possible toxic effects. Recently, some emphases have been placed on the anticancer properties of bovine whey protein and its components, especially lactoferrin. The present study aimed to evaluate and compare the antihepatocarcinogenic activity of bovine whey protein concentrate (WPC, 300 and 600 mg/kg body weight) and lactoferrin (30 and 60 mg/kg body weight), orally and daily for 14 weeks, in the mice model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. The results showed that both WPC and lactoferrin (in a dose-dependent manner) alleviated significantly (P < .001) the elevation in serum markers of liver carcinoma and inflammation in the DEN-treated mice. Also, they exhibited a great amelioration in the livers' histological structure of the DEN-treated mice by 37.0% to 66.7%. In addition, they decreased significantly (P < .001) the hepatic DNA fragmentation in the DEN-treated mice by 23.1% to 32.7%. Only, the high doses of WPC and lactoferrin completely modulated the decrease in the activity of liver enzymic antioxidant defense system (catalase, glutathione peroxidase, and superoxide dismutase) and improved significantly (P < .01-.001) the concentration of hepatic reduced glutathione of the DEN-treated mice. Moreover, the high doses of WPC and lactoferrin reduced significantly (P < .05-.001) the elevation in the concentrations of hepatic active caspases 3, 8, and 9 of the DEN-treated mice. In conclusion, both WPC and lactoferrin were effective in inhibiting the hepatocarcinogenic activity of DEN in mice model through their ability to alleviate the hepatic inflammation and apoptosis.


Assuntos
Anticarcinógenos/uso terapêutico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Fígado/efeitos dos fármacos , Proteínas do Soro do Leite/uso terapêutico , Animais , Anticarcinógenos/administração & dosagem , Antioxidantes/metabolismo , Bovinos , Dietilnitrosamina/administração & dosagem , Relação Dose-Resposta a Droga , Lactoferrina/administração & dosagem , Lactoferrina/uso terapêutico , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Masculino , Camundongos , Proteínas do Soro do Leite/administração & dosagem
2.
Nano Lett ; 19(4): 2231-2242, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30873838

RESUMO

Bexarotene has shown inhibition of lung and mammary gland tumorigenesis in preclinical models and in clinical trials. The main side effects of orally administered bexarotene are hypertriglyceridemia and hypercholesterolemia. We previously demonstrated that aerosolized bexarotene administered by nasal inhalation has potent chemopreventive activity in a lung adenoma preclinical model without causing hypertriglyceridemia. To facilitate its future clinical translation, we modified the formula of the aerosolized bexarotene with a clinically relevant solvent system. This optimized aerosolized bexarotene formulation was tested against lung squamous cell carcinoma mouse model and lung adenocarcinoma mouse model and showed significant chemopreventive effect. This new formula did not cause visible signs of toxicity and did not increase plasma triglycerides or cholesterol. This aerosolized bexarotene was evenly distributed to the mouse lung parenchyma, and it modulated the microenvironment in vivo by increasing the tumor-infiltrating T cell population. RNA sequencing of the lung cancer cell lines demonstrated that multiple pathways are altered by bexarotene. For the first time, these studies demonstrate a new, clinically relevant aerosolized bexarotene formulation that exhibits preventive efficacy against the major subtypes of lung cancer. This approach could be a major advancement in lung cancer prevention for high risk populations, including former and present smokers.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Aerossóis/administração & dosagem , Bexaroteno/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Administração Oral , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/efeitos adversos , Bexaroteno/efeitos adversos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Modelos Animais de Doenças , Composição de Medicamentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/patologia , Hipercolesterolemia/prevenção & controle , Pulmão/efeitos dos fármacos , Pulmão/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Camundongos , Transdução de Sinais/efeitos dos fármacos
3.
Biomed Res Int ; 2019: 8670398, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30882001

