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1.
Adv Exp Med Biol ; 1308: 55-89, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33861437

RESUMO

Malignant conditions of the gastrointestinal tract and accessory organs of digestion, including the oral cavity, esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus, are referred to as gastrointestinal cancers. Curcumin is a natural compound derived from turmeric with a wide range of biological activities. Several in vitro and in vivo studies have investigated the effects of curcumin on gastrointestinal cancers. In the current review, we aimed to provide an updated summary on the recent findings regarding the beneficial effects of curcumin on different gastrointestinal cancers in the recent decade. For this purpose, ScienceDirect," "Google Scholar," "PubMed," "ISI Web of Knowledge," and "Wiley Online Library" databases were searched using "curcumin", "cancer", and "gastrointestinal organs" as keywords. In vitro studies performed on different gastrointestinal cancerous cell lines have shown that curcumin can inhibit cell growth through cycle arrest at the G2/M and G1 phases, as well as stimulated apoptosis and autophagy by interacting with multiple molecular targets. In vivo studies performed in various animal models have confirmed mainly the chemopreventive effects of curcumin. Several nano-formulations have been proposed to improve the bioavailability of curcumin and increase its absorption. Moreover, curcumin has been used in combinations with many anti-tumor drugs to increase their anticarcinogenic properties. Taken together, curcumin falls within the category of plant-derived substances capable of preventing or treating gastrointestinal cancers. Further studies, particularly clinical trials, on the efficacy and safety of curcumin are suggested in this regard.


Assuntos
Anticarcinógenos , Antineoplásicos , Curcumina , Neoplasias Gastrointestinais , Animais , Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Curcumina/farmacologia , Curcumina/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico
2.
Molecules ; 26(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801899

RESUMO

Natural products are important sources for drug discovery, especially anti-tumor drugs. ß-Elemene, the prominent active ingredient extract from the rhizome of Curcuma wenyujin, is a representative natural product with broad anti-tumor activities. The main molecular mechanism of ß-elemene is to inhibit tumor growth and proliferation, induce apoptosis, inhibit tumor cell invasion and metastasis, enhance the sensitivity of chemoradiotherapy, regulate the immune system, and reverse multidrug resistance (MDR). Elemene oral emulsion and elemene injection were approved by the China Food and Drug Administration (CFDA) for the treatment of various cancers and bone metastasis in 1994. However, the lipophilicity and low bioavailability limit its application. To discover better ß-elemene-derived anti-tumor drugs with satisfying drug-like properties, researchers have modified its structure under the premise of not damaging the basic scaffold structure. In this review, we comprehensively discuss and summarize the potential anti-tumor mechanisms and the progress of structural modifications of ß-elemene.


Assuntos
Sesquiterpenos/química , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacologia , Anticarcinógenos/metabolismo , Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , China , Curcuma/metabolismo , Humanos , Sesquiterpenos Monocíclicos/química , Sesquiterpenos Monocíclicos/metabolismo , Sesquiterpenos Monocíclicos/farmacologia , Rizoma/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Life Sci ; 274: 119335, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713663

RESUMO

AIM: Evaluating the possible protective effect of thymol as an approach against 1,2 N,N-dimethylhydrazine and/or high-fat diet (HFD)-induced colon cancer. MAIN METHODS: Adult male Wistar rats were divided into 7 groups, namely a normal control group, colon cancer groups received DMH (40 mg/kg i.p., twice weekly), 20% HFD and DMH/HFD, thymol (20 mg/kg/day, p.o.), thymol/DMH and thymol/DMH/HFD (treatment of all groups continued for 16 weeks). KEY FINDINGS: Thymol significantly reduced the elevated serum levels of colon related tumor markers carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) as well as the apoptotic marker, caspase-3 compared with the colon cancer group. In addition, it mitigated colonic tissue oxidative stress markers and inflammatory mediators. Moreover, the histopathological study revealed reduction of mucous secretion with elongated nuclei, frequent mitotic figures, focal nuclear stratification, mild interstitial edema, and markedly dilated congested blood vessels, aberrant crypt foci (ACF); adenoma with moderate to severe dysplasia of colon corrected by thymol treatment. SIGNIFICANCE: The administration of thymol had a promising preclinical protective efficacy and could be considered as a new strategy for the prophylaxis from colon cancer in clinical practices.


