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1.
Int J Nanomedicine ; 14: 6249-6268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496684

RESUMO

Purpose: To develop an intravesical instillation system for the treatment of bladder cancer, rapamycin (Rap) was encapsulated into liposomes and then homogeneously dispersed throughout a poloxamer 407 (P407)-based hydrogel. Methods: Rap-loaded conventional liposomes (R-CL) and folate-modified liposomes (R-FL) were prepared using a film hydration method and pre-loading technique, and characterized by particle size, drug entrapment efficiency, and drug loading. The cellular uptake behavior in folate receptor-expressing bladder cancer cells was observed by flow cytometry and confocal laser scanning microscopy using a fluorescent probe. In vitro cytotoxic effects were evaluated using MTT assay, colony forming assay, and Western blot. For in vivo intravesical instillation, Rap-loaded liposomes were dispersed in P407-gel, generating R-CL/P407 and R-FL/P407. Gel-forming capacities and drug release were evaluated. Using the MBT2/Luc orthotopic bladder cancer mouse model, in vivo antitumor efficacy was evaluated according to regions of interest (ROI) measurement. Results: R-CL and R-FL were successfully prepared, at approximately <160 nm, 42% entrapment efficiency, and 57 µg/mg drug loading. FL cellular uptake was enhanced over 2-fold than that of CL; folate receptor-mediated endocytosis was confirmed using a competitive assay with folic acid pretreatment. In vitro cytotoxic effects increased dose-dependently. Rap-loaded liposomes inhibited mTOR signaling and induced autophagy in urothelial carcinoma cells. With gelation time of <30 seconds and gel duration of >12 hrs, both R-CL/P407 and R-FL/P407 preparations transformed into gel immediately after instillation into the mouse bladder. Drug release from the liposomal gel was erosion controlled. In orthotopic bladder cancer mouse model, statistically significant differences in ROI values were found between R-CL/P407 and R-FL/P407 groups at day 11 (P=0.0273) and day 14 (P=0.0088), indicating the highest tumor growth inhibition by R-FL/P407. Conclusion: Intravesical instillation of R-FL/P407 might represent a good candidate for bladder cancer treatment, owing to its enhanced retention and FR-targeting.


Assuntos
Ácido Fólico/química , Hidrogéis/química , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Temperatura Ambiente , Administração Intravesical , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Coloides , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Feminino , Receptores de Folato com Âncoras de GPI/metabolismo , Humanos , Lipossomos , Camundongos , Tamanho da Partícula , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico
2.
J Cancer Res Clin Oncol ; 145(11): 2649-2661, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31529191

RESUMO

PURPOSE: The incidence of Urothelial carcinoma of bladder (UBC) is gradually increasing by changing lifestyle and environment. The development of a tumor has been noted to be accompanied by modifications in the extracellular matrix (ECM) consisting of CD44, hyaluronic acid (HA) and its family members. The importance of CD44 splice variants and HA family members has been studied in UBC. METHODS: The cohort of study included 50 UBC patients undergoing radical cystectomy and 50 healthy subjects. The molecular expression of CD44 and HA family members was determined. Effect of CD44 variant-specific silencing on downstream signaling in HT1376 cells was investigated. Combinatorial treatment of 4-MU (4-methylumbelliferone) with cisplatin or doxorubicin on chemosensitivity was also explored. RESULTS: Higher expression of HA, HAS2, and CD44 was observed in Indian UBC patients which also showed the trend with severity of disease. Splice variant assessment of CD44 demonstrated the distinct role of CD44v3 and CD44v6 in bladder cancer progression. shRNA-mediated downregulation of CD44v3 showed an increase effect on cell cycle, apoptosis and multiple downstream signaling cascade including pAkt, pERK and pSTAT3. Furthermore, 4-MU, an HA synthesis inhibitor, observed to complement the effect of Cisplatin or Doxorubicin by enhancing the chemosensitivity of bladder cancer cells. CONCLUSIONS: Our findings exhibit involvement of CD44 splice variants and HA family members in UBC and significance of 4-MU in enhancing chemosensitivity suggesting their novel therapeutic importance in disease therapeutics.