RESUMO

Tyrosine kinases play crucial roles in cellular development and tumorigenesis. Tyrosine kinase inhibitors (TKIs) are effective and widely used drug molecules in targeted cancer therapies. Altered expressions of protooncogenes and tumor suppressor genes after DMBA (7,12-dimethylbenz[a]anthracene) treatment have been described as early markers of tumor induction; however their tissue-specific effects remain still unclear. Our study was aimed at examining the short-term possible antineoplastic and chemopreventive effects of a TKI compound (imatinib mesylate) on a DMBA-induced mouse tumor model. In addition, we also investigated the tissue-specific expressions of Hras, Kras, Myc, and Trp53 genes in the brain, bone marrow, spleen, liver, abdominal lymph nodes, thymus, lungs, and kidneys, respectively. 24 hours after the imatinib mesylate injection, we observed significant Kras downregulation in the bone marrow and lung of the DMBA-treated mice. Moreover, the mRNA expression of Myc was also found to be decreased significantly in the spleen. Interestingly, while Trp53 expression was significantly increased in the lung, it was decreased in the other tissues. However, there was also a tendency in the decreased Myc level in the bone marrow, brain, kidneys, lungs, and lymph nodes and in the decreased Hras level in the bone marrow, kidneys, and lungs, although no significant differences were observed. Our findings indicate rapid tissue-specific impact of imatinib mesylate on DMBA-induced gene expression in vivo, supporting the chemopreventive potential of imatinib mesylate in cancer.


Assuntos
Anticarcinógenos/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Antracenos/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias/induzido quimicamente , Neoplasias/patologia , Especificidade de Órgãos/efeitos dos fármacos , Piperidinas/toxicidade , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética
4.
Pharmacology ; 103(5-6): 263-272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30783055

RESUMO

BACKGROUND: Crocetin is a carotenoid extracted from the traditional Chinese medical herb saffron. Previous studies have demonstrated that crocetin possesses anticancer properties that are effective against various cancers. As an extension of our earlier study, the present study explored the underlying mechanisms in crocetin's anticancer effect on KYSE-150 cells. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), Mitogen-activated protein kinases (MAPK), and p53/p21 signal pathways play an important role in carcinogenesis, progression, and metastasis of carcinoma cells. Thus, we investigated crocetin's effects on the PI3K/AKT, MAPK, and p53/p21 pathways in esophageal squamous carcinoma cell line KYSE-150 cells. METHODS: KYSE-150 cells were treated with various concentrations of crocetin. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltertrazolium bromide assay, Annexin V/PI stain as well as Rh123 stain were used to evaluate the cell viability, apoptosis, and MMP. Western blot was used to detect the expression of PI3K, AKT, ERK1/2, p38, c-Jun NH-terminal kinase (JNK), P53, P21, Bcl-2, Bax, and cleaved caspase-3, which were associated with cell proliferation and apoptosis. RESULTS: Our results showed that crocetin significantly inhibited the proliferation of KYSE-150 cells in a dose- and time-dependent manner. Crocetin also markedly induced cell apoptosis. Furthermore, we have found that crocetin not only inhibited the activation of PI3K/AKT, extracellular signal-regulated kinase-1/2 (ERK1/2), and p38 but also upregulated the p53/p21 level. These regulations ultimately triggered the mitochondrial-mediated apoptosis pathway with an eventual disruption of MMP, increased levels of Bax and cleaved caspase-3, and decreased levels of Bcl-2. CONCLUSIONS: These findings suggested that crocetin interfered with multiple signal pathways in KYSE-150 cells. Therefore, this study suggested that crocetin could potentially be used as a therapeutic candidate for the treatment of esophageal cancer.


Assuntos
Anticarcinógenos/farmacologia , Carotenoides/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Anticarcinógenos/administração & dosagem , Apoptose/efeitos dos fármacos , Carotenoides/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
5.
Food Funct ; 10(2): 893-902, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30694275

RESUMO

Isothiocyanates from cruciferous vegetables are known for their potential anti-carcinogenic activities. These isothiocyanates are frequently consumed together as part of a regular diet, but their combined effects on carcinogenesis have not been well studied. Herein, we tested the hypothesis that combination of two isothiocyanates, i.e. allyl isothiocyanate and sulforaphane, produced a synergy in inhibiting the growth of A549 lung cancer cells. Our results showed that the combination treatment led to a stronger growth inhibition than the singular treatment. Isobologram analysis proved that the enhanced inhibitory effect of the combination treatment was synergistic. Flow cytometry demonstrated that the combination treatment caused more extensive cell cycle arrest and apoptosis than the singular treatment with modified expression of key proteins regulating these cellular processes. The combined treatment resulted in the production of intracellular reactive oxygen species, which might contribute to the inhibitory effects on cancer cells. Moreover, a synergy between allyl isothiocyanate and sulforaphane was also observed in anti-cell migration. Collectively, our results have demonstrated the potential of different isothiocyanates used in combination to produce enhanced protective effects against carcinogenesis.