Assuntos
1,2-Dimetilidrazina/toxicidade , Anticarcinógenos/farmacologia , Carcinógenos/toxicidade , Neoplasias do Colo/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , NF-kappa B/metabolismo , Timol/farmacologia , Animais , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Masculino , NF-kappa B/genética , Ratos , Ratos Wistar
4.
Mol Carcinog ; 60(3): 213-223, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33544936

RESUMO

The overexpression and amplification of the protooncogene neu (ERBB2) play an important role in the development of aggressive breast cancer (BC) in humans. Ral-interacting protein (RLIP), a modular stress-response protein with pleiotropic functions, is overexpressed in several types of cancer, including BC. Here, we show that blocking RLIP attenuates the deleterious effects caused by the loss of the tumor suppressor p53 and inhibits the growth of human BC both in vitro and in vivo in MMTV-neu mice. In addition, we show that treatment with the diet-derived, RLIP-targeting chemotherapeutic 2'-hydroxyflavanone (2HF), alone or in combination with RLIP-specific antisense RNA or antibodies, significantly reduced the cumulative incidence and/or burden of mammary hyperplasia and carcinoma in MMTV-neu mice. 2HF treatment correlated with reduced tumor cell proliferation and increased apoptosis, and the average number of Ki67-positive (proliferating) cells was significantly lower in the tumors of 2HF-treated mice than in the tumors of control mice. Furthermore, targeting RLIP also resulted in the overexpression of E-cadherin and the infiltration of CD3+ T cells into mammary tumors. Taken together, these results underscore the translational potential of RLIP-targeting agents and provide a strong rationale to validate them in the clinic.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Anticarcinógenos/farmacologia , Neoplasias da Mama/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Neoplasias Mamárias Experimentais/prevenção & controle , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Flavanonas/farmacologia , Proteínas Ativadoras de GTPase/genética , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos Transgênicos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor ErbB-2/metabolismo
5.
Phytomedicine ; 83: 153489, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33571919

RESUMO

BACKGROUND: Patients with inflammatory bowel disease are at increased risks of developing ulcerative colitis-associated colorectal cancer (CAC). Vitexin can suppress the proliferation of colorectal carcinoma cells in vitro orin vivo. However, different from colorectal carcinoma, CAC is more consistent with the transformation from inflammation to cancer in clinical chronic IBD patients. Therefore, we aim to investigated that vitexin whether possess benefic effects on CAC mice. PURPOSE: We aimed to determine the beneficial effects of vitexin on CAC mice and reveal its underlying mechanism. METHODS: The mouse CAC model was induced by Azoxymethane and dextran sodium sulfate (AOM/DSS) and CAC mice were treated with vitexin. At the end of this study, inflammatory cytokines of IL-1ß, IL-6, TNF-α, IL-10 as well as nitric oxide (NO) were detected by kits after long-term treatment of vitexin. Pathological changes and macrophage polarization were determined by H&E and immunofluorescence in adjacent noncancerous tissue and carcinomatous tissue respectively of CAC mice. RESULTS: Our results showed that oral administration of vitexin could significantly improve the clinical signs and symptoms of chronic colitis, relieve colon damage, regulate colonic inflammatory cytokines, as well as suppress tumor incidence and tumor burden. Interesting, vitexin caused a significant increase in serum level of NO and a higher content of NO in tumor tissue. In addition, vitexin significantly decreased M1 phenotype macrophages in the adjacent noncancerous tissue, while markedly up-regulated M1 macrophage polarization in the tumor tissue in the colon of CAC mice. CONCLUSION: Vitexin can attenuate chronic colitis-associated carcinogenesis induced by AOM/DSS in mice and its protective effects are partly associated with its alternations in macrophage polarization in the inflammatory and tumor microenvironment .


