Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 75
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Exp Ther Med ; 22(3): 970, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34335912

RESUMO

Neuroinflammation is associated with many neurodegenerative diseases. Abnormal activation of microglial cells in the central nervous system (CNS) is a major characteristic of neuroinflammation. Nitric oxide (NO) free radicals are produced by activated microglia and prolonged presence of large quantities of NO in the CNS can lead to neuroinflammation and disease. Hispidin is a polyphenol derived from Phellinus linteus (a valuable medicinal mushroom) with strong antioxidant, anticancer and antidiabetic properties. A previous study demonstrated that hispidin significantly inhibited NO production via lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Therefore, the present study used MTT assay was used to detect the effect of hispdin on cell viability. Griess reagent analysis was used to measure NO production. Reverse transcription-semi quantitative PCR and western blotting were used to evaluate the effects of hispdin on iNOS mRNA and MAPK/ERK/JNK protein levels. Fluorescence microscopy and flow cytometry were used to detect the effects of hispdin on the production of ROS and phagocytosis of cells. The present results indicated that hispidin could significantly inhibit the increase of NO production and iNOS expression in BV-2 microglial cells stimulated by LPS. The inhibitory effect of hispidin on NO production was similar to that of S-methylisothiourea sulfate, an iNOS inhibitor. Signaling studies demonstrated that hispidin markedly suppresses LPS-induced mitogen activated protein kinases and JAK1/STAT3 activation, although not the NF-κB signaling pathway. The present observations in LPS-stimulated BV-2 microglial cells indicated that hispidin might serve as a therapeutic candidate for the treatment of NO-induced neuroinflammation and, potentially, as a novel iNOS inhibitor.

2.
Cancer Lett ; 516: 38-47, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34082024

RESUMO

Olaparib, a potent PARP inhibitor, has been shown to have great anti-tumor effects in some tumor types. Although biliary tract cancer (BTC) is a good candidate for DNA damage response (DDR)-targeted agents, targeted DDR inhibitors, including olaparib, are currently rarely evaluated in BTC. In our project, a total of ten BTC cell lines were used to assess the efficacy of olaparib. Olaparib alone showed moderate anti-proliferative effects in BTC cells and increased p-ATR and PD-L1 expression levels. In combination with an ATR inhibitor (AZD6738, ceralasertib) showed synergistic anti-proliferative effects and increased DNA strand breaks in vitro. PD-L1 induced by olaparib was also downregulated by ceralasertib through p-STAT-3 and YAP reduction with or without human primary peripheral blood mononuclear cells. In SNU478-xenograft models, the combination treatment significantly suppressed tumor growth. PD-L1 and YAP were strongly downregulated, similar to in vitro conditions, and expression of CXCR2 and CXCR4 was further reduced. In the current ongoing clinical trial (NCT04298021), BTC patients treated with olaparib and ceralasertib combination have shown tumor response. In conclusion, co-targeting of PARP and ATR might be a potential therapeutic approach for patients with BTC.

3.
Aging (Albany NY) ; 13(10): 13926-13940, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34030134

RESUMO

Peroxiredoxin II (Prx II) is involved in proliferation, differentiation, and aging in various cell types. However, Prx II-mediated stem cell regulation is poorly understood. Here, dermal mesenchymal stem cells (DMSCs), cell-growth factor-rich conditioned medium from DMSCs (DMSC-CM), and DMSC-derived exosomes (DMSC-Exos) were used to explore the regulatory role of Prx II in DMSC wound healing. Following treatment, wound healing was significantly decelerated in Prx II-/- DMSCs than in Prx II+/+ DMSCs. In vitro stimulation with 10 µM H2O2 significantly increased apoptosis in Prx II-/- DMSCs compared with Prx II+/+ DMSCs. The mRNA expression levels of EGF, b-FGF, PDGF-B, and VEGF did not significantly differ between Prx II-/- and Prx II+/+ DMSCs. Fibroblasts proliferated comparably when treated with Prx II+/+ DMSC-CM or Prx II-/- DMSC-CM. Wound healing was significantly higher in the Prx II-/- DMSC-Exos-treated group than in the Prx II+/+ DMSCs-Exos-treated group. Moreover, microRNA (miR)-21-5p expression levels were lower and miR-221 levels were higher in Prx II-/- DMSCs than in Prx II+/+ DMSCs. Therefore, our results indicate that Prx II accelerated wound healing by protecting DMSCs from reactive oxygen species-induced apoptosis; however, Prx II did not regulate cell/growth factor secretion. Prx II potentially regulates exosome functions via miR-21-5p and miR-221.