Assuntos
Anticarcinógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Isotiocianatos/uso terapêutico , Células A549 , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sinergismo Farmacológico , Conservantes de Alimentos/administração & dosagem , Conservantes de Alimentos/farmacocinética , Conservantes de Alimentos/uso terapêutico , Humanos , Isotiocianatos/administração & dosagem , Isotiocianatos/farmacocinética
6.
Int J Pharm ; 558: 311-318, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30641176

RESUMO

A new combination of sulforaphane (a natural compound obtained from Brassicaceae vegetables) and the cytostatic drug doxorubicin was entrapped in nanometer-sized liposomes. In vitro experiments were performed to investigate the cytotoxicity of these structures on the human breast cancer cell line MDA-MB-231. Confocal microscopy studies revealed enhanced cellular endocytotic internalization, followed by the release of the examined combination from the lysosomes. The in vitro interaction analysis using the Chou-Talalay approach showed high synergistic activity of the examined combination. This synergistic activity enables a considerable reduction in cytostatic dosage and an increase in cancer treatment efficiency.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Anticarcinógenos/administração & dosagem , Doxorrubicina/administração & dosagem , Isotiocianatos/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Lipossomos
7.
AAPS PharmSciTech ; 20(2): 49, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617655

RESUMO

3,3'-Diindolylmethane (DIM) is a phytochemical that presents health benefits (antitumor, antioxidant, and anti-inflammatory effects). However, it is water insoluble and thermo- and photolabile, restraining its pharmaceutical applications. As a strategy to overcome such limitations, this study aimed the development and characterization of DIM-loaded nanocapsules (NCs) prepared with different compositions as well as the in vitro assessment of scavenging activity and cytotoxicity. The formulations were obtained using the interfacial deposition of preformed polymer method and were composed by Eudragit® RS100 or ethylcellulose as polymeric wall and primula or apricot oil as the core. All the formulations had adequate physicochemical characteristics: nanometric size (around 190 nm), low polydispersity index (< 0.2), pH value at acid range, high values of zeta potential, drug content, and encapsulation efficiency (~ 100%). Besides, nanoencapsulation protected DIM against UVC-induced degradation and increased the scavenging activity assessed by the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) and 1-1-diphenyl-2-picrylhydrazyl methods. The developed DIM-loaded nanocapsules were further evaluated regarding the in vitro release profile and cytotoxicity against a human glioblastoma cell line (U87 cells). The results demonstrated that the nanoencapsulation promoted a sustained release of the bioactive compound (in the range of 58-78% after 84 h) in comparison to its free form (86% after 12 h), as well as provided a superior cytotoxic effect against the U87 cells in the highest concentrations. Therefore, our results suggest that nanoencapsulation could be a promising approach to overcome the DIM physicochemical limitations and potentialize its biological properties.


Assuntos
Anticarcinógenos/química , Citotoxinas/química , Depuradores de Radicais Livres/química , Glioma , Indóis/química , Nanocápsulas/química , Estimulação Luminosa/efeitos adversos , Anticarcinógenos/administração & dosagem , Anticarcinógenos/metabolismo , Linhagem Celular Tumoral , Citotoxinas/administração & dosagem , Citotoxinas/metabolismo , Estabilidade de Medicamentos , Depuradores de Radicais Livres/administração & dosagem , Depuradores de Radicais Livres/metabolismo , Glioma/metabolismo , Humanos , Indóis/administração & dosagem , Indóis/metabolismo , Nanocápsulas/administração & dosagem , Tamanho da Partícula , Óleos Vegetais/administração & dosagem , Óleos Vegetais/química , Óleos Vegetais/metabolismo
8.
Clin Sci (Lond) ; 132(24): 2583-2598, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30545896