Assuntos
Apigenina/farmacologia , Colite/patologia , Neoplasias Colorretais/prevenção & controle , Macrófagos/efeitos dos fármacos , Animais , Anticarcinógenos/farmacologia , Azoximetano/toxicidade , Carcinogênese/efeitos dos fármacos , Colite/induzido quimicamente , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo
6.
Nutrients ; 13(2)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33503851

RESUMO

BACKGROUND: Earlier studies have demonstrated that a single-domain intervention, such as a brain-training (BT) game alone and a sulforaphane (SFN) intake, positively affects cognition. This study examined whether a combined BT and SFN intake intervention has beneficial effects on cognitive function in older adults. METHODS: In a 12-week double-blinded randomized control trial, 144 older adults were randomly assigned to one of four groups: BT with SFN (BT-S), BT with placebo (BT-P), active control game (AT) with SFN (AT-S), and active control game with placebo (AT-P). We used Brain Age in BT and Tetris in AT. Participants were asked to play BT or AT for 15 min a day for 12 weeks while taking a supplement (SFN or placebo). We measured several cognitive functions before and after the intervention period. RESULTS: The BT (BT-S and BT-P) groups showed more improvement in processing speed than the active control groups (AT-S and AT-P). The SFN intake (BT-S and AT-S) groups recorded significant improvements in processing speed and working memory performance unlike the placebo intake groups (BT-P and AT-P). However, we did not find any evidence of the combined intervention's beneficial effects on cognition. DISCUSSION: We discussed a mechanism to improve cognitive functions in the BT and SFN alone interventions.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Jogos Experimentais , Isotiocianatos/farmacologia , Sulfóxidos/farmacologia , Idoso , Anticarcinógenos/farmacologia , Método Duplo-Cego , Função Executiva/efeitos dos fármacos , Função Executiva/fisiologia , Feminino , Humanos , Masculino , Testes Neuropsicológicos
7.
Aging (Albany NY) ; 13(2): 1649-1670, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33471780

RESUMO

The broccoli-derived isothiocyanate sulforaphane inhibits inflammation, oxidative stress and cancer, but its effect on healthspan and longevity are unclear. We used the C. elegans nematode model and fed the wildtype and 9 mutant strains ±sulforaphane. The lifespan, phenotype, pharyngeal pumping, mobility, lipofuscin accumulation, and RNA and protein expression of the nematodes were assessed by using Kaplan-Meier survival analysis, in vivo live imaging, fluorescence microscopy, and qRT-PCR. Sulforaphane increased the lifespan and promoted a health-related phenotype by increasing mobility, appetite and food intake and reducing lipofuscin accumulation. Mechanistically, sulforaphane inhibited DAF-2-mediated insulin/insulin-like growth factor signaling and its downstream targets AGE-1, AKT-1/AKT-2. This was associated with increased nuclear translocation of the FOXO transcription factor homolog DAF-16. In turn, the target genes sod-3, mtl-1 and gst-4, known to enhance stress resistance and lifespan, were upregulated. These results indicate that sulforaphane prolongs the lifespan and healthspan of C. elegans through insulin/IGF-1 signaling. Our results provide the basis for a nutritional sulforaphane-enriched strategy for the promotion of healthy aging and disease prevention.


Assuntos
Anticarcinógenos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Isotiocianatos/farmacologia , Longevidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sulfóxidos/farmacologia , Animais , Apetite/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Receptor de Insulina/metabolismo
8.
Phytomedicine ; 81: 153432, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33310310

RESUMO

BACKGROUND: A natural pterostilbene analogue isolated from the herb Sphaerophysa salsula, 3'-hydroxypterostilbene (HPSB), exhibits antiproliferative activity in several cancer cell lines; however, the inhibitory effects of HPSB on skin carcinogenesis remains unclear. PURPOSE: The aim of this study was to evaluate the inhibitory effects of HPSB on two-stage skin carcinogenesis in mice and its potential mechanism. STUDY DESIGN AND METHODS: This study investigated the anti-inflammatory and anti-tumor effects of HPSB in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated acute skin inflammation and 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced two-stage skin carcinogenesis model. In addition, the effects of HPSB on the modulation of the phase I and phase II metabolizing enzymes in the DMBA-induced HaCaT cell model were investigated. RESULTS: The results provide evidence that topical treatment with HPSB significantly inhibits TPA-induced epidermal hyperplasia and leukocyte infiltration through the down-regulation of cyclooxygenase-2 (COX-2), matrix metalloprotein-9 (MMP-9), and ornithine decarboxylase (ODC) protein expression in mouse skin. Furthermore, HPSB suppresses DMBA/TPA-induced skin tumor incidence and multiplicity via the inhibition of proliferating cell nuclear antigen (PCNA), Cyclin B1 and cyclin-dependent kinase 1 (CDK1) expression in the two-stage skin carcinogenesis model. In addition, pretreatment with HPSB markedly reduces DMBA-induced cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) gene expression in human keratinocytes; however, HPSB does not significantly affect the gene expression of the phase II enzymes. CONCLUSION: This is the first study to show that topical treatment with HPSB prevents mouse skin tumorigenesis. Overall, our study suggests that natural HPSB may serve as a novel chemopreventive agent capable of preventing carcinogen activation and inflammation-associated tumorigenesis.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Anticarcinógenos/farmacologia , Neoplasias Cutâneas/prevenção & controle , Estilbenos/farmacologia , Acetato de Tetradecanoilforbol/toxicidade , Administração Tópica , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos/administração & dosagem , Carcinógenos/toxicidade , Ciclo-Oxigenase 2/metabolismo , Erupção por Droga/etiologia , Erupção por Droga/prevenção & controle , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Camundongos Endogâmicos ICR , Ornitina Descarboxilase/metabolismo , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia , Estilbenos/administração & dosagem
9.
Biomed Pharmacother ; 134: 111140, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33360052

