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1.
Adv Exp Med Biol ; 1164: 73-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576541

RESUMO

The purpose of this review is to briefly summarize the roles of alcohol (ethanol) and related compounds in promoting cancer and inflammatory injury in many tissues. Long-term chronic heavy alcohol exposure is known to increase the chances of inflammation, oxidative DNA damage, and cancer development in many organs. The rates of alcohol-mediated organ damage and cancer risks are significantly elevated in the presence of co-morbidity factors such as poor nutrition, unhealthy diets, smoking, infection with bacteria or viruses, and exposure to pro-carcinogens. Chronic ingestion of alcohol and its metabolite acetaldehyde may initiate and/or promote the development of cancer in the liver, oral cavity, esophagus, stomach, gastrointestinal tract, pancreas, prostate, and female breast. In this chapter, we summarize the important roles of ethanol/acetaldehyde in promoting inflammatory injury and carcinogenesis in several tissues. We also review the updated roles of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and other cytochrome P450 isozymes in the metabolism of various potentially toxic substrates, and consequent toxicities, including carcinogenesis in different tissues. We also briefly describe the potential implications of endogenous ethanol produced by gut bacteria, as frequently observed in the experimental models and patients of nonalcoholic fatty liver disease, in promoting DNA mutation and cancer development in the liver and other tissues, including the gastrointestinal tract.


Assuntos
Transtornos Relacionados ao Uso de Álcool , Carcinogênese , Citocromo P-450 CYP2E1 , Sistema Enzimático do Citocromo P-450 , Etanol , Acetaldeído/toxicidade , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Citocromo P-450 CYP2E1/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Etanol/toxicidade , Humanos , Isoformas de Proteínas
2.
Cancer Sci ; 110(8): 2442-2455, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148345

RESUMO

The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease-free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer-driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal-epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer-driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Metástase Neoplásica/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
3.
Nat Commun ; 10(1): 2678, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213601

RESUMO

Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte/metabolismo , Melanoma Experimental/imunologia , Proteínas de Membrana/metabolismo , Monócitos/imunologia , Neoplasias Cutâneas/imunologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem Celular Tumoral/transplante , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Feminino , Ativação Linfocitária/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
4.
Anticancer Res ; 39(5): 2443-2446, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092437

RESUMO

BACKGROUND/AIM: TLR-4 Knock-out (KO) mice are protected from colitis-associated cancer in the established AOM/DSS mouse model. The aim of this study was to assess whether the TLR4 KO mice would still be protected from carcinogenesis after platelet depletion and transfusion with TLR4 wild-type platelets. MATERIALS AND METHODS: Thirty-two female C57BL6 mice were divided into 6 groups. Among the three groups that received Azoxymethane/Dextran Sulfate Sodium (AOM/DSS), one group included TLR4KO mice, which were depleted of their platelets and were then transfused with platelets from TLR4 wild-type mice. The other two groups included wild-type and TLR-4KO mice that only received AOM/DSS. RESULTS: All 6 animals in the KO group that underwent platelet depletion/transfusion succumbed. Three of them died before the administration of DSS and three in the week following DSS administration. In contrast, mice in the other two groups experienced less weight loss and only 1 mouse died in each of them. CONCLUSION: Platelet depletion/transfusion was detrimental in TLR-4 transgenic mice that received AOM/DSS.


Assuntos
Plaquetas/metabolismo , Colite/sangue , Neoplasias do Colo/sangue , Transfusão de Plaquetas/efeitos adversos , Receptor 4 Toll-Like/genética , Animais , Azoximetano/toxicidade , Plaquetas/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Colite/induzido quimicamente , Colite/complicações , Colite/genética , Neoplasias do Colo/etiologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout
5.
Nat Commun ; 10(1): 2205, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101821

RESUMO

Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Indazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/secundário , Carcinogênese/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/secundário , Linhagem Celular Tumoral , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Feminino , Humanos , Indazóis/uso terapêutico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Cancer Res Clin Oncol ; 145(7): 1665-1679, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127362