RESUMO

Estrogens generated within endocrine organs and the reproductive system act as ligands for at least three types of estrogen receptors. Estrogen receptors α (ERα) and ß (ERß) belong to the so-called classical family of estrogen receptors, whereas the G protein-coupled receptor GPR30, also known as GPER-1, has been described as a novel estrogen receptor sited in the cell membrane of target cells. Furthermore, these receptors are under stimulation of a family of exogenous estrogens, known as phytoestrogens, which are a diverse group of non-steroidal plant compounds derived from plant food consumed by humans and animals. Because phytoestrogens are omnipresent in our daily diet, they are becoming increasingly important in both human health and disease. Recent evidence indicates that in addition to classical estrogen receptors, phytoestrogens also activate GPER-1 a relevant observation since GPER-1 is involved in several physiopathological disorders and especially in estrogen-dependent diseases such as breast cancer.The first estrogen receptors discovered were the classical ERα and ERß, but from an evolutionary point of view G protein-coupled receptors trace their origins in history to over a billion years ago suggesting that estrogen receptors like GPER-1 may have been the targets of choice for ancient phytoestrogens and/or estrogens.This review provides a comprehensive and systematic literature search on phytoestrogens and its relationship with classical estrogen receptors and GPER-1 including its role in breast cancer, an issue still under discussion.


Assuntos
Anticarcinógenos/administração & dosagem , Neoplasias da Mama/metabolismo , Antagonistas de Estrogênios/administração & dosagem , Glândulas Mamárias Humanas/efeitos dos fármacos , Fitoestrógenos/administração & dosagem , Receptores Acoplados a Proteínas-G/agonistas , Animais , Anticarcinógenos/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Exposição Dietética/efeitos adversos , Antagonistas de Estrogênios/efeitos adversos , Feminino , Humanos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Fitoestrógenos/efeitos adversos , Fatores de Proteção , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Medição de Risco , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos
9.
Food Funct ; 9(7): 3640-3656, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-29923573

RESUMO

High doses of ß-phenylethyl isothiocyanate (PEITC), a phytochemical in cruciferous vegetables, are not feasible for consumption due to a strong mouth-tingling effect. This study investigated the anti-cancer effect of PEITC at sensory acceptable doses. In vitro, PEITC was selectively toxic to oral cancer cells (CAL-27, FaDu, SCC4, SCC 9, SCC15, SCC25 and TU138), compared to oral keratinocytes (OKF6/TERT2 and NOK/Si). In vivo, 5 and 10 mg kg-1 PEITC, equivalent to human organoleptically acceptable doses, retarded tumor growth and prolonged the survival of mice bearing p53-mutated oral cancer cells - TU138 xenograft. Mechanistically, PEITC induced ROS accumulation, nuclear translocation of p53 and p21 and G1/S cell cycle arrest in vitro; increased p53 and 8-oxo-dG levels; and decreased Ki-67 intense/mild staining ratios without TUNEL changes in vivo. These findings suggested that the sensory acceptable doses of PEITC selectively induced ROS-mediated cell cycle arrest leading to delayed tumor progression and extended survival. PEITC could be a functional ingredient for oral cancer prevention.


Assuntos
Anticarcinógenos/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Isotiocianatos/administração & dosagem , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/fisiopatologia , Proteína Supressora de Tumor p53/genética , Animais , Anticarcinógenos/análise , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isotiocianatos/análise , Masculino , Camundongos , Camundongos Nus , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Paladar , Proteína Supressora de Tumor p53/metabolismo
10.
Nutrients ; 10(7)2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29941777

RESUMO

Lung cancer and chronic obstructive pulmonary disease have shared etiology, including key etiological changes (e.g., DNA damage and epigenetics change) and lung function impairment. Focusing on those shared targets may help in the prevention of both. Certain micronutrients (vitamins and minerals) and phytochemicals (carotenoids and phenols) have potent antioxidant or methyl-donating properties and thus have received considerable interest. We reviewed recent papers probing into the potential of nutrients with respect to lung function preservation and prevention of lung cancer risk, and suggest several hypothetical intervention patterns. Intakes of vitamins (i.e., A, C, D, E, B12), carotenoids, flavonoids, curcumins, resveratrol, magnesium, and omega-3 fatty acids all show protective effects against lung function loss, some mainly by improving average lung function and others through reducing decline rate. Dietary interventions early in life may help lung function reserve over the lifespan. Protective nutrient interventions among smokers are likely to mitigate the effects of cigarettes on lung health. We also discuss their underlying mechanisms and some possible causes for the inconsistent results in observational studies and supplementation trials. The role of the lung microbiome on lung health and its potential utility in identifying protective nutrients are discussed as well. More prospective cohorts and well-designed clinical trials are needed to promote the transition of individualized nutrient interventions into health policy.