RESUMO

Theanine and theobromine are abundantly present in tea and cocoa, respectively. This study was performed to assess the chemopreventive effects of these phytochemicals, alone or together, on dimethylhydrazine (DMH)-induced colon cancer. Thirty male Wistar rats were divided into five groups and subcutaneously injected with saline (negative control group) or 30 mg/kg DMH (the other groups) two times/week for 12 weeks. The negative and positive control animals were orally treated with drinking water, and the other groups were gavaged with theanine (400 mg/kg), theobromine (100 mg/kg), or their mixture for two weeks before and throughout the injection period. At the end of the study, the morphological and histopathological features, Ki-67 proliferation marker, and the expression of Akt/mTOR, JAK2/STAT3, MAPK/ERK, and TGF-ß/Smad pathways were investigated. Theanine and theobromine, alone or together, reduced the number of cancerous and precancerous lesions, the volume of tumors, the Ki-67 immunostaining, and the expression of Akt/mTOR and JAK2/STAT3 oncogenic pathways. The simultaneous treatment was more effective in the down-regulation of Akt and mTOR compared to either theanine or theobromine alone. Theobromine administration also caused more inhibitory effects on the Ki-67 and Akt/mTOR expression than theanine. Besides, all dietary interventions increased the mRNA and protein expression of Smad2. In conclusion, theanine and theobromine, alone and in combination, inhibited tumorigenesis through down-regulation of the Akt/mTOR and JAK2/STAT3 pathways and an increment of the Smad2 tumor suppressor. The inhibition of the Akt/mTOR pathway was more pronounced by simultaneous treatment.


Assuntos
Anticarcinógenos/farmacologia , Colo/efeitos dos fármacos , Neoplasias do Colo/prevenção & controle , Glutamatos/farmacologia , Teobromina/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dimetilidrazinas , Modelos Animais de Doenças , Janus Quinase 2/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
10.
Molecules ; 25(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33322081

RESUMO

Selenium (Se) is an essential trace element, which represents an integral part of glutathione peroxidase and other selenoproteins involved in the protection of cells against oxidative damage. Selenomethionine (SeMet), selenocysteine (SeCys), and methylselenocysteine (MeSeCys) are the forms of Se that occur in living systems. Se-containing compounds have been found to reduce carcinogenesis of animal models, and dietary supplemental Se might decrease cancer risk. Se is mainly taken up by plant roots in the form of selenate via high-affinity sulfate transporters. Consequently, owing to the chemical similarity between Se and sulfur (S), the availability of S plays a key role in Se accumulation owing to competition effects in absorption, translocation, and assimilation. Moreover, naturally occurring S-containing compounds have proven to exhibit anticancer potential, in addition to other bioactivities. Therefore, it is important to understand the interaction between Se and S, which depends on Se/S ratio in the plant or/and in the growth medium. Brassicaceae (also known as cabbage or mustard family) is an important family of flowering plants that are grown worldwide and have a vital role in agriculture and populations' health. In this review we discuss the distribution and further interactions between S and Se in Brassicaceae and provide several examples of Se or Se/S biofortifications' experiments in brassica vegetables that induced the chemopreventive effects of these crops by enhancing the production of Se- or/and S-containing natural compounds. Extensive further research is required to understand Se/S uptake, translocation, and assimilation and to investigate their potential role in producing anticancer drugs.