RESUMO

PURPOSE: Phytochemicals are naturally occurring plant-derived compounds and some of them have the potential to serve as anticancer drugs. Based on recent evidence, aberrantly regulated expression of microRNAs (miRNAs) is closely associated with malignancy. MicroRNAs are characterized as small non-coding RNAs functioning as posttranscriptional regulators of gene expression. Accordingly, miRNAs regulate various target genes, some of which are involved in the process of carcinogenesis. RESULTS: This comprehensive review emphasizes the anticancer potential of phytochemicals, either isolated or in combination, mediated by miRNAs. The ability to modulate the expression of miRNAs demonstrates their importance as regulators of tumorigenesis. Phytochemicals as anticancer agents targeting miRNAs are widely studied in preclinical in vitro and in vivo research. Unfortunately, their anticancer efficacy in targeting miRNAs is less investigated in clinical research. CONCLUSIONS: Significant anticancer properties of phytochemicals as regulators of miRNA expression have been proven, but more studies investigating their clinical relevance are needed.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , MicroRNAs/biossíntese , Neoplasias/tratamento farmacológico , Neoplasias/genética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Humanos , MicroRNAs/genética , Neoplasias/patologia
7.
Cancer Sci ; 110(8): 2529-2539, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31119819

RESUMO

Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5-FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Oncogenes/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Fluoruracila/farmacologia , Xenoenxertos/efeitos dos fármacos , Humanos , Leucovorina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Compostos Organoplatínicos/farmacologia
8.
J Exp Clin Cancer Res ; 38(1): 180, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036057

RESUMO

BACKGROUND: Lung cancer often ranks one of the most prevalent malignancies in the world. One of the most challenging aspects of treating late-stage lung cancer patients is the development of drug resistance, from both conventional chemo- and targeted therapeutic agents. Tumor-associated microphages (TAMs) have been shown to promote the survival and distant metastasis of lung cancer cells. METHODS: This study investigated the TAMs - modulating potential of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines, A549R and H460R by using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony, lung sphere formation and xenograft tumorigenecity assays. RESULTS: In this study, we first demonstrated the elevated expression of oncogenic and stemenss markers such as Src, Notch1, macrophage inhibitory factor (MIF) and CD155 in trained cisplatin (CDDP)-resistant A549 and H460 cells (A549R and H460R cells). When co-cultured with TAMs, A549R and H460R cells promoted the M2-polarization in TAMs. In addition, A549R and H460R cells showed an increased self-renewal ability as they formed tumor spheres at higher frequency comparing to their parental counterparts. The increased MIF secretion by the A549R and H460R cells could be suppressed by a multiple kinase inhibitor, dasatinib, which resulted in the decreased of oncogenic network of Src, CD155 and MIF expression. Similarly, dasatinib treatment reduced the M2 polarization in TAMs and suppressed self-renewal ability of the A549R and H460R cells. CONCLUSION: In summary, cisplatin resistant lung cancer cells not only showed an increased self-renewal ability but also promoted M2 polarization of TAMs via the secretion of MIF. These findings were linked to the increased Src-associated signaling as dasatinib treatment significantly reversed these phenomena. Thus, kinase inhibitors such as dasatinib may be of potential for treating cisplatin-resistant lung cancer by targeting both tumor and the tumor microenvironment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Oxirredutases Intramoleculares/genética , Neoplasias Pulmonares/tratamento farmacológico , Fatores Inibidores da Migração de Macrófagos/genética , Receptores Virais/genética , Células A549 , Animais , Carcinogênese/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Dasatinibe/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genética
9.
J Exp Clin Cancer Res ; 38(1): 189, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072375