Assuntos
Anticarcinógenos/administração & dosagem , Dieta Saudável , Neoplasias Pulmonares/prevenção & controle , Pulmão , Micronutrientes/administração & dosagem , Compostos Fitoquímicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Fatores Etários , Animais , Anticarcinógenos/efeitos adversos , Transformação Celular Neoplásica/patologia , Medicina Baseada em Evidências , Humanos , Pulmão/microbiologia , Pulmão/patologia , Pulmão/fisiopatologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/patologia , Micronutrientes/efeitos adversos , Estado Nutricional , Compostos Fitoquímicos/efeitos adversos , Prognóstico , Fatores de Proteção , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Fumar/efeitos adversos
11.
Nutrients ; 10(7)2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29954131

RESUMO

Several B vitamins are essential in the one-carbon metabolism pathway, which is central to DNA methylation, synthesis, and repair. Moreover, an imbalance in this pathway has been linked to certain types of cancers. Here, we performed a meta-analysis in order to investigate the relationship between the intake of four dietary one-carbon metabolism-related B vitamins (B2, B6, folate, and B12) and the risk of esophageal cancer (EC). We searched PubMed, Web of Science, and Embase for relevant studies published through 1 March 2018. The odds ratio (OR) with 95% confidence interval (CI) for the highest versus the lowest level of each dietary B vitamin was then calculated. From 21 articles reporting 26 studies including 6404 EC cases and 504,550 controls, we found an inverse correlation between the consumption of vitamin B6 and folate and the risk of EC; this association was specific to the US, Europe, and Australia, but was not found in Asia. A dose-response analysis revealed that each 100 μg/day increase in folate intake reduced the risk of EC by 12%. Moreover, each 1 mg/day increase in vitamin B6 intake decreased the risk of EC by 16%. Surprisingly, we found that each 1 μg/day increase in vitamin B12 intake increased the risk of esophageal adenocarcinoma by 2%, particularly in the US and Europe, suggesting both geographic and histological differences. Together, our results suggest that an increased intake of one-carbon metabolism-related B vitamins may protect against EC, with the exception of vitamin B12, which should be consumed in moderation.


Assuntos
Adenocarcinoma/prevenção & controle , Anticarcinógenos/administração & dosagem , Dieta , Neoplasias Esofágicas/prevenção & controle , Comportamento de Redução do Risco , Complexo Vitamínico B/administração & dosagem , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticarcinógenos/efeitos adversos , Metilação de DNA , Reparo do DNA , Replicação do DNA , DNA de Neoplasias/genética , Dieta/efeitos adversos , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Razão de Chances , Fatores de Proteção , Recomendações Nutricionais , Medição de Risco , Fatores de Risco , Vitamina B 12/administração & dosagem , Vitamina B 12/efeitos adversos , Complexo Vitamínico B/efeitos adversos , Adulto Jovem
12.
Biochem Biophys Res Commun ; 502(2): 187-193, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29792865

RESUMO

Aspirin is a novel chemopreventive agent against malignancy. However, outcomes of aspirin monotherapy of renal cell carcinoma (RCC) are inconsistent across studies. ABT-737, an BH3 mimetic inhibitor, is also a promising antitumor drug. Cancer cells including those from RCC, that have high levels of Mcl-1, are refractory to ABT-737-induced apoptosis. We here investigated how aspirin treatment modulates the ABT-737-induced apoptosis. Using the in vitro model of human 786-O cells, we showed that aspirin had sensitized cells to ABT-737 induced apoptosis. Such aspirin-induced changes of ABT-737 resistance was accompanied by a host of biochemical events like protein phosphatase 2A (PP2A) activation, AKT dephosphorylation, Mcl-1/FLICE inhibiting protein (FLIP)/XIAP downregulation, and Bax mitochondrial redistribution. The PP2A inhibitor, okadaic acid, was able to reverse the apirin-induced apoptotic changes. Apart from the aspirin treatment, Mcl-1 silencing also rendered cells vulnerable to ABT-737 induced apoptosis. Since PP2A, Akt, and Mcl-1 play critical roles in RCC malignancy and treatment resistance, our present study showed that aspirin, an alternative adjuvant agent, had recalled ABT-737 sensitivity in the RCC cells through processes involving the PP2A/Akt/Mcl-1 axis.