Assuntos
Anticarcinógenos/química , Anticarcinógenos/farmacologia , Brassicaceae/química , Quimioprevenção , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Selênio/química , Enxofre/química , Animais , Humanos , Compostos de Selênio/química , Compostos de Selênio/farmacologia , Relação Estrutura-Atividade , Compostos de Enxofre/química , Compostos de Enxofre/farmacologia , Verduras
11.
Sci Rep ; 10(1): 22244, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335263

RESUMO

Effective drugs are needed for lung cancer, as this disease remains the leading cause of cancer-related deaths. Rexinoids are promising drug candidates for cancer therapy because of their ability to modulate genes involved in inflammation, cell proliferation or differentiation, and apoptosis through activation of the retinoid X receptor (RXR). The only currently FDA-approved rexinoid, bexarotene, is ineffective as a single agent for treating epithelial cancers and induces hypertriglyceridemia. Here, we used a previously validated screening paradigm to evaluate 23 novel rexinoids for biomarkers related to efficacy and safety. These biomarkers include suppression of inducible nitric oxide synthase (iNOS) and induction of sterol regulatory element-binding protein (SREBP). Because of its potent iNOS suppression, low SREBP induction, and activation of RXR, MSU-42011 was selected as our lead compound. We next used MSU-42011 to treat established tumors in a clinically relevant Kras-driven mouse model of lung cancer. KRAS is one of the most common driver mutations in human lung cancer and correlates with aggressive disease progression and poor patient prognosis. Ultrasound imaging was used to detect and monitor tumor development and growth over time in the lungs of the A/J mice. MSU-42011 markedly decreased the tumor number, size, and histopathology of lung tumors compared to the control and bexarotene groups. Histological sections of lung tumors in mice treated with MSU-42011 exhibited reduced cell density and fewer actively proliferating cells compared to the control and bexarotene-treated tumors. Although bexarotene significantly (p < 0.01) elevated plasma triglycerides and cholesterol, treatment with MSU-42011 did not increase these biomarkers, demonstrating a more favorable toxicity profile in vivo. The combination of MSU-42011 and carboplatin and paclitaxel reduced macrophages in the lung and increased activation markers of CD8+T cells compared to the control groups. Our results validate our screening paradigm for in vitro testing of novel rexinoids and demonstrate the potential for MSU-42011 to be developed for the treatment of KRAS-driven lung cancer.


Assuntos
Anticarcinógenos/farmacologia , Carcinógenos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores X Retinoide/agonistas , Tetra-Hidronaftalenos/farmacologia , Animais , Anticarcinógenos/química , Apoptose/efeitos dos fármacos , Bexaroteno/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Imuno-Histoquímica , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Camundongos , Estrutura Molecular , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Tetra-Hidronaftalenos/química , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Environ Pathol Toxicol Oncol ; 39(2): 137-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749123

RESUMO

Lung carcinogenesis is one of the main sources of cancer-related mortality globally and it is estimated that nearly 1 million people die from it every year. The 5-year survival rate of lung carcinogenesis is reported at just 15%. The aim of the current research was to investigate the immunomodulatory effect of eriocitrin against benzo(a)pyrene [B(a) P]-induced lung tumorigenesis in Swiss albino mice. The lung sarcoma was provoked through oral gavage of B(a)P (50 mg/kg body weight) two times/week for four weeks. CEA, lung weight, lipid peroxidation (LPO), body weight, immuno-globulin (IgG, IgA, and IgM), tumor incidence, serum marker enzymes (LDH, AHH, λ-GT, and 5'-NTs), hematological counts (leucocytes, lymphocytes, neutrophils, absolute numbers of lymphocytes and neutrophils), antioxidants (SOD and CAT), inflammatory modulators (IL-1ß, IL-6, and TNF-α), immune complexes (avidity index, phagocyte index, NBT reduction, and SIC) and histopathological changes were analyzed. Moreover, the status of apoptosis proteins (Bax, caspase-9, and caspase-3) and cell proliferative protein (cyclin D1 and cyclin A) expression was determined by Western blot and PCNA by immunohistochemical analysis. B(a)P-challenged cancer-bearing mice exhibited augmented levels of lipid peroxidation, tumor incidence, lung weight, CEA, serum marker enzymes, IgA, SIC, cell proliferative markers, and inflammatory cytokines with concurrent decrease in body weight, antioxidant levels, hematological counts, immunoglobulins, immune complexes, and apoptotic protein expression. The eriocitrin treatments caused significant reversion of all these marker to previous levels. Overall, the results propose the immunomodulatory prospective of eriocitrin against B(a) P-induced lung carcinogenesis on Swiss albino mice.