Assuntos
Derme/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Peroxirredoxinas/metabolismo , Cicatrização , Animais , Apoptose , Meios de Cultivo Condicionados/farmacologia , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Exossomos/ultraestrutura , Deleção de Genes , Peróxido de Hidrogênio/toxicidade , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Cicatrização/genética
4.
Gastric Cancer ; 24(5): 1003-1020, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33723720

RESUMO

BACKGROUND: To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance. METHODS: In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). RESULTS: Here, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro. CONCLUSION: Taken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients.

5.
Cancer Res Treat ; 53(1): 199-206, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33070562

RESUMO

PURPOSE: The soluble form programmed death-ligand 1 (sPDL1) has immunosuppressive properties and is being studied as a candidate biomarker for immuno-oncology drug development. We measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC). Materials and Methods: We prospectively enrolled 68 GC patients who were candidates for palliative standard first-line chemotherapy, and serially collected blood at baseline and after one cycle of chemotherapy, at the best response and after disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progressionfree survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off value of sPDL1 levels for survival analysis was found using C-statistics. RESULTS: The median baseline sPDL1 was 0.8 ng/mL (range, 0.06 to 6.06 ng/mL). The median OS and PFS were 14.9 months and 8.0 months, respectively. sPDL1 and NLR showed a weak positive correlation (Spearman's rho=0.301, p=0.013). Patients with low levels of sPDL1 at diagnosis (< 1.92 ng/mL) showed a better OS and PFS than patients with a high sPDL1. The baseline sPDL1 before treatment was higher in the progressive disease group than in the stable disease and partial response groups. Patients whose sPDL1 increased after the first cycle of chemotherapy showed worse PFS and OS. Following disease progression, sPDL1 increased compared with the baseline. CONCLUSION: sPDL1 at prechemotherapy confers a prognostic value for PFS and OS in GC patients under palliative first-line chemotherapy. Dynamics of sPDL1 during chemotherapy correlates with disease progression.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Neoplasias Gástricas/mortalidade
6.
Liver Int ; 41(2): 388-395, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32780918

RESUMO

BACKGROUND: This study aimed to evaluate the association between soluble TGF-ß (sTGF-ß) and soluble PD-L1 (sPDL1), the dynamics of sTGF-ß during treatment and its prognostic role in biliary tract cancer (BTC). METHODS: The study population consisted of 90 BTC patients with first-line chemotherapy (cohort 1) and 35 BTC patients with second- or third-line chemotherapy (cohort 2). Plasma sTGF-ß and sPDL1 levels were measured using an enzyme-linked immunosorbent assay. RESULTS: In both groups, sTGF-ß was positive correlated with sPDL1 for baseline and change values after treatment. sTGF-ß was elevated at disease progression compared to baseline in cohort 1 (P < .001). Increased sTGF-ß after treatment revealed worse DFS and OS (P = .024, P = .028, respectively) in cohort 1 and significantly shorter OS (P = .020) in cohort 2. In multivariable analysis, this prognostic value of increased sTGF-ß for OS retained its significance in both cohorts (Hazard ratio (HR) = 1.8, 95% CI, 1.1-3.0, P = .028, in cohort 1; HR = 4.7, 95% CI, 1.5-14.6, P = .007, in cohort 2). CONCLUSIONS: In BTC, sTGF-ß was positively correlated with sPDL1 for baseline and changes after chemotherapy, and increased as tumour burden. sTGF-ß could be associated with survival; particularly, an elevated value after treatment suggests worse prognosis.