Assuntos
Aspirina/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nitrofenóis/administração & dosagem , Sulfonamidas/administração & dosagem , Anticarcinógenos/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Piperazinas/administração & dosagem , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética
13.
Biomed Pharmacother ; 103: 473-481, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29677532

RESUMO

Sulforaphane (SF) exhibits an anti-tumor effect in a variety of cancers, but little is known about its function in nasopharyngeal carcinoma. SF could decrease the expression of stem cell markers, ß-catenin, Nanog, c-Myc, Oct3/4 and Sox2 in nasopharyngeal cancer cells (HONE1 and SUN1), and inhibit the formation of tumor spheres. Moreover, SF inhibits proliferation and induces apoptosis decreasing the stemness of nasopharyngeal cancer cells through a mechanism related to STAT3 signaling in vitro. We found that SF inhibits total STAT3 expression level and STAT3 phosphorylation (troy 704 and troy 705) by upregulation of miRNA-124-3p. Our results provide the evidence for discovering the novel drugs against nasopharyngeal carcinoma, and potential drugs targeting STAT3 signaling pathway.


Assuntos
Autorrenovação Celular/efeitos dos fármacos , Isotiocianatos/administração & dosagem , Neoplasias Nasofaríngeas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fator de Transcrição STAT3/biossíntese , Anticarcinógenos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Autorrenovação Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Humanos , MicroRNAs/agonistas , MicroRNAs/biossíntese , Neoplasias Nasofaríngeas/tratamento farmacológico , Células-Tronco Neoplásicas/citologia , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
14.
Nutrients ; 10(4)2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29617306

RESUMO

Colorectal cancer occurs due to various factors. The important risks are dietary lifestyle and inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis. It has been found that the inhibitory enzyme cyclooxygenase-2 (COX-2) in the colorectal region can potentially reduce the risk of colorectal cancer. The present study investigated rice bran oil from natural purple rice bran, which exhibits antioxidant and anti-inflammatory activity. This study aimed to evaluate the bioactive compound content of natural purple rice bran oil (NPRBO) derived from native Thai purple rice and the anti-inflammatory activity of NPRBO in colorectal cancer cells, and to develop a colorectal delivery platform in the form of film-coated tablets. NPRBO from the rice bran of five different Thai purple rice cultivars, namely Khao’ Gam Leum-Phua (KGLP), Khao’ Gam Boung (KGB), Khao’ Gam Thor (KGT), Khao’ Gam Pah E-Kaw (KGPEK), and Khao’ Niaw Dam (KND), were extracted using the supercritical carbon dioxide extraction technique. The amount of γ-oryzanol (ORY), tocotrienols, and tocopherols present in NPRBOs and the in vitro anti-inflammatory activity of NPRBO were investigated. The highest anti-inflammatory NPRBO was transformed into a dry and free-flowing powder by liquisolid techniques. Then, it was compressed into core tablets and coated with Eudragit®L100 and Eudragit® NE30D. The in vitro release study of the film-coated NPRBO tablets was performed in three-phase simulated gastrointestinal media. The cultivar KGLP was superior to the other samples in terms of the ORY, tocotrienol and tocopherol contents and anti-inflammatory activity. Aerosil® was the most suitable absorbent for transforming NPRBO into a free-flowing powder and was used to prepare the NPRBO core tablets. The in vitro KGLP-NPRBO film-coated tablet release profile showed that no ORY was released at gastric pH while 85% of ORY was released at pH 7.4 after 6 h; this would be expected to occur in the colorectal area. Therefore, this study demonstrates the potential of KGLP-NPRBO to prevent colorectal cancer via a specific colorectal dietary supplement delivery system.


Assuntos
Anticarcinógenos/administração & dosagem , Neoplasias Colorretais/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Suplementos Nutricionais , Óleo de Farelo de Arroz/administração & dosagem , Administração Oral , Animais , Anticarcinógenos/química , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Suco Gástrico/química , Células HCT116 , Células HT29 , Humanos , Concentração de Íons de Hidrogênio , Secreções Intestinais/química , Metacrilatos/química , Camundongos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Polímeros/química , Ácidos Polimetacrílicos/química , Pós , Células RAW 264.7 , Óleo de Farelo de Arroz/química , Solubilidade , Comprimidos com Revestimento Entérico , Tecnologia Farmacêutica/métodos
15.
PLoS One ; 13(4): e0193544, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29617381

RESUMO

Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00828984.


