Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.635
Filtrar
1.
Medicine (Baltimore) ; 99(33): e21775, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872077

RESUMO

BACKGROUND: Gastric cancer is a common gastrointestinal tumor, seriously threatening human health. Radical surgery is the preferred treatment for gastric cancer. However, due to the late diagnosis and postoperative recurrence and metastasis, the prognosis is dismal. In China, traditional Chinese medicine (TCM) has been used to treat gastric cancer for many years. The purpose of this study is to explore the efficacy and safety of Yiqi Huayu Jiedu decoction in the treatment of postoperative gastric caner. METHODS/DESIGN: 226 eligibility patients altogether will be randomly allocated to the treatment group and the control group at a ratio of 1:1. After enrollment, every patients will obtain 6 months of treatment, as well as 2 years of follow-up. At the end of this study, primary outcomes including 1-year progression-free survival rate, 2-year progression-free survival rate and disease-free survival, secondary outcomes containing tumor markers, TCM syndrome points, quality of life scale, imageological examination and the safety indicators will be assessed. DISCUSSION: This study will provide the evidence-based evidence for the efficacy of Yiqi Huayu Jiedu decoction reducing the risk of postoperative gastric cancer recurrence and metastasis, which will be beneficial to form the therapeutic regimen in postoperative gastric cancer with integrated TCM and Western medicine. TRAIL REGISTRATION: ChiCTR2000032802.


Assuntos
Recidiva Local de Neoplasia/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Neoplasias Gástricas/prevenção & controle , Humanos , Metástase Neoplásica/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/cirurgia
2.
Nat Commun ; 11(1): 4308, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855399

RESUMO

Distant metastasis (DM) is the main cause of treatment failure in locally advanced rectal cancer. Adjuvant chemotherapy is usually used for distant control. However, not all patients can benefit from adjuvant chemotherapy, and particularly, some patients may even get worse outcomes after the treatment. We develop and validate an MRI-based radiomic signature (RS) for prediction of DM within a multicenter dataset. The RS is proved to be an independent prognostic factor as it not only demonstrates good accuracy for discriminating patients into high and low risk of DM in all the four cohorts, but also outperforms clinical models. Within the stratified analysis, good chemotherapy efficacy is observed for patients with pN2 disease and low RS, whereas poor chemotherapy efficacy is detected in patients with pT1-2 or pN0 disease and high RS. The RS may help individualized treatment planning to select patients who may benefit from adjuvant chemotherapy for distant control.


Assuntos
Antineoplásicos/uso terapêutico , Nomogramas , Protectomia , Neoplasias Retais/terapia , Reto/diagnóstico por imagem , Adulto , Idoso , Quimioterapia Adjuvante/estatística & dados numéricos , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/estatística & dados numéricos , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/prevenção & controle , Estadiamento de Neoplasias , Planejamento de Assistência ao Paciente , Seleção de Pacientes , Radioterapia Adjuvante/estatística & dados numéricos , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/patologia , Reto/patologia , Reto/cirurgia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco/métodos
3.
Life Sci ; 257: 118065, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32659366

RESUMO

AIMS: Pyroptosis is a newly discovered inflammatory programmed cell death. This study was to investigate whether pyroptosis is involved in the anti-colorectal cancer process of FL118. MATERIALS AND METHODS: The relationship between NLRP3 and caspase-1 and colorectal cancer was analyzed by bioinformatics. MTT was used to detect the cell viability. Cell membrane integrity was examined by LDH release. Wound healing assay and Transwell were used to detect the cell migration and invasion respectively. TUNEL was to check the cell death. The expression of pyroptosis-related factors was detected using qRT-PCR, Western blotting, Immunofluorescence and Elisa. And H&E staining was used to detect the toxicity of FL118 in colorectal cancer. KEY FINDINGS: In vitro, FL118 significantly inhibited the proliferation, migration and invasion of colorectal cancer, and the morphological characteristics of pyroptosis were observed under the microscope. With the change of FL118 concentration, the release rate of LDH in the supernatant and the expression of pyroptosis-related factors emerged an increase. However, pyroptosis induced by FL118 was reversed with the participation of MCC950 and VX-765, which suppressed the antitumor effect of FL118. In vivo, the result in the xenograft animal model and lung metastasis model experimental showed that FL118 could activate pyroptosis and thus inhibit the metastasis of colorectal cancer. SIGNIFICANCE: FL118 restrains the growth and metastasis of colorectal cancer by inducing NLRP3-ASC-Caspase-1 mediated pyroptosis, which provides important evidence in the study on the role of pyroptosis and different tumors.