Assuntos
Antígeno B7-H1 , Neoplasias do Sistema Biliar , Neoplasias do Sistema Biliar/tratamento farmacológico , Humanos , Prognóstico , Fator de Crescimento Transformador beta , Fatores de Crescimento Transformadores
7.
Exp Ther Med ; 20(5): 82, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32968439

RESUMO

The aim of the present study was to verify the pro-apoptotic anticancer potential of several 5,8-dimethoxy-1,4-phthoquinone (DMNQ) derivatives in Ras-mediated tumorigenesis. MTT assays were used to detect cellular viability and flow cytometry was performed to assess intracellular reactive oxygen species (ROS) levels and apoptosis. The expression levels of proteins were detected via western blotting. Among the 12 newly synthesized DMNQ derivatives, 2-benzylthio-5,8-dimethoxynaphthalene-1,4-dione (BZNQ; component #1) significantly reduced cell viability both in mouse NIH3T3 embryonic fibroblasts cells (NC) and H-RasG12V transfected mouse NIH3T3 embryonic fibroblasts cells (NR). Moreover, BZNQ resulted in increased cytotoxic sensitivity in Ras-mutant transfected cells. Furthermore, the reactive oxygen species (ROS) levels in H-RasG12V transfected HepG2 liver cancer cells (HR) were significantly higher compared with the levels in HepG2 liver cancer cells (HC) following BZNQ treatment, which further resulted in increased cellular apoptosis. Eliminating cellular ROS using an ROS scavenger N-acetyl-L-cysteine markedly reversed BZNQ-induced cellular ROS accumulation and cell apoptosis in HC and HR cells. Western blotting results revealed that BZNQ significantly downregulated H-Ras protein expression and inhibited the Ras-mediated downstream signaling pathways such as protein kinase B, extracellular signal-related kinase and glycogen synthase kinase phosphorylation and ß-catenin protein expression. These results indicated that the novel DMNQ derivative BZNQ may be a therapeutic drug for Ras-mediated liver tumorigenesis. The results of the current study suggest that BZNQ exerts its effect by downregulating H-Ras protein expression and Ras-mediated signaling pathways.

8.
Biochem Biophys Res Commun ; 529(3): 635-641, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32736685

RESUMO

Keratinocyte hyperproliferation is an essential link in skin cancer pathogenesis. Peroxiredoxin I (Prx I) is known to regulate cancer cell proliferation, differentiation, and apoptosis, but its role in skin cancer remains unclear. This study aimed to elucidate the role and mechanism of Prx I in skin cancer pathogenesis. Dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were used to create a skin tumor model of the initiation/promotion stage of cancer. The role of Prx I in H2O2-induced keratinocyte apoptosis was also investigated. After DMBA/TPA treatment, Prx I deficiency was significantly associated with less skin tumors, lower Bcl-2 expression, and higher p-p38 and cleaved caspase-3 expressions in Prx I knockout tumors than in wild-type controls. H2O2 stimulation caused more cellular apoptosis in Prx I knockdown HaCaT cells than in normal HaCaT cells. The signaling study revealed that Bcl-2, p-p38, and cleaved caspase-3 expressions were consistent with the results in the tumors. In conclusion, the deletion of Prx I triggered the DMBA/TPA-induced skin tumor formation in vivo and in vitro by regulating the reactive oxygen species (ROS)-p38 mitogen-activated protein kinase (MAPK) pathway. These findings provide a theoretical basis for treating skin cancer.


Assuntos
Apoptose/genética , Queratinócitos/metabolismo , Peroxirredoxinas/genética , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Células HEK293 , Humanos , Peróxido de Hidrogênio/farmacologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Camundongos da Linhagem 129 , Camundongos Knockout , Oxidantes/farmacologia , Peroxirredoxinas/deficiência , Interferência de RNA , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
9.
In Vivo ; 34(4): 1823-1833, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606152

RESUMO

BACKGROUND/AIM: Picrasma quassioides (P. quassioides) is used in traditional Asian medicine widely for the treatment of anemopyretic cold, eczema, nausea, loss of appetite, diabetes mellitus, hypertension etc. In this study we aimed to understand the effect of P. quassioides ethanol extract on SiHa cervical cancer cell apoptosis. MATERIALS AND METHODS: The P. quassioides extract-induced apoptosis was analyzed using the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: P. quassioides extract induced cellular apoptosis by increasing the accumulation of cellular and mitochondrial reactive oxygen species (ROS) levels and inhibiting ATP synthesis. Pretreatment with N-Acetylcysteine (NAC), a classic antioxidant, decreased the intracellular ROS production and inhibited apoptosis. In addition, the P38 MAPK signaling pathway is a key in the apoptosis of SiHa cells induced by the P. quassioides extract. CONCLUSION: The P. quassioides extract exerts its anti-cancer properties on SiHa cells through ROS-mitochondria axis and P38 MAPK signaling. Our data provide a new insight for P. quassioides as a therapeutic strategy for cervical cancer treatment.