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is still the most common cause of tumor-related death worldwide and accumulating studies report that long non-coding RNAs (LncRNAs) are closely related with HCC development, metastasis and prognosis. Cisplatinum, a well-known chemotherapeutic drug, has been widely used for treatment of numerous human cancers including HCC. This study aimed to investigate the differential expressions of LncRNAs in HCC cells treated with cisplatinum and its underlying mechanism. METHODS: The differential expressions of LncRNAs in HCC cells treated with cisplatinum were determined by RNA-seq. The roles of TPTEP1 in HCC development by applying gene function gain and loss analysis in MHCC97H and QYG-7703 cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR), cell proliferation, colony formation, cell invasion and flow cytometry assays. The underlying mechanism of TPTEP1 sensitizing hepatocellular carcinoma cells to cisplatinum was examined by RNA-pull down, western blotting, subcellular fractionation, RNA immunoprecipitation and dual luciferase reporter assays. The effect of TPTEP1 on tumorigenesis in vivo was performed with a subcutaneous xenograft mouse model of HCC. In addition, TPTEP1 expression was detected in clinical tumor tissue samples by qRT-PCR. RESULTS: LncRNA TPTEP1 was highly expressed in cisplatinum-treated HCC cells, which sensitizes hepatocellular carcinoma cell to cisplatinum-induced apoptosis. TPTEP1 overexpression inhibited, while TPTEP1 knockdown promoted HCC cell proliferation, tumorigenicity and invasion. Furthermore, TPTEP1 exerted its tumor suppressing activities by interacting with signal transducer and activator of transcription 3 (STAT3) to inhibit its phosphorylation, homodimerization, nuclear translocation and down-stream genes transcription. Moreover, TPTEP1 overexpression obviously inhibits tumor masses in vivo in a subcutaneous xenograft mouse model of HCC and TPTEP1 is frequently downregulated in HCC tissues, compared to its corresponding pre-tumor tissues. CONCLUSION: LncRNA TPTEP1 inhibits hepatocellular carcinoma cells progression by affecting IL-6/STAT3 signaling. Taken together, our findings suggest a tumor suppressing role of TPTEP1 in HCC progression and provide a novel understanding of TPTEP1 during the chemotherapy for HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/genética , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Fosforilação , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
10.
World J Gastroenterol ; 25(15): 1797-1816, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057295

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pancreáticas/genética , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Reposicionamento de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Metformina/farmacologia , Metformina/uso terapêutico , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fosfoproteínas/antagonistas & inibidores , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética
11.
Nat Commun ; 10(1): 2197, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097693

RESUMO

In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/ß-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Antineoplásicos/uso terapêutico , Biópsia , Sistemas CRISPR-Cas/genética , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Plasticidade Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Intestinos/citologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteômica , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismo
12.
Nanomedicine (Lond) ; 14(9): 1077-1093, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31050580

RESUMO

Aim: The present study was aimed at determining the antiproliferative, antioxidant, anti-inflammatory and antitumor activity of developed silymarin-nanostructured lipid carrier (NLC) gel. Materials & methods: B16 melanoma cell line and albino mice were used as ex vivo and in vivo models, respectively, to evaluate the aforementioned pharmacological activities. Results: The volume of large tumors significantly (p < 0.05) reduced from 5.02 to 3.05 mm3, levels of IL-1α and TNF-α were significantly (p < 0.001) lower and levels of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) significantly (p < 0.0001) increased in the group treated with silymarin-NLC gel. Furthermore, in skin treated with placebo and conventional gels, a basosquamous carcinoma and squamous cell carcinoma were noticed, respectively. Conclusion: Silymarin-NLC gel presented better treatment outcomes compared with silymarin-conventional gel.


Assuntos
Antineoplásicos/uso terapêutico , Lipídeos/química , Melanoma Experimental/tratamento farmacológico , Nanocápsulas/química , Silimarina/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Catalase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Feminino , Géis , Glutationa/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Melanoma Experimental/patologia , Camundongos , Silimarina/administração & dosagem , Neoplasias Cutâneas/patologia , Superóxido Dismutase/metabolismo , Resultado do Tratamento
13.
J Food Sci ; 84(5): 990-1001, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30945309

RESUMO

Red chicory leaves are appreciated sensorially and their constituents contain bioactive properties. The objectives of this study were as follows: to use an experimental design to extract anthocyanins from red chicory in aqueous solution at pH 2.5; to determine the stability of the extracts in relation to temperature and pH; and to evaluate the antioxidant activity and in vitro cytotoxic effect of the lyophilized and purified extracts. The best extraction conditions for the bioactive compounds from red chicory were a temperature of 64.2 °C for 25 min; the anthocyanin content was 73.53 ± 0.13 mg per 100 g fresh weight basis sample. The EC50 (Half maximal effective concentration) value for the antioxidant activity assay in relation to DPPH (2,2-diphenyl-1-picrylhydrazyl) with optimized extract was 0.363, which corresponds to a concentration of 39.171 µmol/L of anthocyanins. The activation energy for the degradation reaction of the anthocyanins from the red chicory extract was 84.88 kJ/mol. The optimized extract, which was rich in anthocyanins, showed chemical and biological antioxidant activity (protection against erythrocyte hemolysis) and inhibited lipid peroxidation in vitro. The Cichorium intybus L. extracts interfered on the levels of reactive oxygen species generation and the crude extract did not present procarcinogenic effect. PRACTICAL APPLICATION: Red chicory is basically consumed as a part of traditional dishes worldwide. Here, we developed a process to extract and purify the anthocyanins from Cichorium intybus leaves and test the extracts in terms of the chemical composition, thermal stability, antioxidant activity, and antiproliferative effects. The anthocyanin-rich extract presented antioxidant activity in chemical and biological assays and low cytotoxicity and cytoprotective effects in relation to HepG2, HCT8, and Caco-2 cell lines. Additionally, the red chicory extract protected human erythrocytes against hemolysis. This extract may be used as a natural colorant/antioxidant in foods.