Assuntos
Antineoplásicos/farmacologia , Benzodioxóis/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Indolizinas/farmacologia , Piroptose/efeitos dos fármacos , Animais , Caspase 1/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/prevenção & controle , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Commun ; 11(1): 3193, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581213

RESUMO

Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.


Assuntos
Neoplasias da Mama/patologia , Transtornos Cronobiológicos/complicações , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Transformação Celular Neoplásica/efeitos dos fármacos , Doença Crônica , Transtornos Cronobiológicos/genética , Transtornos Cronobiológicos/imunologia , Citocinas/genética , Feminino , Regulação da Expressão Gênica , Imunossupressão , Transdução de Sinal Luminoso/genética , Camundongos , Camundongos Transgênicos , Metástase Neoplásica/prevenção & controle , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/genética
5.
Life Sci ; 251: 117604, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32243929

RESUMO

AIMS: Opioids (i.e. morphine) were found to induce triple negative breast cancer (TNBC) metastasis while nonsteroidal anti-inflammatory drugs (i.e. ketolorac) were associated with decreased metastasis in TNBC. These contradictory findings demand clarification on the effect of postoperative morphine and ketorolac on TNBC metastasis. MATERIALS AND METHODS: TNBC xenograft mice were established using MDA-MB-231 cells. When tumors reached ~100 mm3, the primary tumor was resected. Mice were then randomly assigned to four groups (n = 14): (i) saline, (ii) morphine (10 mg kg-1) (iii) morphine + ketorolac (10 mg kg-1 of morphine and 20 mg kg-1 of ketorolac) (iv) ketorolac (20 mg kg-1); administrated for three consecutive days after resection. Three weeks after resection, the number of lung metastases was measured. Microvessel density, thrombospondin-1 (TSP-1) and c-Myc expression in recurrent tumors were determined. To elucidate the above phenomenon in vitro, MDA-MB-231 cells were treated according to the regiment above; with or without supplementation of an AKT inhibitor to determine the activation of PI3K/AKT/c-Myc pathway. KEY FINDINGS: In mice, morphine promoted TNBC metastasis and angiogenesis, decreased TSP-1 expression and increased c-Myc expression, while co-administration of ketorolac significantly reversed the phenotypes above (p < .05). Mechanistically, morphine inhibited TSP-1 secretion by activating PI3K/AKT/c-Myc pathway (p < .05), while ketorolac promoted TSP-1 secretion (p < .05) by suppressing PI3K/AKT/c-Myc pathway. SIGNIFICANCE: Our study indicated that morphine enhanced TNBC metastasis and angiogenesis while ketorolac suppressed this effect. Mechanistically, this may be related to the enhancement of TSP-1 synthesis after ketorolac administration which further de-activated PI3K/AKT/c-Myc pathway.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cetorolaco/farmacologia , Morfina/toxicidade , Neovascularização Patológica/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Analgésicos Opioides/toxicidade , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Arch Biochem Biophys ; 687: 108384, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32343974