Assuntos
Picrasma , Neoplasias do Colo do Útero , Apoptose , Feminino , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Picrasma/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
10.
Mol Med Rep ; 22(3): 1831-1838, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32705184

RESUMO

Apoptosis of pancreatic ß­cells is involved in the pathogenesis of type I and II diabetes. Peroxiredoxin I (Prx I) serves an important role in regulating cellular apoptosis; however, the role of Prx I in pancreatic ß­cell apoptosis is not completely understood. In the present study, the role of peroxiredoxin 1 (Prx I) during streptozotocin (STZ)­induced apoptosis of pancreatic ß­cells was investigated. The expression level of Prx I was decreased by STZ treatment in a time­dependent manner, and apoptosis of Prx I knockdown MIN6 cells was increased by STZ stimulation, compared with untransduced MIN6 cells. Furthermore, an intraperitoneal injection of STZ increased pancreatic islet damage in Prx I knockout mice, compared with wild­type and Prx II knockout mice. AKT and glycogen synthase kinase (GSK)­3ß phosphorylation significantly decreased following Prx I knockdown in MIN6 cells. However, phosphorylated ß­catenin and p65 levels significantly increased after STZ stimulation, compared with untransduced cells. The results of the present study indicate that deletion of Prx I mediated STZ­induced pancreatic ß­cell death in vivo and in vitro by regulating the AKT/GSK­3ß/ß­catenin signaling pathway, as well as NF­κB signaling. These findings provide a theoretical basis for treatment of pancreatic damage.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo , Células Secretoras de Insulina/citologia , Peroxirredoxinas/genética , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
11.
Anticancer Res ; 40(7): 3819-3830, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620621

RESUMO

BACKGROUND: Picrasma quassioides (PQ) is a traditional Asian herbal medicine with anti-tumor properties that can inhibit the viability of HepG2 liver cancer cells. H-Ras is often mutated in liver cancer, however, the effect of PQ treatment on H-Ras mutated liver cancer is unclear. This study aimed to investigate the role of PQ on ROS accumulation and mitochondrial dysfunction in H-ras mutated HepG2 (HepG2G12V) cells. MATERIALS AND METHODS: PQ ethanol extract-induced HepG2G12V apoptosis was analyzed by the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: PQ treatment affected cell migration and colony formation in HepG2G12V cells. Cleaved-caspase-3, cleaved-caspase-9 and BCL2 associated agonist of cell death (BAD) expression levels were increased, while the levels of B-cell lymphoma-extra large (Bcl-xL) were decreased with PQ treatment. PQ treatment led to a reduction of H-Ras expression levels in liver cancer cells, thus reducing their abnormal proliferation. Furthermore, it led to increased expression levels of Peroxiredoxin VI, which regulates the redox signal in cells. CONCLUSION: Taken together these results provide a new functional significance for the role of PQ in treating HepG2G12V liver cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias Hepáticas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Genes ras , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Picrasma/química , Proteínas Proto-Oncogênicas p21(ras)/biossíntese
12.
Anticancer Res ; 40(8): 4491-4504, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727779