Assuntos
Flavanonas/farmacologia , Fatores Imunológicos/farmacologia , Neoplasias Pulmonares/prevenção & controle , Animais , Anticarcinógenos/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Benzo(a)pireno/toxicidade , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Imunoglobulinas/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Fagócitos/efeitos dos fármacos
13.
Life Sci ; 261: 118348, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860803

RESUMO

AIMS: 3,3'-Diindolylmethane (DIM) has limited anti-cancer effects in gastric cancer. Hydrogen sulfide (H2S) plays an important role in the tumor development and therapy, cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE), two key endogenous H2S biosynthesis enzymes, can affect endogenous H2S levels and alter cancer treatment. Our main objective was to investigate whether the aminooxyacetic acid (AOAA) and DL-Propargylglycine (PAG), two specific inhibitors of CBS and CSE, could assist DIM to exert a stronger anti-cancer effects in gastric cancer BGC-823 and SGC-7901 cells. MATERIALS AND METHODS: Cell proliferation was assayed by MTT and cell colony-forming assay. Apoptosis and migration were detected by Hoechst staining and scratch test respectively. Western blot was used to evaluate the expression of proteins related to proliferation, apoptosis and migration. KEY FINDINGS: Combination of AOAA or PAG with DIM synergistically inhibited proliferation and migration, increased apoptosis in gastric cancer cells. The p38-p53 axis was also further activated by the combination of AOAA or PAG with DIM. Exogenous H2S from sodium hydrosulfide, attenuated the efficacy of DIM in cancer cells by reducing the activation level of p38-p53 axis. Taken together, AOAA or PAG inhibited the expression of endogenous H2S biosynthesis enzymes and effectively enhanced susceptibility of gastric cancer to DIM through activating p38-p53 axis. SIGNIFICANCE: The current study highlight more precise requirements for the clinical application of sulfur-containing anti-cancer drugs, and open a new way to enhance the sensitivity of DIM in chemotherapy of gastric cancer.


Assuntos
Anticarcinógenos/farmacologia , Sulfeto de Hidrogênio/antagonistas & inibidores , Indóis/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Alquinos/administração & dosagem , Alquinos/farmacologia , Ácido Amino-Oxiacético/administração & dosagem , Ácido Amino-Oxiacético/farmacologia , Anticarcinógenos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Sinergismo Farmacológico , Glicina/administração & dosagem , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Indóis/administração & dosagem , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Mutat Res ; 854-855: 503201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32660825

RESUMO

Oxidative stress is a critical factor in the pathogenesis of several gastrointestinal diseases. Sulforaphane (SFN), a bioactive compound found in cruciferous vegetables, activates the redox-sensitive nuclear erythroid 2-related factor 2 (NRF2). In addition to its protective role, SFN exerts cytotoxic effects on cancer cells. However, there is a lack of information concerning the toxicity of SFN in normal cells. We investigated the effects of SFN on cell viability, antioxidant defenses, and gene expression in human stomach mucosa cells (MNP01). SFN reduced ROS formation and protected the cells against induced oxidative stress but high concentrations increased apoptosis. An intermediate SFN concentration (8 µM) was chosen for RNA sequencing studies. We observed upregulation of genes of the NRF2 (antioxidant) pathway, the DNA damage response, and apoptosis signaling; whereas SFN downregulated cell cycle and DNA repair pathway genes. SFN may be cytoprotective at low concentrations and cytotoxic at high concentrations.