RESUMO

Epithelial mesenchymal transition (EMT) is a well-known and important step in metastasis and thus can be a key target in cancer treatment. Here, we tested the EMT inhibitory actions of Selaginella tamariscina and its active component, amentoflavone (AF). EMT was examined in vitro using wound-healing and invasion assays and by monitoring changes in the expression of the EMT-related proteins, E-cadherin, Snail, and Twist. Metastasis was examined in vivo using SCID mice injected with luciferase-labeled A549 cells. We confirmed that aqueous extracts of S. tamariscina (STE) and AF inhibited EMT in human cancer cell lines. We found that STE and AF at nontoxic concentrations exerted remarkable inhibitory effects on migration (wound healing assay) and invasion (Transwell assay) in tumor necrosis factor (TGF)-ß-treated cancer cells. Western blotting and immunofluorescence imaging show that AF treatment also restored E-cadherin expression in these cells compared to cells treated with TGF-ß only. Suppression of metastasis by AF was investigated by monitoring migration of tail-vein-injected, circulating A549-luc cells to the lungs in mice. After 3 wk, fewer nodules were observed in mice co-treated with AF compared with those treated with TGF-ß only. Our findings indicate that STE and AF are promising EMT inhibitors and, ultimately, potentially potent antitumor agents.


Assuntos
Antineoplásicos/uso terapêutico , Biflavonoides/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Selaginellaceae/química , Células A549 , Animais , Antígenos CD/metabolismo , Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Caderinas/metabolismo , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Camundongos SCID , Proteínas Nucleares/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Proteína 1 Relacionada a Twist/metabolismo
7.
Clin Exp Metastasis ; 37(2): 283-292, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020377

RESUMO

We explored the role of the transcription factor, NF-κB, and its upstream kinase IKKß in regulation of migration, invasion, and metastasis of cisplatin-resistant head and neck squamous cell carcinoma (HNSCC). We showed that cisplatin-resistant HNSCC cells have a stronger ability to migrate and invade, as well as display higher IKKß/NF-κB activity compared to their parental partners. Importantly, we found that knockdown of IKKß, but not NF-κB, dramatically impaired cell migration and invasion in these cells. Consistent with this, the IKKß inhibitor, CmpdA, also inhibited cell migration and invasion. Previous studies have already shown that N-Cadherin, an epithelial-mesenchymal transition (EMT) marker, and IL-6, a pro-inflammatory cytokine, play important roles in regulation of HNSCC migration, invasion, and metastasis. We found that cisplatin-resistant HNSCC expressed higher levels of N-Cadherin and IL-6, which were significantly inhibited by CmpdA. More importantly, we showed that CmpdA treatment dramatically abated cisplatin-resistant HNSCC cell metastasis to lungs in a mouse model. Our data demonstrated the crucial role of IKKß in control of migration, invasion, and metastasis, and implicated that targeting IKKß may be a potential therapy for cisplatin-resistant metastatic HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Quinase I-kappa B/antagonistas & inibidores , Neoplasias Pulmonares/prevenção & controle , NF-kappa B/metabolismo , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/genética , Metástase Neoplásica/prevenção & controle , Oxazinas/farmacologia , Piridinas/farmacologia , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Biosci Trends ; 14(1): 23-34, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32092745

RESUMO

The roots of Angelica dahurica have long been used as a traditional medicine in Korea to treat various diseases such as toothache and cold. In this study, we investigated the effect of ethanol extract from the roots of this plant on metastatic melanoma, a highly aggressive skin cancer, in B16F10 melanoma cells and B16F10 cell inoculated-C57BL/6 mice. Our results showed that the ethanol extracts of Angelicae dahuricae Radix (EEAD) suppressed cell growth and induced apoptotic cell death in B16F10 cells. EEAD also activated the mitochondria-mediated intrinsic apoptosis pathway, with decreased mitochondrial membrane potential, and increased production of intracellular reactive oxygen species and ration of Bax/Bcl-2 expression. Furthermore, EEAD reduced the migration, invasion, and colony formation of B16F10 cells through the reduced expression and activity of matrix metalloproteinase (MMP)-2 and -9. In addition, in vivo results demonstrated that oral administration of EEAD inhibited lactate dehydrogenase activity, hepatotoxicity, and nephrotoxicity without weight loss in B16F10 cell inoculated-mice. Importantly, EEAD was able to markedly suppress lung hypertrophy, the incidence of B16F10 cells lung metastasis, and the expression of tumor necrosis factor-alpha in lung tissue. Taken together, our findings suggest that EEAD may be useful for managing metastasis and growth of malignant cancers, including melanoma.