Assuntos
Antocianinas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Chicória/química , Aditivos Alimentares/farmacologia , Extratos Vegetais/farmacologia , Antocianinas/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/metabolismo , Células CACO-2 , Carcinogênese/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Aditivos Alimentares/isolamento & purificação , Células Hep G2 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Picratos/metabolismo , Extratos Vegetais/química , Folhas de Planta/química
14.
Phytomedicine ; 59: 152759, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004883

RESUMO

BACKGROUND: Pseudolaric acid B (PAB), a diterpene acid isolated from the root bark of Pseudolarix kaempferi, exhibits a potent anti-cancer activity in a variety of tumor cells. PURPOSE: The present study was designed to evaluate the anti-cancer effects of PAB on hepatocellular carcinoma (HCC) cell lines in vitro, and to explore the underlying mechanism. METHODS: The anti-proliferative activity of PAB on HCC cells were assessed via sulforhodamine B staining, colony formation, cell cycle analysis, respectively. Apoptosis was detected using Annexin V/propidium iodide double staining and diamidino-phenyl-indole staining, respectively. Protein expression regulated by PAB treatment was tested by western blotting. RESULTS: The present results showed that PAB significantly inhibited the proliferation of HepG2, SK-Hep-1, and Huh-7 HCC cell lines in vitro with IC50 values of 1.58, 1.90, and 2.06 µM, respectively. Furthermore, PAB treatment repressed the colony formation in HepG2, SK-Hep-1, and Huh-7 HCC cell lines. Flow cytometry analysis revealed that PAB caused an obvious cell cycle arrest in G2/M phase and induced apoptosis with the induction of p21, Bax, cleaved-caspase-3, and cleaved-PARP in human HepG2 and SK-Hep-1 cells. Mechanistically, PAB treatment down-regulated the phosphorylation of STAT3, ERK1/2, and Akt. Moreover, abnormal GSK-3ß/ß-catenin signaling in HepG2 cells was remarkably suppressed by PAB treatment. Finally, proliferation markers including cyclin D1 and c-Myc, and anti-apoptosis proteins such as Bcl-2 and survivin were also down-regulated by PAB treatment in HepG2 cells. CONCLUSION: Taken together, our results suggest that PAB exerts anti-cancer activity in HCC cells through inhibition of STAT3, ERK1/2, Akt, and GSK-3ß/ß-catenin carcinogenic signaling pathways, and may be used as a phytomedicine in the treatment of HCC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Diterpenos/farmacologia , Neoplasias Hepáticas/metabolismo , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/uso terapêutico , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Hep G2 , Humanos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Pinaceae/química , Transdução de Sinais/efeitos dos fármacos
15.
Int J Oncol ; 54(4): 1295-1305, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968157