RESUMO

BACKGROUND: Peroxiredoxin II (PRDX2) performs unique roles in cells. It can reduce peroxides through cysteine residues, and helps prevent the effects of oxidative stress on cells. It is closely related to the occurrence and development of various diseases, especially alcoholic liver injury and even liver cancer. The metabolism of alcohol in hepatocytes leads to the increase in the levels of reactive oxygen species (ROS), oxidative stress, injury, and apoptosis. Therefore, this study focused on the investigating the protection conferred by PRDX2 against alcohol-induced apoptosis of hepatocytes. MATERIALS AND METHODS: PRDX2 inhibition of alcohol-induced apoptosis in L02 hepatocytes was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, fluorescence microscopy, flow cytometry, western blotting and hematoxylin and eosin staining. RESULTS: The results showed that the levels of reactive oxygen species, protein kinase B, ß-catenin, B-cell lymphoma-2 (BCL2), BCL-XL, BCL2-associated X, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase in PRDX2-silenced cells were increased significantly after the treatment of cells with ethanol. Similar results were obtained in an in vivo Prdx2-knockout mouse model of alcoholic liver injury. Therefore, PRDX2 may regulate the phosphorylation of the AKT signal protein by eliminating reactive oxygen species from cells, and it inhibits the downstream mitochondria-dependent apoptosis pathway, and, thereby, the apoptosis of cells. CONCLUSION: Thus, PRDX2 may be a potential molecular target for the prevention and treatment of alcoholic liver injury.


Assuntos
Etanol/efeitos adversos , Hepatócitos/citologia , Peroxirredoxinas/genética , Transdução de Sinais , Apoptose , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fosforilação/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo
13.
Cancer Res Treat ; 52(3): 945-956, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32311864

RESUMO

PURPOSE: Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC. Materials and Methods: In this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models. RESULTS: AZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy. CONCLUSION: Taken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Neoplasias do Sistema Biliar/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Sulfóxidos/farmacologia , Animais , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/patologia , Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cancer Med ; 9(1): 43-51, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31701645

RESUMO

OBJECTIVES: Transforming growth factor-beta (TGF-ß) is a multifunctional regulatory factor. Here we measured serum soluble TGF-ß (sTGF-ß) levels and evaluated its dynamics and prognostic capabilities during chemotherapy in unresectable pancreatic cancer patients. METHODS: We prospectively enrolled 60 patients treated with FOLFIRINOX as the first-line palliative chemotherapy. We collected blood samples at the time of diagnosis, first response assessment, and disease progression and measured serum sTGF-ß using an enzyme-linked immunosorbent assay. RESULTS: The patients' median overall survival (OS) and progression-free survival (PFS) were 10.3 (95% confidence interval [CI], 8.5-12.1) and 6.5 (95% CI, 4.9-8.1) months, respectively. Patients with low sTGF-ß at diagnosis (<31.2 ng/mL) had better OS and PFS than patients with high sTGF-ß, respectively, (OS, 13.7 vs 9.2 months; hazard ratio [HR], 2.602; P = .004; PFS, 9.0 vs 5.8 months; HR, 2.010; P = .034). At the time of disease progression, sTGF-ß was increased compared with that of diagnosis (mean, 26.4 vs 23.9 ng/mL). In particular, sTGF-ß was significantly increased at disease progression in patients with a partial response (mean, 25.7 vs 31.0 ng/mL; P = .049). CONCLUSIONS: Pretreatment sTGF-ß levels can serve as a prognostic indicator in unresectable pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Likewise, the dynamics of sTGF-ß during chemotherapy have prognostic value.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Cuidados Paliativos/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Fator de Crescimento Transformador beta/sangue , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Estimativa de Kaplan-Meier , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos
15.
Cancer Res Treat ; 52(1): 149-166, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31291716

RESUMO

PURPOSE: Pancreatic cancer (PC) is one of the most lethal cancers worldwide, but there are currently no effective treatments. The DNA damage response (DDR) is under investigation for the development of novel anti-cancer drugs. Since DNA repair pathway alterations have been found frequently in PC, the purpose of this study was to test the DDR-targeting strategy in PC using WEE1 and ATM inhibitors. Materials and Methods: We performed in vitro experiments using a total of ten human PC cell lines to evaluate antitumor effect of AZD1775 (WEE1 inhibitor) alone or combination with AZD0156 (ATM inhibitor). We established Capan-1-mouse model for in vivo experiments to confirm our findings. RESULTS: In our research, we found that WEE1 inhibitor (AZD1775) as single agent showed anti-tumor effects in PC cells, however, targeting WEE1 upregulated p-ATM level. Here, we observed that co-targeting of WEE1 and ATM acted synergistically to reduce cell proliferation and migration, and to induce DNA damage in vitro. Notably, inhibition of WEE1 or WEE1/ATM downregulated programmed cell death ligand 1 expression by blocking glycogen synthase kinase-3ß serine 9 phosphorylation and decrease of CMTM6 expression. In Capan-1 mouse xenograft model, AZD1775 plus AZD0156 (ATM inhibitor) treatment reduced tumor growth and downregulated tumor expression of programmed cell death ligand 1, CMTM6, CD163, and CXCR2, all of which contribute to tumor immune evasion. CONCLUSION: Dual blockade of WEE1 and ATM might be a potential therapeutic strategy for PC. Taken toget.