Assuntos
Angelica/química , Melanoma Experimental/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Apoptose , Linhagem Celular Tumoral , Hipertrofia , L-Lactato Desidrogenase/antagonistas & inibidores , Pulmão/patologia , Neoplasias Pulmonares , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Metástase Neoplásica/prevenção & controle , Raízes de Plantas/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
9.
J Oncol Pharm Pract ; 26(4): 972-981, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32098554

RESUMO

AIM: To define the inclusion/exclusion status of patients with brain metastasis in phase-III clinical trials and the effect of systemic therapies in metastatic renal cell cancer patients with brain metastasis. METHODS: "kidney neoplasms"[MeSH Terms] OR ("kidney"[All Fields] AND "neoplasms"[All Fields]) OR "kidney neoplasms"[All Fields] OR ("kidney"[All Fields] AND "cancer"[All Fields]) OR "kidney cancer"[All Fields] AND "brain metastasis" were used for searching "PubMed" electronic database and "clinicaltrials.gov" website. RESULTS: Five of 19 landmark phase-III clinical trials included patients with stable or asymptomatic brain metastasis and there was no data about outcomes of brain metastasis. The effect of systemic therapy on prevention of brain metastasis in renal cell cancer was evaluated in four studies. Two studies showed that the incidence of brain metastasis decreased, while the other two studies showed no effect of antiangiogenic agents on the prevention of brain metastasis in patients with renal cell cancer. There were 10 trials regarding systemic therapy of renal cell cancer brain metastasis. The overall response rate improved through a combination of targeted therapies and local treatment. The results of the trials studying the effect of tyrosine kinase inhibitors without local treatment were controversial. None of the ongoing clinical trials included patients with active brain metastasis. CONCLUSION: In metastatic renal cell cancer patients with brain metastasis, the overall response rate improved with the combination of targeted agents and local treatment. Further trials are needed to evaluate the effect of systemic treatment on the prevention or treatment of brain metastasis in patients with renal cell cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Neoplasias Encefálicas/prevenção & controle , Ensaios Clínicos Fase III como Assunto/métodos , Humanos , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controle
10.
Life Sci ; 243: 117245, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926253

RESUMO

AIM: To determine the anti-metastatic potential of combinations of two bioactive carotenoids of saffron, crocin and crocetin, on 4T1 breast cancer and on a mice model of TNBC, and assess the effect of the most potent combination on the Wnt/ß-catenin pathway. MAIN METHODS: The effects of the carotenoid combinations on the viability of 4T1 cells were determined by MTT assay. The effects of the nontoxic doses on migration, mobility, invasion and adhesion to ECM were examined by scratch assay, Transwell/Matrigel-coated Transwell chamber and adhesion assay respectively. Tumors were inoculated by injecting mice with 4T1 cells. The weights and survival rates of the mice and tumor sizes were monitored. Histological analysis of the tissues was conducted. The expression levels of Wnt/ß-catenin pathway genes were measured by Real-time PCR and western blotting. KEY FINDINGS: Treatment of 4T1 cells with combination doses inhibited viability in a dose-dependent manner. The nontoxic combinations significantly inhibited migration, cell mobility and invasion, also attenuating adhesion to ECM. The combination therapy mice possessed more weight, higher survival rates and smaller tumors. Histological examination detected remarkably fewer metastatic foci in their livers and lungs. It was also demonstrated that the combinations exerted anti-metastatic effects by disturbing the Wnt/ß-catenin target genes in the liver and tumors. SIGNIFICANCE: Our findings propose a carotenoid combination as an alternative potent herbal treatment for TNBC, which lacks the adverse effects associated with either chemotherapeutic agents or herb-chemotherapeutic drugs.