Assuntos
Apoptose/efeitos dos fármacos , Isotiocianatos/farmacologia , Membrana Mucosa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estômago/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Membrana Mucosa/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
15.
Toxicol Appl Pharmacol ; 401: 115100, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512070

RESUMO

(-)-Epigallocatechin-3-gallate (EGCG) is the main bioactive component in tea (Camellia sinensis) catechins, and exhibits potential antitumor activity against colorectal cancer (CRC). However, the underlying mechanisms are largely unclear. We investigated the effects of EGCG on activities of CRC cells and the exact molecular mechanism. We used human colon cancer cells (HT-29) and exposed them to EGCG at various concentrations. The MTT assay, flow cytometry, and TUNEL staining were used to study the underlying mechanisms of EGCG (proliferation, apoptosis, autophagy). Western blotting was used to measure expression of marker proteins of the cell cycle, apoptosis, and autophagy. Using a combined microarray-based transcriptomic and ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-QTOF/MS)-based metabolomic approach, we investigated the perturbed pathways induced by EGCG treatment at transcript and metabolite levels. Transcriptomic analyses showed that 486 genes were differentially expressed between untreated and EGCG-treated cells. Also, 88 differentially expressed metabolites were identified between untreated and EGCG-treated cells. The altered metabolites were involved in the metabolism of glutathione, glycerophospholipids, starch, sucrose, amino sugars, and nucleotide sugars. There was substantial agreement between the results of transcriptomics and metabolomics analyses. Our data indicate that the anticancer activity of EGCG against HT-29 cells is mediated by induction of cell-cycle arrest, apoptosis, and autophagy. EGCG modulates cancer-cell metabolic pathways. These results provide a platform for future molecular mechanistic studies of EGCG.


Assuntos
Anticarcinógenos/farmacologia , Catequina/análogos & derivados , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Metabolômica/métodos , Transcriptoma/efeitos dos fármacos , Anticarcinógenos/uso terapêutico , Catequina/farmacologia , Catequina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias do Colo/tratamento farmacológico , Células HT29 , Humanos , Transcriptoma/fisiologia
16.
PLoS One ; 15(4): e0232009, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353018

RESUMO

Non-melanoma skin cancer (NMSC) has a high and increasing incidence all over the world. Solar radiation is the main aetiology for humans. Although most research into photocarcinogenesis uses UVB as a source of radiation, UVA is also carcinogenic in long term. Pomegranate (PGE) and cocoa (CE) extracts have been used for medicinal purposes for time immemorial. Recently, it has been claimed that some of their properties may be an effective preventative measure against photocarcinogenesis and photoaging, but to date in vivo models have not been tested using RUVA, the objective of the present work. A lower incidence of lesions was observed in SKH-1 mice treated with PGE (p<0.001), and lower incidence of invasive squamous carcinoma in both treatment groups (p<0.001 for PGE and p<0.05 for CE); the PGE group also showed a lower level of cell proliferation than the control group (p<0.001). Significantly greater p53 alteration was observed in the control group than the treatment groups (p<0.001 for PGE and p = 0.05 for CE). No significant differences were found in relation to TIMP-1 and MMP-9. Taken together, the results suggest that oral feeding of PGE and CE to SKH-1 mice affords substantial protection against the adverse effects of RUVA, especially PGE.


Assuntos
Quimioprevenção/métodos , Neoplasias Induzidas por Radiação/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Anticarcinógenos/farmacologia , Cacau/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Pelados , Neoplasias Induzidas por Radiação/patologia , Romã (Fruta)/efeitos dos fármacos , Pele/patologia , Neoplasias Cutâneas/patologia , Raios Ultravioleta/efeitos adversos
18.
Curr Pharm Biotechnol ; 21(11): 1028-1041, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32297580