RESUMO

The mechanisms through which cancer­upregulated gene 2 (CUG2), a novel oncogene, affects Wnt/ß­catenin signaling, essential for tumorigenesis, are unclear. In this study, we aimed to elucidate some of these mechanisms in A549 lung cancer cells. Under the overexpression of CUG2, the protein levels and activity of ß­catenin were evaluated by western blot analysis and luciferase assay. To examine a biological consequence of ß­catenin under CUG2 overexpression, cell migration, invasion and sphere formation assay were performed. The upregulation of ß­catenin induced by CUG2 overexpression was also accessed by xenotransplantation in mice. We first found that CUG2 overexpression increased ß­catenin expression and activity. The suppression of ß­catenin decreased cancer stem cell (CSC)­like phenotypes, indicating that ß­catenin is involved in CUG2­mediated CSC­like phenotypes. Notably, CUG2 overexpression increased the phosphorylation of ß­catenin at Ser33/Ser37, which is known to recruit E3 ligase for ß­catenin degradation. Moreover, CUG2 interacted with and enhanced the expression and kinase activity of never in mitosis gene A­related kinase 2 (NEK2). Recombinant NEK2 phosphorylated ß­catenin at Ser33/Ser37, while NEK2 knockdown decreased the phosphorylation of ß­catenin, suggesting that NEK2 is involved in the phosphorylation of ß­catenin at Ser33/Ser37. Treatment with CGK062, a small chemical molecule, which promotes the phosphorylation of ß­catenin at Ser33/Ser37 through protein kinase C (PKC)α to induce its degradation, reduced ß­catenin levels and inhibited the CUG2­induced features of malignant tumors, including increased cell migration, invasion and sphere formation. Furthermore, CGK062 treatment suppressed CUG2­mediated tumor formation in nude mice. Taken together, the findings of this study suggest that CUG2 enhances the phosphorylation of ß­catenin at Ser33/Ser37 by activating NEK2, thus stabilizing ß­catenin. CGK062 may thus have potential for use as a therapeutic drug against CUG2­overexpressing lung cancer cells.


Assuntos
Carcinogênese/efeitos dos fármacos , Proteínas Cromossômicas não Histona/metabolismo , Quinases Relacionadas a NIMA/metabolismo , Neoplasias/tratamento farmacológico , beta Catenina/metabolismo , Células A549 , Acrilatos/farmacologia , Acrilatos/uso terapêutico , Animais , Carcinogênese/patologia , Cromanos/farmacologia , Cromanos/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Quinases Relacionadas a NIMA/genética , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
16.
Environ Toxicol ; 34(7): 869-877, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033183

RESUMO

As a human carcinogen, coal tar pitch (CTP) can significantly increase the risk of lung cancer. However, the mechanism underlying CTP-induced lung carcinogenesis has not been well understood. This study aims to explore the role of the LncRNA-ENST00000501520 in the proliferation of malignant-transformed human bronchial epithelial cells (BAES-2B) induced by CTP extract for the first time. BEAS-2B cells were stimulated with 2.4 µg/mL CTP extract, and then passaged for three times, which were named passage 1 and then passaged until passage 30 (named as CTP group). The ENST000001520 of cells in CTP group was interfered using siRNA. The results showed that ENST000001520 located in cell nucleus (>80%) had no or weak ability of protein encoding. After interference of ENST000001520, the migration and proliferation of cells in CTP group were inhibited, and the cell cycle was arrested in the G0/G1 phase; however, the apoptosis of cells in CTP group was promoted. The target genes (SKB1, CLTB, TAP2, PIPK2, and SOCS3) of ENST000001520 were screened out, and the mRNA and protein expression of SBK1 and SOCS3 was significantly decreased after ENST000001520 interference. SBK1 and SOCS3 may play a promoting role in occurrence and development of cancers. The study suggests that LncRNA-ENST00000501520 could promote the proliferation in malignant-transformed BEAS-2B cells induced with CTP extract which may be mediated by target genes. This study may provide a new target for prevention and treatment of lung cancer.


Assuntos
Brônquios/efeitos dos fármacos , Proliferação de Células , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Alcatrão/toxicidade , RNA Longo não Codificante/fisiologia , Mucosa Respiratória/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mucosa Respiratória/metabolismo
17.
Molecules ; 24(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018549

RESUMO

Carcinogenesis is the process whereby a normal cell is transformed into a neoplastic cell. This action involves several steps starting with initiation and followed by promotion and progression. Driving these stages are oxidative stress and inflammation, which in turn encompasses a myriad of aberrant gene expressions, both within the transforming cell population and the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review, we discuss whereby the chemoprevention activities of the red beetroot itself may disrupt carcinogenesis and the activities of the water-soluble betalains extracted from the plant.