Assuntos
Carotenoides/uso terapêutico , Medicina Herbária , Metástase Neoplásica/prevenção & controle , Neoplasias de Mama Triplo Negativas/patologia , Animais , Carotenoides/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Invasividade Neoplásica/prevenção & controle , Neoplasias de Mama Triplo Negativas/prevenção & controle
11.
Cancer Lett ; 473: 50-61, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31899298

RESUMO

Many cancers occur from locations of inflammation due to chronic irritation and/or infection. Tumor microenvironment contains various different inflammatory cells and mediators that orchestrate diverse neoplastic processes, including proliferation, survival, adhesion and migration. In parallel, tumor cells have adapted some of the signaling molecules used by inflammatory cells, such as selectins and chemokines as well as their receptors for invasion, extravasation and subsequently metastasis. Expression and/or activation of the majority of these molecules is mediated by the proprotein convertases (PCs); proteases expressed by both tumor cells and inflammatory cells. This review analyzes the potential role of these enzymatic system in inflammation-associated cancer impacting on the malignant and metastatic potential of cancer cells, describing the possible use of PCs as a new anti-inflammatory therapeutic approach to tumor progression and metastasis.


Assuntos
Carcinogênese/imunologia , Inflamação/tratamento farmacológico , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Pró-Proteína Convertases/metabolismo , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Carcinogênese/efeitos dos fármacos , Quimiocinas/imunologia , Quimiocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Inflamação/imunologia , Inflamação/patologia , Metástase Neoplásica/prevenção & controle , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Proteína Convertases/antagonistas & inibidores , Selectinas/imunologia , Selectinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
Food Chem Toxicol ; 135: 110993, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765702

RESUMO

3S, 3'S-Astaxanthin is the most powerful antioxidant to scavenge free radicals in the world. In this study, a 3S, 3'S-astaxanthin biosynthesis pathway was constructed in a probiotic yeast, Kluveromyces marxianus, denoted YEAST, and its bioactive metabolites were extracted for biofunctional assessments. The bio-safety examination was achieved by two animal models as following: First, no significant toxic effects on YEAST groups were found in zebrafish; Second, after feeding YEAST for 4 weeks, the rat-groups showed no visible abnormality, and no significant change of the body weight and blood biochemistry tests. The inhibition of lung metastasis of melanoma cells and the increment of the survival rate were demonstrated by feeding YEAST and injecting the intravenous commercial astaxanthin in vivo rodent model. Based on in vitro assays of 1,1-diphenyl-2-picryl-hydrazyl (DPPH) scavenging analysis, ferrous ion chelating ability, reducing power assessment, and mushroom tyrosinase inhibition evaluation, YEAST-astaxanthin showed anti-oxidative and tyrosinase suppressive properties. Taken together, the 3S, 3'S-astaxanthin producing probiotic yeast is safe to be used in the bio-synthesis of functional and pharmaceutical compounds, which have broad industrial applications on cosmetic, food and feed additive and healthcare.


Assuntos
Kluyveromyces/metabolismo , Melanoma Experimental/patologia , Engenharia Metabólica , Metástase Neoplásica/prevenção & controle , Probióticos , Animais , Antioxidantes/farmacologia , Feminino , Masculino , Melanoma Experimental/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Monofenol Mono-Oxigenase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Xantofilas/química , Xantofilas/metabolismo , Xantofilas/farmacologia , Peixe-Zebra
13.
Artigo em Inglês | MEDLINE | ID: mdl-31879981