Assuntos
Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Antígeno B7-H1/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pancreáticas/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Citocinas , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Pontos de Checagem da Fase S do Ciclo Celular , Ensaios Antitumorais Modelo de Xenoenxerto
16.
In Vivo ; 34(1): 133-141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882472

RESUMO

BACKGROUND/AIM: Dermal mesenchymal stem cells (DMSCs) are pluripotent stem cells found in the skin which maintain the thickness of the dermal layer and participate in skin wound healing. MATERIALS AND METHODS: The MTT assay was performed to detect cell proliferation and cell-cycle progression and cell-surface markers were assessed by flow cytometry. The levels of proteins in related signaling pathways were detected by western blotting assay and the translocation of ß-catenin into the nucleus were detected by immunofluorescence. Red oil O staining was performed to examine the differentiational ability of DMSCs. RESULTS: Knockout of PRDX2 inhibited DMSC cell growth, and cell-cycle arrest at G0/G1 phase; p16, p21 and cyclin D1 expression levels in Prdx2 knockout DMSCs were significantly increased. Furthermore, AKT phosphorylation were significantly increased in Prdx2 knockout DMSCs, GSK3ß activity were inhibited, result in ß-Catenin accumulated in the nucleus. CONCLUSION: In conclusion, these results demonstrated that PRDX2 plays a pivotal role in regulating the proliferation of DMSCs, and this is closely related to the AKT/glycogen synthase kinase 3 beta/ß-catenin signaling pathway.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/genética , Fase G1/genética , Células-Tronco Mesenquimais/patologia , Peroxirredoxinas/genética , Fase de Repouso do Ciclo Celular/genética , Transdução de Sinais/genética , Animais , Apoptose/genética , Linhagem Celular , Glicogênio Sintase Quinase 3 beta/genética , Camundongos , Camundongos Knockout , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/genética , beta Catenina/genética
17.
Antioxidants (Basel) ; 9(1)2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861323

RESUMO

Excessive alcohol intake can significantly reduce cognitive function and cause irreversible learning and memory disorders. The brain is particularly vulnerable to alcohol-induced ROS damage; the hippocampus is one of the most sensitive areas of the brain for alcohol neurotoxicity. In the present study, we observed significant increasing of intracellular ROS accumulations in Peroxiredoxin II (Prx II) knockdown HT22 cells, which were induced by alcohol treatments. We also found that the level of ROS in mitochondrial was also increased, resulting in a decrease in the mitochondrial membrane potential. The phosphorylation of GSK3ß (Ser9) and anti-apoptotic protein Bcl2 expression levels were significantly downregulated in Prx II knockdown HT22 cells, which suggests that Prx II knockdown HT22 cells were more susceptible to alcohol-induced apoptosis. Scavenging the alcohol-induced ROS with NAC significantly decreased the intracellular ROS levels, as well as the phosphorylation level of GSK3ß in Prx II knockdown HT22 cells. Moreover, NAC treatment also dramatically restored the mitochondrial membrane potential and the cellular apoptosis in Prx II knockdown HT22 cells. Our findings suggest that Prx II plays a crucial role in alcohol-induced neuronal cell apoptosis by regulating the cellular ROS levels, especially through regulating the ROS-dependent mitochondrial membrane potential. Consequently, Prx II may be a therapeutic target molecule for alcohol-induced neuronal cell death, which is closely related to ROS-dependent mitochondria dysfunction.