Assuntos
Focos de Criptas Aberrantes/prevenção & controle , Anticarcinógenos/uso terapêutico , Neoplasias Colorretais/prevenção & controle , Receptores ErbB/análise , Laxantes/uso terapêutico , Polietilenoglicóis/uso terapêutico , Focos de Criptas Aberrantes/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticarcinógenos/administração & dosagem , Biomarcadores Tumorais/análise , Quimioprevenção , Neoplasias do Colo/patologia , Neoplasias do Colo/prevenção & controle , Neoplasias Colorretais/patologia , Método Duplo-Cego , Feminino , Humanos , Laxantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Polietilenoglicóis/administração & dosagem , Reto/patologia
16.
Eur J Pharm Sci ; 119: 49-61, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29630938

RESUMO

Coaxial electrospinning was used to develop gallic acid (GA) loaded poly(ethylene oxide)/zein nanofibers in order to improve its chemopreventive action on human gallbladder cancer cells. Using a Plackett-Burman design, the effects of poly(ethylene oxide) and zein concentration and applied voltage on the diameter and morphology index of nanofibers were investigated. Coaxial nanofibers were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). GA loading efficiency as high as 77% was obtained under optimal process conditions. The coaxial nanofibers controlled GA release in acid and neutral pH medium. Cytotoxicity and reactive oxygen species (ROS) production on gallbladder cancer cell lines GB-d1 and NOZ in the presence of GA-nanofibers were assessed. GA-nanofibers triggered an increase in the cellular cytotoxicity compared with free GA on GB-d1 and NOZ cells. Statistically significant differences were found in ROS levels of GA-nanofibers compared with free GA on NOZ cells. Differently, ROS production on GB-d1 cell line was similar. Based on these results, the coaxial nanofibers obtained in this study under optimized operational conditions offer an alternative for the development of a GA release system with improved chemopreventive action on gallbladder cancer cells.


Assuntos
Anticarcinógenos/administração & dosagem , Antineoplásicos/administração & dosagem , Ácido Gálico/administração & dosagem , Nanofibras/administração & dosagem , Polietilenoglicóis/administração & dosagem , Zeína/administração & dosagem , Anticarcinógenos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioprevenção , Liberação Controlada de Fármacos , Neoplasias da Vesícula Biliar/prevenção & controle , Ácido Gálico/química , Humanos , Concentração de Íons de Hidrogênio , Nanofibras/química , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Zeína/química
17.
PLoS One ; 13(3): e0193918, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29518137

RESUMO

Breast cancer is the most common malignancy in women of the Western world. Doxorubicin (DOX) continues to be used extensively to treat early-stage or node-positive breast cancer, human epidermal growth factor receptor-2 (HER2)-positive breast cancer, and metastatic disease. We have previously demonstrated in a mouse model that sulforaphane (SFN), an isothiocyanate isolated from cruciferous vegetables, protects the heart from DOX-induced toxicity and damage. However, the effects of SFN on the chemotherapeutic efficacy of DOX in breast cancer are not known. Present studies were designed to investigate whether SFN alters the effects of DOX on breast cancer regression while also acting as a cardioprotective agent. Studies on rat neonatal cardiomyocytes and multiple rat and human breast cancer cell lines revealed that SFN protects cardiac cells but not cancer cells from DOX toxicity. Results of studies in a rat orthotopic breast cancer model indicated that SFN enhanced the efficacy of DOX in regression of tumor growth, and that the DOX dosage required to treat the tumor could be reduced when SFN was administered concomitantly. Additionally, SFN enhanced mitochondrial respiration in the hearts of DOX-treated rats and reduced cardiac oxidative stress caused by DOX, as evidenced by the inhibition of lipid peroxidation, the activation of NF-E2-related factor 2 (Nrf2) and associated antioxidant enzymes. These studies indicate that SFN not only acts synergistically with DOX in cancer regression, but also protects the heart from DOX toxicity through Nrf2 activation and protection of mitochondrial integrity and functions.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Isotiocianatos/farmacologia , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Citocinas/sangue , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Isotiocianatos/administração & dosagem , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Food Funct ; 9(4): 2398-2408, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29595853

RESUMO

Phenethyl isothiocyanate (PEITC) is a naturally occurring compound found in some cruciferous vegetables. Dibenzoylmethane (DBM) is a minor constituent of licorice. Both compounds have been shown to exert anticancer activities. In the present study, we determined the effects of PEITC and DBM alone or in combination on androgen-independent growth of human prostate cancer cells cultured in vitro and prostate VCaP xenograft tumors in severe combined immunodeficient (SCID) mice. PEITC and DBM in combination had stronger effects on inhibiting the growth and inducing apoptosis than either compound alone in cultured prostate cancer cells. The combination also strongly inhibited cell migration and the formation of tumorspheres in VCaP cells. Mechanistic studies showed that the combined effects of PEITC and DBM on growth inhibition and apoptosis were associated with suppression of nuclear factor-κB (NF-κB), and a decrease in the levels of survivin and phospho-Akt (pAkt). In the in vivo study, SCID mice bearing VCaP tumors were surgically castrated and treated with PEITC and/or DBM. Treatment with PEITC and DBM in combination resulted in a strong inhibition of the progression of androgen-dependent VCaP prostate tumors to androgen independence. Our results indicate that administration of DBM and PEITC in combination may be an effective strategy for inhibiting/delaying the progression of prostate cancer to androgen independence.


Assuntos
Androgênios/metabolismo , Anticarcinógenos/administração & dosagem , Chalconas/administração & dosagem , Isotiocianatos/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Masculino , Camundongos , Camundongos SCID , Neoplasias da Próstata/fisiopatologia
19.
Int J Pharm ; 541(1-2): 206-213, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29486285

RESUMO

This study sought to evaluate the antitumor effects of and elucidate the mechanisms underlying (-)-epigallocatechin-3-O-gallate (EGCG) and polyethyleneglycol (PEG)-modified liposomes. EGCG functions as a target ligand of the 67-kDa laminin receptor (67LR), which is expressed on high-grade tumor cells. An EGCG derivative was synthesized for binding to the end of PEG. Doxorubicin (DOX)-loaded EGCG-PEG-modified liposome (EPL) significantly decreased tumor size in mice bearing high 67LR-high-expressing tumors. Caspase-3 activity, which indicates induction of apoptosis, was also elevated only in the EPL group. The importance of PEG for the antitumor effects of EGCG was noted, as soluble EGCG did not accumulate at a sufficient concentration to exert an apoptotic effect. Moreover, EPL significantly increased caspase-8 activity, suggesting that EPL-induced apoptosis occurred due to caspase-8 activity induced following the binding of EGCG to 67LR as a cell-death ligand. In conclusion, EPL appear to have superior antitumor activity against high 67LR-expressing tumor cells, as the liposomes had dual effects, namely antitumor effects due to the loaded DOX and apoptosis induced by the bound EGCG.


Assuntos
Anticarcinógenos/administração & dosagem , Catequina/análogos & derivados , Doxorrubicina/administração & dosagem , Polietilenoglicóis/química , Receptores de Laminina/metabolismo , Inibidores da Topoisomerase II/administração & dosagem , Animais , Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Catequina/administração & dosagem , Catequina/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Humanos , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Tecidual , Inibidores da Topoisomerase II/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nutrients ; 10(1)2018 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-29300347

RESUMO

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, accounting for 15% of all cancers in men worldwide. Asian populations consume soy foods as part of a regular diet, which may contribute to the lower PCa incidence observed in these countries. This meta-analysis provides a comprehensive updated analysis that builds on previously published meta-analyses, demonstrating that soy foods and their isoflavones (genistein and daidzein) are associated with a lower risk of prostate carcinogenesis. Thirty articles were included for analysis of the potential impacts of soy food intake, isoflavone intake, and circulating isoflavone levels, on both primary and advanced PCa. Total soy food (p < 0.001), genistein (p = 0.008), daidzein (p = 0.018), and unfermented soy food (p < 0.001) intakes were significantly associated with a reduced risk of PCa. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with PCa risk. Neither soy food intake nor circulating isoflavones were associated with advanced PCa risk, although very few studies currently exist to examine potential associations. Combined, this evidence from observational studies shows a statistically significant association between soy consumption and decreased PCa risk. Further studies are required to support soy consumption as a prophylactic dietary approach to reduce PCa carcinogenesis.


Assuntos
Anticarcinógenos/administração & dosagem , Dieta , Neoplasias da Próstata/prevenção & controle , Comportamento de Redução do Risco , Alimentos de Soja , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Dieta/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Nutritivo , Razão de Chances , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/etnologia , Fatores de Proteção , Fatores de Risco
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