RESUMO

Functional amyloids produced in bacteria as nanoscale inclusion bodies are intriguing but poorly explored protein materials with wide therapeutic potential. Since they release functional polypeptides under physiological conditions, these materials can be potentially tailored as mimetic of secretory granules for slow systemic delivery of smart protein drugs. To explore this possibility, bacterial inclusion bodies formed by a self-assembled, tumor-targeted Pseudomonas exotoxin (PE24) are administered subcutaneously in mouse models of human metastatic colorectal cancer, for sustained secretion of tumor-targeted therapeutic nanoparticles. These proteins are functionalized with a peptidic ligand of CXCR4, a chemokine receptor overexpressed in metastatic cancer stem cells that confers high selective cytotoxicity in vitro and in vivo. In the mouse models of human colorectal cancer, time-deferred anticancer activity is detected after the subcutaneous deposition of 500 µg of PE24-based amyloids, which promotes a dramatic arrest of tumor growth in the absence of side toxicity. In addition, long-term prevention of lymphatic, hematogenous, and peritoneal metastases is achieved. These results reveal the biomedical potential and versatility of bacterial inclusion bodies as novel tunable secretory materials usable in delivery, and they also instruct how therapeutic proteins, even with high functional and structural complexity, can be packaged in this convenient format.


Assuntos
Amiloide/metabolismo , Antineoplásicos/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/química , Corpos de Inclusão/metabolismo , Nanopartículas/química , Amiloide/administração & dosagem , Amiloide/efeitos adversos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Proteínas de Bactérias/química , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Células HeLa , Humanos , Corpos de Inclusão/química , Camundongos , Conformação Molecular , Terapia de Alvo Molecular , Metástase Neoplásica/prevenção & controle , Células-Tronco Neoplásicas/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Engenharia de Proteínas , Receptores CXCR4/química , Proteínas Recombinantes/química
14.
Cancer Lett ; 473: 118-129, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31843555

RESUMO

Early studies suggest that the androgen receptor (AR) may play differential roles in influencing prostate cancer (PCa) and bladder cancer (BCa) metastasis, but the underlying mechanisms remain unclear. Here, we found that the AR might function via differentially altering vasculogenic mimicry (VM) formation to either decrease PCa metastasis or increase BCa metastasis. Mechanism dissection showed that the AR could differentially alter the expression of the VM marker SLPI through miR-525-5p to regulate SLPI; moreover, it could either increase miR-525-5p transcription in PCa or decrease it in BCa via binding to different androgen-response-elements (AREs) located at different positions in the miR-525 precursor promoter. Further, results from liquid chromatography-mass spectrometry (LC-MS) showed that the co-factors of AR in PCa and BCa are NFIX and HDAC2, respectively. Together, these results provide the first detailed mechanism of how the AR can differentially alter PCa and BCa metastasis; thus, targeting the newly identified AR-miR-525-5p-SLPI axis may help suppress metastasis.


Assuntos
MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Neoplasias da Bexiga Urinária/genética , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histona Desacetilase 2/metabolismo , Humanos , Masculino , Fatores de Transcrição NFI/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/genética , Inibidor Secretado de Peptidases Leucocitárias/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/patologia
15.
Cancer Res ; 80(4): 771-783, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843981

RESUMO

Integrin ß4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSC). Immune targeting of ITGB4 represents a novel approach to target this cell population, with potential clinical benefit. We developed two immunologic strategies to target ITGB4: ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination and adoptive transfer of anti-CD3/anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed tumor-draining lymph node T cells. Two immunocompetent mouse models were utilized to assess the efficacy of these immunotherapies in targeting both CSCs and bulk tumor populations: 4T1 mammary tumors and SCC7 head and neck squamous carcinoma cell line. Immunologic targeting of ITGB4 utilizing either ITGB4-DC or ITGB4 BiAb-T cells significantly inhibited local tumor growth and metastases in both the 4T1 and SCC7 tumor models. Furthermore, the efficacy of both of these ITGB4-targeted immunotherapies was significantly enhanced by the addition of anti-PD-L1. Both ITGB4-targeted immunotherapies induced endogenous T-cell cytotoxicity directed at CSCs as well as non-CSCs, which expressed ITGB4, and immune plasma-mediated killing of CSCs. As a result, ITGB4-targeted immunotherapy reduced not only the number of ITGB4high CSCs in residual 4T1 and SCC7 tumors but also their tumor-initiating capacity in secondary mouse implants. In addition, treated mice demonstrated no apparent toxicity. The specificity of these treatments was demonstrated by the lack of effects observed using ITGB4 knockout 4T1 or ITGB4-negative CT26 colon carcinoma cells. Because ITGB4 is expressed by CSCs across a variety of tumor types, these results support immunologic targeting of ITGB4 as a promising therapeutic strategy.Significance: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients.