Assuntos
Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Beta vulgaris/química , Betalaínas/farmacologia , Carcinogênese/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/prevenção & controle , Animais , Anticarcinógenos/química , Anticarcinógenos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Betalaínas/química , Betalaínas/isolamento & purificação , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Flavonóis/química , Flavonóis/isolamento & purificação , Flavonóis/farmacologia , Humanos , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/farmacologia , Extratos Vegetais/química , Raízes de Plantas/química , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Oncol Rep ; 41(6): 3219-3232, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002364

RESUMO

The inactivation of tumor suppressor gene positive regulatory domain containing I (PRDM1) and activation of signal transducer and activator of transcription 3 (STAT3) have been detected in the majority of extranodal NK/T­cell lymphoma, nasal type (EN­NK/T­NT) cases. In the present study, their association with and effects on the clinicopathologic features of EN­NK/T­NT are described. PRDM1 was revealed to be expressed in 19 out of 58 patients (32.8%) with EN­NK/T­NT, and phosphorylated STAT3 was overexpressed in 42 out of 58 (72.4%). Oncogenic pathways were investigated by NanoString encounter technology in 5 PRDM1(+) and 5 PRDM1(­) EN­NK/T­NT specimens. Multiple oncogenic pathways involved in cell apoptosis, cellcycle (CC) and angiogenesis were discriminately activated in EN­NK/T­NT cases, and in PRDM1(+) cases in particular. The sustained activation of the Janus kinase 3 (JAK)/STAT3 pathway was more pronounced. In addition, missense mutations in the SRC homology 2 domain of STAT3 were detected in 7 out of 37 EN­NK/T­NT cases (18.92%), and the acquired mutation was related to the activation of the JAK3/STAT3 pathway. The downregulation of PRDM1 and upregulation of phospho­STAT3 (Tyr705) were associated with angiocentric infiltration of EN­NK/T­NT (P=0.039). Notably, the prognosis of patients in the PRDM1(+)/STAT3 [mutated (mut­)] group was considerably improved than that of patients in the STAT3(mut+)/PRDM(­) group (P=0.037). In addition, the inhibition of NK/T cell lymphoma cell lines by Stattic and tofacitinib could suppress cell proliferation by inducing cell apoptosis or arresting the CC. The present results revealed that the JAK3/STAT3 oncogenic pathway and PRDM1 expression could stratify clinicopathologic features of EN­NK/T­NT. The inhibition of the JAK3/STAT3 pathway may serve as a treatment option for EN­NK/T­NT.


Assuntos
Janus Quinase 3/genética , Linfoma de Células T/tratamento farmacológico , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator de Transcrição STAT3/genética , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia
19.
Phytother Res ; 33(6): 1597-1603, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937987

RESUMO

Pharmacological studies have shown that various species of Ficus have antiviral, antidiarrheal, antipyretic, hypolipidemic, antidiabetic, antioxidant, anticancer, antiparasitic, antiangiogenic, anti-inflammatory, antibacterial, antiplatelet, reproductive, dermatological, immunological, endocrine, and hepato and nephron protective effects. But there is no sufficient research on biomolecules present in the leaf extract of Ficus religiosa and its mechanism of action. We have previously reported that bioavailable constituents of F. religiosa leaf extract exert photosensitizing and apoptosis-inducing capability through the generation of intracellular reactive oxygen species on breast cancer cells. In this review, we have evaluated the expression of checkpoint proteins of G1/S and sub G0 phase with wet lab data and also have done a data mining of other research for other potential mechanistic action of the F. religiosa leaf extract.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinogênese/efeitos dos fármacos , Ficus/química , Extratos Vegetais/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Extratos Vegetais/farmacologia
20.
Cancer Invest ; 37(2): 99-112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30836770

RESUMO

Platelet-derived growth factor D (PDGF-D) has been shown to mediate cellular processes of importance in cancer progression. This study aimed to investigate the expression and putative involvement of PDGF-D signaling in colorectal carcinogenesis. PDGF-D was expressed in vascular endothelial cells in tumor and normal tissues. PDGF-D stimulation of cells altered genes of importance in carcinogenic processes. In addition, PDGF-D increased the proliferation rate while imatinib inhibited these effects. PDGF-D and its PDGF receptor beta (PDGFR-ß) are expressed in colorectal cancer and blockage of PDGF-D/PDGFR-ß signaling using tyrosine kinase inhibitors, such as imatinib, might be important in inhibiting tumor-promoting actions.


Assuntos
Neoplasias Colorretais/metabolismo , Linfocinas/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia , Células CACO-2 , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias Colorretais/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células HT29 , Humanos , Mesilato de Imatinib/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos
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