18.
Pharmacol Ther ; 203: 107391, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31299316

RESUMO

Alterations in DNA damage response (DDR) pathways are hallmarks of cancer. Incorrect repair of DNA lesions often leads to genomic instability. Ataxia telangiectasia mutated (ATM), a core component of the DNA repair system, is activated to enhance the homologous recombination (HR) repair pathway upon DNA double-strand breaks. Although ATM signaling has been widely studied in different types of cancer, its research is still lacking compared with other DDR-involved molecules such as PARP and ATR. There is still a vast research opportunity for the development of ATM inhibitors as anticancer agents. Here, we focus on the recent findings of ATM signaling in DNA repair of cancer. Previous studies have identified several partners of ATM, some of which promote ATM signaling, while others have the opposite effect. ATM inhibitors, including KU-55933, KU-60019, KU-59403, CP-466722, AZ31, AZ32, AZD0156, and AZD1390, have been evaluated for their antitumor effects. It has been revealed that ATM inhibition increases a cancer cell's sensitivity to radiotherapy. Moreover, the combination with PARP or ATR inhibitors has synergistic lethality in some cancers. Of note, among these ATM inhibitors, AZD0156 and AZD1390 achieve potent and highly selective ATM kinase inhibition and have an excellent ability to penetrate the blood-brain barrier. Currently, AZD0156 and AZD1390 are under investigation in phase I clinical trials. Taken together, targeting ATM may be a promising strategy for cancer treatment. Hence, further development of ATM inhibitors is urgently needed in cancer research.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Reparo do DNA , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Transdução de Sinais
19.
In Vivo ; 33(4): 1183-1192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280208

RESUMO

BACKGROUND/AIM: Peroxiredoxin (Prx) protein family is aberrantly expressed in various cancers including gastric cancer. Among the six family members, Prx V has been known as an antioxidant enzyme which scavenges intracellular reactive oxygen species (ROS) and modulates cellular apoptosis. This study aimed at investigating the role of Prx V in apoptosis of gastric cancer cells. MATERIALS AND METHODS: Stably constructed Prx V knockdown, over-expression and mock AGS cells (a human gastric adenocarcinoma cell line) were used to study the effect of Prx V on emodin-induced apoptosis by western blotting, cell viability, apoptosis and ROS detection assays. RESULTS: Overexpression of Prx V significantly decreased emodin-induced cellular apoptosis and ROS levels compared to Mock and Prx V knockdown AGS cells. Also, overexpression of Prx V down-regulated the expression of pro-apoptotic proteins, Bad and cleaved PARP, and increased the expression of anti-apoptotic protein, Bcl2. CONCLUSION: Prx V suppresses AGS cell apoptosis via scavenging intracellular ROS and modulating apoptosis-related markers.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/genética , Emodina/farmacologia , Peroxirredoxinas/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Imunofluorescência , Expressão Gênica , Humanos , Peroxirredoxinas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
20.
Anticancer Res ; 39(7): 3677-3686, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262894

RESUMO

BACKGROUND/AIM: Peroxiredoxin (Prx) V has been known as an antioxidant enzyme which scavenges intracellular reactive oxygen species (ROS). Also, Prx V has been shown to mediate cell apoptosis in various cancers. However, the mechanism of Prx V-induced apoptosis in colon cancer cells remains unknown. Thus, in this study we analyzed the effects of Prx V in ß-lapachone-induced apoptosis in SW480 human colon cancer cells. MATERIALS AND METHODS: ß-lapachone-induced apoptosis was analyzed by the MTT assay, western blotting, fluorescence microscopy, Annexin V staining and flow cytometry. RESULTS: Overexpression of Prx V, significantly decreased ß-lapachone-induced cellular apoptosis and Prx V silencing increased ß-lapachone-induced cellular apoptosis via modulating ROS scavenging activity compared to mock SW480 cells. In addition, to further explore the mechanism of Prx V regulated ß-lapachone-induced SW480 cells apoptosis, the Wnt/ß-catenin signaling was studied. The Wnt/ ß-catenin signaling pathway was found to be induced by ß-lapachone. CONCLUSION: Prx V regulates SW480 cell apoptosis via scavenging ROS cellular levels and mediating the Wnt/ß-catenin signaling pathway, which was induced by ß-lapachone.


Assuntos
Apoptose , Neoplasias do Colo/metabolismo , Naftoquinonas , Peroxirredoxinas/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Colo/metabolismo , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...