Assuntos
Vacinas Anticâncer/administração & dosagem , Imunoterapia Adotiva/métodos , Integrina beta4/metabolismo , Neoplasias/terapia , Células-Tronco Neoplásicas/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Complexo CD3/antagonistas & inibidores , Complexo CD3/imunologia , Vacinas Anticâncer/imunologia , Carcinogênese/imunologia , Linhagem Celular Tumoral/transplante , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Humanos , Integrina beta4/genética , Integrina beta4/imunologia , Linfonodos/citologia , Camundongos , Terapia de Alvo Molecular/métodos , Metástase Neoplásica/imunologia , Metástase Neoplásica/prevenção & controle , Neoplasias/imunologia , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante
16.
Toxicol Appl Pharmacol ; 388: 114870, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31866380

RESUMO

Gastric cancer ranks as the third leading cause of cancer-related death worldwide. The uncontrolled tumor growth and robust metastasis are key factors to cause the cancer patient death. Mechanistically, aberrant activation of Notch and NF-κB signaling pathways plays pivotal roles in the initiation and metastasis of gastric cancer. Despite great efforts have been made in recent decades, the effective drug against the advanced and metastatic gastric cancer is still lacking in the clinical setting. In this study, we found that triptonide, a small molecule (MW358) purified from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, effectively suppressed tumor growth and metastasis in xenograft mice without obvious toxicity at the doses we tested, resulting in potent anti-gastric cancer effect with low toxicity. Triptonide markedly inhibited human metastatic gastric cancer cell migration, invasion, proliferation, and tumorigenicity. Molecular mechanistic studies revealed that triptonide significantly reduced Notch1 protein levels in metastatic gastric cancer cells through degrading the oncogenic protein Notch1 via the ubiquitin-proteasome pathway. Consequently, the levels of Notch1 downstream proteins RBPJ, IKKα, IKKß were significantly diminished, and nuclear factor-kappa B (NF-κB) phosphorylation was significantly reduced. Together, triptonide effectively suppresses gastric cancer growth and metastasis via inhibition of the oncogenic Notch1 and NF-κB signaling pathways. Our findings provide a new strategy and drug candidate for treatment of the advanced and metastatic gastric cancer.


Assuntos
NF-kappa B/metabolismo , Receptor Notch1/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Triterpenos/farmacologia , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/prevenção & controle , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/patologia , Triterpenos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Sci Adv ; 5(11): eaav9810, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31799386

RESUMO

Although intrinsically disordered protein regions (IDPRs) are commonly engaged in promiscuous protein-protein interactions (PPIs), using them as drug targets is challenging due to their extreme structural flexibility. We report a rational discovery of inhibitors targeting an IDPR of MBD2 that undergoes disorder-to-order transition upon PPI and is critical for the regulation of the Mi-2/NuRD chromatin remodeling complex (CRC). Computational biology was essential for identifying target site, searching for promising leads, and assessing their binding feasibility and off-target probability. Molecular action of selected leads inhibiting the targeted PPI of MBD2 was validated in vitro and in cell, followed by confirming their inhibitory effects on the epithelial-mesenchymal transition of various cancer cells. Identified lead compounds appeared to potently inhibit cancer metastasis in a murine xenograft tumor model. These results constitute a pioneering example of rationally discovered IDPR-targeting agents and suggest Mi-2/NuRD CRC and/or MBD2 as a promising target for treating cancer metastasis.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas Intrinsicamente Desordenadas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Domínios Proteicos/efeitos dos fármacos , Animais , Biologia Computacional , Descoberta de Drogas/métodos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/antagonistas & inibidores , Camundongos , Modelos Moleculares , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Food Funct ; 10(12): 8172-8181, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730141