Assuntos
Processamento Alternativo , Receptores de Hialuronatos/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Apoptose , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
4.
Chem Biodivers ; 16(10): e1900334, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31448497

RESUMO

Cernumidine (CER) is a guanidinic alkaloid isolated from Solanum cernuum leaves. In this work, we investigated the cytotoxicity, chemosensitizing effect of cernumidine to cisplatin (cDDP) and the possible mechanism of action of the combination on bladder cancer cells. Cernumidine showed cytotoxicity and could sensitize bladder cancer cells to cisplatin. The combination of CER+cDDP inhibited cell migration on T24 cells. CER+cDDP down-regulated MMP-2/9 and p-ERK1/2, while it increased EGFR activity corroborating the observed cell migration inhibition. Down-regulation of Bcl-2 and up-regulation pro-apoptotic Bax and further depletion of the mitochondrial membrane potential (ΔΨm) indicates that mitochondria play a central role in the combination treatment inducing the mitochondrial signaling pathway of apoptosis in T24 cells. Our data showed that the alkaloid cernumidine is worthy of further studies as a chemosensitizing agent to be used in complementary chemotherapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ácidos Cafeicos/farmacologia , Guanidinas/farmacologia , Solanum/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Ácidos Cafeicos/química , Ácidos Cafeicos/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Guanidinas/química , Guanidinas/isolamento & purificação , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Folhas de Planta/química , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
6.
Anticancer Res ; 39(7): 3641-3649, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262890

RESUMO

BACKGROUND/AIM: Amentoflavone has been shown to be effective against a variety of cancer cells, but its role in bladder cancer remains unclear. Thus, the aim of this study is to evaluate whether amentoflavone may induce toxicity effect of bladder cancer. MATERIALS AND METHODS: Herein, we evaluated amentoflavone effects in a human bladder cancer cell line TSGH8301 in vitro. RESULTS: Amentoflavone caused significant cytotoxicity in TSGH8301 cells at a concentration as low as 200 µM. FAS/FASL-dependent extrinsic apoptosis and mitochondria-dependent intrinsic apoptosis were observed in amentoflavone-treated cells in a dose-dependent manner. Levels of several proapoptotic proteins, such as FAS, FAS-ligand and BAX (B-cell lymphoma 2 associated X) were increased following amentoflavone treatment. Meanwhile, anti-apoptotic MCL-1 (myeloid cell leukemia sequence 1) and cellular FLICE-inhibitory protein (C-FLIP) protein levels were reduced. Additionally, angiogenesis and proliferation-related proteins, including matrix metalloproteinase (MMP)-2, -9, vascular endothelial growth factor (VEGF), urokinase-type plasminogen actvator (uPA) and cyclin D1 were diminished by amentoflavone. CONCLUSION: Amentoflavone induced toxicity of bladder cancer by inhibiting tumor progression and inducing apoptosis signaling transduction.


Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/fisiopatologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/fisiopatologia , Receptor fas/metabolismo
7.
J Cancer Res Clin Oncol ; 145(8): 2131-2140, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31227894

RESUMO

PURPOSE: This study aimed at determining the relationship between classification according to the papillary tumor pattern of carcinoma in situ (CIS) of the bladder and prognosis, as this has not yet been well established. METHODS: This study comprised a consecutive cohort of 254 patients (primary CIS: 66 patients, stage Ta-CIS: 52 patients, and stage T1-CIS: 136 patients) with CIS-associated bladder cancer. We classified CIS according to the pathological pattern of papillary tumors and analyzed prognostic factors, including CIS classification, for progression. We evaluated progression using two endpoints: infiltrative tumors detected at stage T1 or higher or at stage T2 or higher. Bacillus Calmette-Guerin (BCG) immunotherapy response was defined as no recurrence within 6 months. RESULTS: Both the BCG immunotherapy response and CIS classification were significant prognostic factors for both the endpoints. Patients with CIS-associated stage Ta urinary bladder cancer had better prognosis for both the endpoints than those with stage T1 cancer or those with primary CIS. BCG immunotherapy response (p < 0.001) and age (p = 0.007) were also significant prognostic factors for the progression of stage T2 or higher infiltrative tumors. The prognosis of patients with recurrent primary CIS (12/26, 46.2%) and T1-CIS (25/45, 55.6%) was poor for progression; distant metastasis occurred in approximately 40% of these patients. CONCLUSIONS: Clinicians should consider radical surgery for poor prognosis in patients with recurrent CIS-associated T1 cancer or primary CIS. The CIS classification according to the tumor pattern reflects the prognosis.


Assuntos
Vacina BCG/uso terapêutico , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/tratamento farmacológico , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/tratamento farmacológico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/patologia , Carcinoma Papilar/patologia , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Progressão da Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologia
8.
J Agric Food Chem ; 67(28): 7844-7854, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31241937

RESUMO

Bladder cancer is the fourth common cancer among men and more than 70% of the bladder cancer is nonmuscle invasive bladder cancer (NMIBC). Because of its high recurrence rate, NMIBC brings to patients physical agony and high therapy costs to the patients' family and society. It is imperative to seek a natural compound to inhibit bladder cancer cell growth and prevent bladder cancer recurrence. Cell proliferation is one of the main features of solid tumor development, and the rapid tumor cell growth usually leads to hypoxia due to the low oxygen environment. In this study we found that sulforaphane, a natural chemical which was abundant in cruciferous vegetables, could suppress bladder cancer cells proliferation in hypoxia significantly stronger than in normoxia (p < 0.05): 20 µM sulforaphane inhibited bladder cancer cell proliferation by 26.1 ± 4.1% in normoxia, while it inhibited cell proliferation by 39.7 ± 5.2% in hypoxia in RT112 cells. Consistently, sulforaphane inhibited cell proliferation by 29.7 ± 4.6% in normoxia, while it inhibited cell proliferation by 48.3 ± 5.2% in hypoxia in RT4 cells. Moreover, we revealed that sulforaphane decreased glycolytic metabolism in a hypoxia microenvironment by downregulating hypoxia-induced HIF-1α and blocking HIF-1α trans-localization to the nucleus in NMIBC cell lines. This study discovered a food sourced compound inhibiting bladder cancer cells proliferation and provided experimental evidence for developing a new bladder cancer preventive and therapeutic strategy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/fisiopatologia , Isotiocianatos/administração & dosagem , Neoplasias da Bexiga Urinária/fisiopatologia , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
9.
Cancer Sci ; 110(9): 2806-2821, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254429

RESUMO

In human and dogs, bladder cancer (BC) is the most common neoplasm affecting the urinary tract. Dog BC resembles human muscle-invasive BC in histopathological characteristics and gene expression profiles, and could be an important research model for this disease. Cancer patient-derived organoid culture can recapitulate organ structures and maintains the gene expression profiles of original tumor tissues. In a previous study, we generated dog prostate cancer organoids using urine samples, however dog BC organoids had never been produced. Therefore we aimed to generate dog BC organoids using urine samples and check their histopathological characteristics, drug sensitivity, and gene expression profiles. Organoids from individual BC dogs were successfully generated, expressed urothelial cell markers (CK7, CK20, and UPK3A) and exhibited tumorigenesis in vivo. In a cell viability assay, the response to combined treatment with a range of anticancer drugs (cisplatin, vinblastine, gemcitabine or piroxicam) was markedly different in each BC organoid. In RNA-sequencing analysis, expression levels of basal cell markers (CK5 and DSG3) and several novel genes (MMP28, CTSE, CNN3, TFPI2, COL17A1, and AGPAT4) were upregulated in BC organoids compared with normal bladder tissues or two-dimensional (2D) BC cell lines. These established dog BC organoids might be a useful tool, not only to determine suitable chemotherapy for BC diseased dogs but also to identify novel biomarkers in human muscle-invasive BC. In the present study, for the 1st time, dog BC organoids were generated and several specifically upregulated organoid genes were identified. Our data suggest that dog BC organoids might become a new tool to provide fresh insights into both dog BC therapy and diagnostic biomarkers.


Assuntos
Técnicas de Cultura de Células/métodos , Doenças do Cão/patologia , Organoides/patologia , Neoplasias da Bexiga Urinária/veterinária , Bexiga Urinária/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doenças do Cão/tratamento farmacológico , Doenças do Cão/genética , Doenças do Cão/urina , Cães , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Masculino , Organoides/efeitos dos fármacos , Organoides/metabolismo , Análise de Sequência de RNA , Regulação para Cima , Bexiga Urinária/citologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/urina , Urina/citologia , Urotélio/citologia
10.
Expert Opin Pharmacother ; 20(11): 1387-1396, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31081702

RESUMO

INTRODUCTION: Bladder cancer (BCa) is a disease that predominantly affects adult and elderly populations. As people live longer, it will become even more frequent and consequently represents a big health problem for health-care providers and is a challenging clinical dilemma. In the elderly, the treatment of BCa presents some peculiarities due to its more aggressive behavior and reduced patient reserves, impacting their response to medical and surgical therapies. AREAS COVERED: The authors provide a non-systematic review of the literature using PubMed to obtain an overview of the therapeutic options for BCa in the elderly, from the low-risk non-muscle-invasive setting to muscle-invasive and advanced/metastatic disease. EXPERT OPINION: The main challenge in the treatment of BCa in the elderly is represented by the need to find a compromise between the risk of under- and overtreatment. The wide spectrum of disease prognoses between low-risk non-muscle invasive BCa and invasive metastatic disease represents a perfect setting for a personalized approach. To pursue this aim, older patients need a multidisciplinary approach and clinical management, in order to optimize oncological outcomes as well as to face and support their frailty during cancer therapies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Anticorpos Monoclonais/uso terapêutico , Vacina BCG/imunologia , Vacina BCG/uso terapêutico , Cisplatino/uso terapêutico , Humanos , Imunoterapia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia
11.
Mar Drugs ; 17(5)2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086026

RESUMO

Flaccidoxide-13-acetate, an active compound isolated from cultured-type soft coral Sinularia gibberosa, has been shown to have inhibitory effects against invasion and cell migration of RT4 and T24 human bladder cancer cells. In our study, we used an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation assay, and flow cytometry to determine the mechanisms of the anti-tumor effect of flaccidoxide-13-acetate. The MTT and colony formation assays showed that the cytotoxic effect of flaccidoxide-13-acetate on T24 and RT4 cells was dose-dependent, and the number of colonies formed in the culture was reduced with increasing flaccidoxide-13-acetate concentration. Flow cytometry analysis revealed that flaccidoxide-13-acetate induced late apoptotic events in both cell lines. Additionally, we found that flaccidoxide-13-acetate treatment upregulated the expressions of cleaved caspase 3, cleaved caspase 9, Bax, and Bad, and down-regulated the expressions of Bcl-2, p-Bad, Bcl-x1, and Mcl-1. The results indicated that apoptotic events were mediated by mitochondrial dysfunction via the caspase-dependent pathway. Flaccidoxide-13-acetate also provoked endoplasmic reticulum (ER) stress and led to activation of the PERK-eIF2α-ATF6-CHOP pathway. Moreover, we examined the PI3K/AKT signal pathway, and found that the expressions of phosphorylated PI3K (p-PI3K) and AKT (p-AKT) were decreased with flaccidoxide-13-acetate concentrations. On the other hand, our results showed that the phosphorylated JNK and p38 were obviously activated. The results support the idea that flaccidoxide-13-acetate-induced apoptosis is mediated by mitochondrial dysfunction, ER stress, and activation of both the p38 and JNK pathways, and also relies on inhibition of PI3K/AKT signaling. These findings imply that flaccidoxide-13-acetate has potential in the development of chemotherapeutic agents for human bladder cancer.


Assuntos
Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/uso terapêutico , Coelhos , Fator de Transcrição CHOP/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
12.
Cancer Sci ; 110(7): 2110-2118, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31120174

RESUMO

The tumor microenvironment is associated with various tumor progressions, including cancer metastasis, immunosuppression, and tumor sustained growth. Tumor-associated macrophages (TAMs) are considered an indispensable component of the tumor microenvironment, participating in the progression of tumor microenvironment remodeling and creating various compounds to regulate tumor activities. This study aims to observe enriched TAMs in tumor tissues during bladder cancer development, which markedly facilitated the proliferation of bladder cancer cells and promoted tumor growth in vivo. We determined that TAMs regulate tumor sustained growth by secreting type I collagen, which can activate the prosurvival integrin α2ß1/PI3K/AKT signaling pathway. Furthermore, traditional chemotherapeutic drugs combined with integrin α2ß1 inhibitor showed intensive anticancer effects, revealing an innovative approach in clinical bladder cancer treatment.


Assuntos
Cromonas/administração & dosagem , Colágeno/metabolismo , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Macrófagos/patologia , Morfolinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Cromonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Integrina alfa2beta1/genética , Integrina alfa2beta1/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Microambiente Tumoral , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Oncol ; 54(6): 2237-2249, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081057

RESUMO

Cytotoxic chemotherapy is the standard treatment for patients with advanced bladder cancer. However, this treatment can cause transient and prolonged neutropenia, which can result in fatal infection. Three recombinant human colony­stimulating factors (CSFs), granulocyte CSF (G­CSF), granulocyte­macrophage CSF (GM­CSF), and macrophage CSF (M­CSF), are currently available to reduce the duration and degree of neutropenia. The present study investigated the pro­ and anti­tumor effects of these three CSFs and the changes in molecular profiles. Xenograft tumors in athymic mice were generated by subcutaneously inoculating the human bladder cancer cell lines MGH­U3 and UM­UC­3. A total of 2 weeks after cell inoculation, mice were randomly divided into four groups (control, G­CSF, GM­CSF and M­CSF) and treated thrice a week for 2 weeks. Tumor growth during monitoring and tumor weight at the time of euthanization were significantly higher in mice treated with G­CSF and lower in mice treated with GM­CSF compared with the control mice. Tumors were examined by immunostaining with antibodies against proteins associated tumor proliferation (Ki­67), angiogenesis [CD31 and vascular endothelial growth factor (VEGF)], anti­immunity (CD204) and epithelial­mesenchymal transition (EMT; E­cadherin). Immunohistochemical staining revealed that tumor proliferation, angiogenesis, recruitment of M2 macrophages and EMT were promoted by G­CSF, whereas lymphangiogenesis and recruitment of M2 macrophages were inhibited by GM­CSF. Treatment­associated changes in serum pro­ and anti­tumoral cytokines and chemokines were evaluated by enzyme­linked immunosorbent assay (ELISA)­based arrays. In the ELISA for serum, the levels of cytokines associated with angiogenesis (interleukin­6 and VEGF), and EMT (transforming growth factor­ß1 and ­ß2) were elevated in mice treated with G­CSF. Treatment with GM­CSF and M­CSF also affected the level of these cytokines characteristically. The current results indicate that administration of exogenous G­CSF to patients with bladder cancer promotes tumor growth through promotion of cell proliferation, angiogenesis, recruitment of M2 macrophages and enhancement of EMT through the modulation of the tumor microenvironment.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Macrófagos/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Interleucina-6/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Distribuição Aleatória , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Carga Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Chem Pharm Bull (Tokyo) ; 67(5): 410-418, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061365

RESUMO

2,4,5-Trichloro-6-((2,4,6-trichlorophenyl)amino)isophthalonitrile (SYD007) is a small molecule compound that was synthesized according to the structure of diarylamine. In this study, we evaluated the anti-bladder activities of SYD007, and determined its cytotoxic mechanism. We found that SYD007 exerted cytotoxicity to bladder cancer cells. Furthermore, SYD007 induced bladder cancer cell early apoptosis and arrested cell cycle. Mechanistically, SYD007 suppressed phosphorylated signal transducer and activator of transcription 3 (p-STAT3) (Tyr705) level in parallel with increases of p-extracellular signal-regulated kinase (ERK) and p-AKT. SYD007 significantly inhibited insulin-like growth factor 1 (IGF-1)-induced STAT3 activation through down-regulation of total IGF-1R level. No dramatic changes in IGF-1R mRNA levels were observed in SYD007-treated cells, suggesting that SYD007 acted primarily at a posttranscriptional level. Using molecular docking analysis, SYD007 was identified as an IGF-1R inhibitor. In summary, we reported that SYD007 exerted anti-bladder activities, and these effects were partially due to inhibition of IGF-1R/STAT3 signaling.


Assuntos
Antineoplásicos/farmacologia , Nitrilos/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Nitrilos/síntese química , Nitrilos/química , Receptor IGF Tipo 1/metabolismo , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/metabolismo
15.
Medicine (Baltimore) ; 98(20): e15727, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096529

RESUMO

RATIONALE: Percutaneous osteoplasty (POP) has been proved effective to relieve pain in metastases of vertebral, pelvis, and femur. Nevertheless, there are few reports about the effectiveness of POP in the humeral head metastases. In this study, we described 2 patients with humeral head metastases treated with POP in our hospital. PATIENT CONCERNS: Case 1 was a 79-year-old man with vertebral and right humeral head metastasis after radical surgery or and periods of chemotherapy for bladder cancer. He suffered constant severe back and right shoulder joint pain even if taking much non-steroidal anti-inflammatory drugs. Case 2 was a 59-year-old woman with vertebral and right humeral head metastasis from lung cancer. She received regular radiotherapy and took much painkillers to relieve pain. However, the pain could not be relieved any more after 1 month and severely affects sleeping and daily activities. DIAGNOSIS: Both 2 patients were diagnosed as vertebral metastases and right proximal humeral head metastases. INTERVENTIONS: POP was performed to treat the right humeral head metastases. Percutaneous vertebroplasty (PVP) was performed to treat vertebral metastases. OUTCOMES: After surgery, the patients experienced significant decrease in pain and better motor function. Both patients did not suffer from pulmonary embolism, infection, nerve injury, and bone cement syndrome. LESSONS: For the pain that cannot be relieved by radiotherapy and analgesic drugs, POP is a safe and beneficial minimally invasive procedure that provides immediate and substantial relief from pain for humerus head metastases.


Assuntos
Neoplasias Ósseas/cirurgia , Cementoplastia/métodos , Cabeça do Úmero/cirurgia , Neoplasias da Coluna Vertebral/cirurgia , Vertebroplastia/métodos , Idoso , Neoplasias Ósseas/secundário , Dor do Câncer/cirurgia , Feminino , Humanos , Cabeça do Úmero/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Neoplasias da Coluna Vertebral/secundário , Resultado do Tratamento , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia
16.
Cancer Treat Rev ; 76: 51-56, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31125908

RESUMO

CONTEXT: Five checkpoint inhibitors have been approved as 1st line (cisplatin-ineligible) or 2nd line therapies for patients with metastatic urothelial carcinoma of the bladder. As only about 30% of patients respond, the need for a biomarker for patient selection exists. OBJECTIVE: To determine if PD-L1 expression is a prognostic factor of objective response rate (ORR) and overall survival (OS) in patients with urothelial carcinoma being treated with checkpoint inhibitors. EVIDENCE ACQUISITION: A search of PubMed and major conference proceedings identified trials of PD-L1 inhibitors as first- or second-line therapies for metastatic bladder cancer. Odds ratios (OR) for ORR and OS compared PD-L1 positive and PD-L1 negative patients. Data were weighted and pooled in a meta-analysis, and subgroup analyses compared PD-L1 status cut-offs. EVIDENCE SYNTHESIS: Ten studies comprising 2755 patients were identified, of which 2030 patients (74%) received immune checkpoint inhibitors. Eight studies were eligible for ORR analysis (1530 patients) and five studies for OS (829 patients). PD-L1 patients had a significantly higher ORR than PD-L1 negative patients (1.82, 95%CI 1.18-2.77; p = 0.007). Weighted mean OS was 11.5 months (range 8.7-15.9 months). PD-L1 status was not prognostic for 12 month OS (OR = 0.81, 95%CI 0.47-1.40; p = 0.45). CONCLUSION: In patients treated with PD-L1 inhibitors for metastatic urothelial carcinoma, PD-L1 status is prognostic for ORR but not OS. Our findings warrant additional investigation. PATIENT SUMMARY: Five immunotherapy drugs are approved for bladder cancer therapy. PD-L1 expression predicts higher ORR but not OS. More data is needed to identify the patient population most benefitted by immunotherapy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/biossíntese , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Antígeno B7-H1/imunologia , Humanos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Bexiga Urinária/metabolismo
17.
Anticancer Res ; 39(4): 1839-1847, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952724

RESUMO

BACKGROUND/AIM: Casticin shows anti-cancer effects in many types of cancer. However, there is no information regarding its role in DNA damage in human bladder cancer. The aim of this study was to investigate the effects of casticin on TSGH-8301 cells in vitro. MATERIALS AND METHODS: Viability of cells was assayed by flow cytometry. DNA damage was assayed by DAPI staining, comet assay, and gel electrophoresis. Protein levels were examined by western blotting and confocal laser microscopy. RESULTS: Casticin decreased viability of cells and induced DNA damage. Furthermore, casticin decreased expression of p-ATM, p-ATR, MDC1 and MGMT levels after 48 h of treatment, however, it increased p-ATR and MGMT levels after 12 h. In contrast, casticin increased the levels of p-p53, p-H2A.X, and PARP after 48 h of treatment. As shown by confocal microscopy, casticin affected the translocation of DNA-PKcs and p-p53 to the nucleus of TSGH-8301 cells. CONCLUSION: Casticin decreased viability of human bladder cancer cells through DNA damage.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Flavonoides/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Transporte Ativo do Núcleo Celular , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteína Quinase Ativada por DNA/metabolismo , Histonas/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Fosforilação , Poli(ADP-Ribose) Polimerases/metabolismo , Transativadores/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
18.
Gene ; 710: 91-97, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31002892

RESUMO

BACKGROUND: Chronic inflammatory microenvironment has been shown to play a key role in initiating tumorigenesis and facilitating malignant progression. Primary tumors surrounded with and infiltrated by tumor-associated macrophages (TAMs) significantly promote the epithelial-to-mesenchymal transition (EMT) and distant metastasis in urothelial bladder cancer. METHODS: In this study, we aimed to explore the potential of targeting TAMs for the treatment of malignant bladder cancer. RESULTS: First, we found a higher number of TAMs, CD68 (pan-macrophage marker), and clever-1 (M2 macrophage marker) was associated with a higher pT category and grade in a cohort of 108 patients. In vitro assays showed that the co-culture of TAMs promoted the metastatic potential in HTB-1 and T24 by up-regulating EMT markers including Snail, VEGF and Vimentin, as well as oncogenic markers such as ß-catenin and NF-κB. More importantly, M2 co-cultured HTB-1 and T24 showed an increased level of metastatic microRNA, miR-30. Silencing of miR-30 resulted in the reduced metastatic potential, migration/invasion, in association with the decreased expression of Twist1 and Vimentin. The addition of BAY11-7082 into the TAM/cancer co-culture system significantly reduced the M2 phenotype and tumorigenic properties. Coincidentally, miR-30a level was significantly lowered in the presence of BAY11-7082. CONCLUSION: Our study demonstrated that AMs promoted metastatic potential of bladder cancer cells via promoting EMT through the increase of miR-30a. BAY11-7082 treatment suppressed both oncogenic and metastatic potential in bladder cancer cells while preventing the M2 polarization of TAMs.


Assuntos
Macrófagos/citologia , Nitrilos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Polaridade Celular/efeitos dos fármacos , Técnicas de Cocultura , Regulação para Baixo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , MicroRNAs/genética , NF-kappa B/metabolismo , Metástase Neoplásica , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
19.
Future Oncol ; 15(13): 1505-1524, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30977669

RESUMO

Bladder cancer (BC) is the most frequent cancer affecting the urinary tract. With the growing era of targeted therapies around the 2000s, many trials evaluated the efficacy of targeted therapy in advanced BC. However, no approval was given yet to any form of targeted therapy when it comes to BC. The aim of this paper was to report the most pivotal trials that evaluated different families of targeted therapy in the treatment of BC, according to their biomarkers (FGFR3, EGFR, HER2, VEGF and PI3K/AKT/mTOR). The ongoing trials testing targeted therapies in advanced BC were then summarized. Finally, the different immunotherapies approved for this disease and their potential combination with targeted therapy were addressed.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Humanos , Proteínas de Neoplasias/metabolismo , Prognóstico , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
20.
Int J Oncol ; 54(6): 2106-2116, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942430

RESUMO

Benzyl isothiocyanate (BITC) is known for its pharmacological properties against malignant neoplasm, including bladder cancer (BC). The current study investigated microRNAs (miRNA or miR) expression profiles with an emphasis on the role of miR­99a­5p in BITC­treated BC cells. A quantitative polymerase chain reaction (qPCR) microarray containing 79 aberrantly expressed miRNAs in BC was used to detect miRNA expression in BITC­treated cells. Several dysregulated miRNAs were identified and further confirmed using miRNA stem­loop reverse transcription (RT)­qPCR in 5637 cells. Insulin­like growth factor 1 receptor (IGF1R), fibroblast growth factor receptor 3 (FGFR3) and mammalian target of rapamycin (mTOR) expression were determined by RT­qPCR and western blotting. Cell viability was evaluated using WST­1 reagent and apoptosis was monitored by determining the levels of cleaved­poly ADP­ribose polymerase and cleaved­caspase­3. BITC treatment significantly upregulated miR­99a­5p levels in a dose­dependent manner. miR­99a­5p overexpression decreased IGF1R, mTOR and FGFR3 expression, predicted targets of miR­99a­5p. In addition, antisense miR­99a­5p sequences inhibited BITC­induced miR­99a­5p overexpression, resulting in the restoration of protein expression and decreased cell viability. The current study identified multiple miRNAs responsive to BITC treatment, including miR­99a­5p. In addition, the induction of miR­99a­5p decreased IGF1R, mTOR and FGFR3 expression in BITC­treated BC cells. The current study provided novel insight into the antitumor mechanism by which BITC restores miR­99a­5p expression and decreases cancer cell survival.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/farmacologia , MicroRNAs/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ensaios de Seleção de Medicamentos Antitumorais , Perfilação da Expressão Gênica , Humanos , Isotiocianatos/uso terapêutico , Análise de Sequência com Séries de Oligonucleotídeos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores de Somatomedina/genética , Serina-Treonina Quinases TOR/genética , Regulação para Cima/efeitos dos fármacos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
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