RESUMO

BACKGROUND: Cancer is the leading cause of death worldwide and the current mode of cancer treatment causes side effects on normal cells and are still the key challenges in its' treatment. However, natural products or active compounds of medicinal plants have shown to be safe, affordable, and effective in diseases cure. METHODS: In this context, scientific studies evidence the health-promoting effects of natural products, which work through its anti-oxidant, anti-inflammatory, and anti-cancer activity. Thymoquinone (TM), a predominant active compound of Nigella sativa, has confirmed anti-neoplastic activity through its ability to regulate various genetic pathways. In addition, thymoquinone has established anti-cancerous effects through killing of various cancerous cells,and inhibiting the initiation, migration, invasion, and progression of the cancer. The anti-cancer effects of TM are chiefly mediated via regulating various cell signaling pathways such as VEGF, bcl2/bax ratio, p53, NF-kB, and oncogenes. RESULTS: The anti-cancer drugs have limitations in efficacy and also causes adverse side effects on normal cells. The combination of anti-cancer drugs and thymoquinone improves the efficacy of drugs which is evident by decrease resistance to drugs and regulation of various cell signaling pathways. Moreover, combination of anti-cancer drugs as well as thymoquinone shows synergistic effect on killing of cancer cells and cells viability. Thus, TM, in combination with anti-cancer drugs, can be a good strategy in the management of various types of cancer. CONCLUSION: In this review article, we deliver an outline of thymoquinone role in cancer inhibition and prevention of cancer-based on in vivo and in vitro studies. Further studies on thymoquinone based on clinical trials are highly required to explore the benefits of thymoquinone in cancer management.


Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Benzoquinonas/farmacologia , Nigella sativa/química , Anticarcinógenos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Benzoquinonas/isolamento & purificação , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Transdução de Sinais/efeitos dos fármacos
19.
Biochem Pharmacol ; 175: 113890, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32119837

RESUMO

Triterpenoids are a powerful group of phytochemicals derived from plant foods and herbs. Many reports have shown that they possess chemopreventive and chemotherapeutic effects not only in cell lines and animal models but also in clinical trials. Because epigenetic changes could potentially occur in the early stages of carcinogenesis preceding genetic mutations, epigenetics are considered promising targets in early interventions against cancer using epigenetic bioactive substances. The biological properties of triterpenoids in cancer prevention and in health have multiple mechanisms, including antioxidant and anti-inflammatory activities, cell cycle regulation, as well as epigenetic/epigenomic regulation. In this review, we will discuss and summarize the latest advances in the study of the pharmacological effects of triterpenoids in cancer chemoprevention and in health, including the epigenetic machinery.


Assuntos
Anticarcinógenos/farmacologia , Epigênese Genética/efeitos dos fármacos , Neoplasias/genética , Neoplasias/prevenção & controle , Compostos Fitoquímicos/farmacologia , Triterpenos/farmacologia , Anticarcinógenos/química , Linhagem Celular Tumoral , Humanos , Compostos Fitoquímicos/química , Triterpenos/química
20.
J Food Sci ; 85(4): 1292-1301, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32144766

RESUMO

Chemoprevention strategies employing the use of multiple dietary bioactive components and their metabolites in combination offer advantages due to their low toxicity and potential synergistic interactions. Herein, for the first time, we studied the combination of curcumin and 3',4'-didemethylnobiletin (DDMN), a primary metabolite of nobiletin, to determine their combinatory effects in inhibiting growth of human colon cancer cells. Isobologram analysis revealed a synergistic interaction between curcumin and DDMN in the inhibition of cell growth of HCT116 colon cancer cells. The combination treatment induced significant G2 -M cell-cycle arrest and extensive apoptosis, which greatly exceeded the effects of individual treatments with curcumin or DDMN. Proteins associated with these heightened anticarcinogenic effects were p53, p21, HO-1, c-poly(ADP-ribose) polymerase, Cdc2, and Cdc25c; each of the proteins was confirmed to be substantially impacted by the combination treatment, more than by individual treatments alone. Interestingly, an increase in the stability of curcumin was also observed with the presence of DDMN in cell culture medium, which could offer an explanation in part for the synergistic interaction between curcumin and DDMN. This newly identified synergy between curcumin and DDMN should be explored further to determine its chemopreventive potential against colon cancer in vivo. PRACTICAL APPLICATION: This study identifies for the first time the synergistic inhibition of colon cancer cell growth by the dietary component curcumin present in turmeric, in combination with a metabolite of nobiletin, a unique citrus flavonoid. The synergism of the combination may be due to cell-cycle arrest and apoptosis induced by the combination as well as an improvement in the stability of curcumin as a result of the antioxidant property of the nobiletin metabolite. These significant findings of synergism between curcumin and the nobiletin metabolite could offer potential chemopreventive value against colon cancer.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Curcumina/farmacocinética , Flavonas/farmacocinética , Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Curcumina/farmacologia , Sinergismo Farmacológico , Flavonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos
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