RESUMO

Metastasis is the most prevalent cause of treatment failure in patients with colon cancer. Gossypol is reported to exhibit antioxidant, anticancer, antivirus and antimicrobial properties. However, the effects of gossypol on cancer invasion and tumour growth of human colon cancer remain unclear. This study aimed to provide molecular evidence associated with the antimetastatic and anti-tumour effects of gossypol on human colorectal carcinoma (CRC) cells. Gossypol inhibited the viability of human colon cancer cells in a dose-dependent manner. Gossypol was sufficient to reduce the invasion, migration and adhesion in DLD-1 and COLO 205 cells. Zymography and western blot assay showed that gossypol reduced the activities and protein expression of urokinase-type plasminogen activator (u-PA), respectively. Gossypol suppressed the level of p-focal adhesion kinase (FAK) and epithelial-to-mesenchymal transition markers, including N-cadherin, fibronectin and vimentin. Gossypol also inhibited the lung metastasis of DLD-1 cells, as indicated by the nude mouse model. These results suggested that gossypol inhibited the metastatic properties of human colon cancer cells by targeting u-PA through the FAK pathway, suggesting that gossypol could be used as an adjuvant therapeutic agent for the treatment of human colon cancer cells.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Gossipol/administração & dosagem , Neoplasias Pulmonares/prevenção & controle , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibronectinas/genética , Fibronectinas/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/genética , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Ativador de Plasminogênio Tipo Uroquinase/genética , Vimentina/genética , Vimentina/metabolismo
19.
Nutrients ; 11(10)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597327

RESUMO

Prostate cancer is the third most common cancer worldwide, and the burden of the disease is increased. Although several chemotherapies have been used, concerns about the side effects have been raised, and development of alternative therapy is inevitable. The purpose of this study is to prove the efficacy of dietary substances as a source of anti-tumor drugs by identifying their carcinostatic activities in specific pathological mechanisms. According to numerous studies, dietary substances were effective through following five mechanisms; apoptosis, anti-angiogenesis, anti-metastasis, microRNA (miRNA) regulation, and anti-multi-drug-resistance (MDR). About seventy dietary substances showed the anti-prostate cancer activities. Most of the substances induced the apoptosis, especially acting on the mechanism of caspase and poly adenosine diphosphate ribose polymerase (PARP) cleavage. These findings support that dietary compounds have potential to be used as anticancer agents as both food supplements and direct clinical drugs.


Assuntos
Anticarcinógenos/administração & dosagem , Dieta , Neoplasias da Próstata/prevenção & controle , Apoptose/efeitos dos fármacos , Inibidores de Caspase/administração & dosagem , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Masculino , MicroRNAs/efeitos dos fármacos , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/prevenção & controle , Compostos Fitoquímicos/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Neoplasias da Próstata/patologia
20.
Proc Natl Acad Sci U S A ; 116(43): 21704-21714, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31591235

RESUMO

Metastatic behavior varies significantly among breast cancers. Mechanisms explaining why the majority of breast cancer patients never develop metastatic outgrowth are largely lacking but could underlie the development of novel immunotherapeutic target molecules. Here we show interplay between nonmetastatic primary breast cancer and innate immune response, acting together to control metastatic progression. The primary tumor systemically recruits IFNγ-producing immune effector monocytes to the lung. IFNγ up-regulates Tmem173/STING in neutrophils and enhances their killing capacity. The immune effector monocytes and tumoricidal neutrophils target disseminated tumor cells in the lungs, preventing metastatic outgrowth. Importantly, our findings could underlie the development of immunotherapeutic target molecules that augment the function of immune effector monocytes and neutrophils.


Assuntos
Citotoxicidade Imunológica/imunologia , Neoplasias Mamárias Animais/patologia , Monócitos/imunologia , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Imunidade Inata/imunologia , Imunoterapia/métodos , Interferon gama/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica/imunologia , Metástase Neoplásica/prevenção & controle , Microambiente Tumoral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA