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1.
BJOG ; 127(3): 389-395, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31794098

RESUMO

OBJECTIVE: Presence of lung metastases in low-risk gestational trophoblastic neoplasia (GTN) is generally considered not to influence prognosis. However, in a recent study in the Netherlands, GTN patients with lung metastases had a higher recurrence rate and more disease-specific deaths compared with patients without metastases. The aim of the present study was to validate these findings in a different country. DESIGN: Historical cohort study. SETTING: Charing Cross Hospital, United Kingdom. POPULATION: A total of 1040 low-risk GTN patients treated with methotrexate (MTX) between 2002 and 2016 were identified: 65 with lung metastases (group 1) and 975 without metastases (group 2). METHODS: Baseline characteristics, MTX resistance, survival and recurrence rates were recorded and compared between both groups. MAIN OUTCOME MEASURES: MTX resistance, recurrence rate and survival. RESULTS: The occurrence of MTX resistance and median number of MTX courses to achieve remission was significantly higher in patients with lung metastases than patients without metastases (60% versus 38.9%, P = 0.001; and nine versus six courses, P < 0.001). All choriocarcinoma patients (n = 4) with lung metastases developed MTX resistance. The recurrence rate was also higher in group I (9.2% versus 2.7%; P = 0.012). Disease-specific survival was 100% in both groups. CONCLUSIONS: The presence of lung metastases at the start of MTX therapy is associated with increased incidence of MTX resistance and recurrence in low-risk GTN without affecting overall survival, which remains 100%. However, individuals with low-risk choriocarcinoma with lung metastases are likely to become resistant to MTX and primary multi-agent chemotherapy should be considered. TWEETABLE ABSTRACT: The presence of lung metastases appears to increase the risk of recurrence in low-risk GTN, but does not affect overall cure rates and survival.


Assuntos
Coriocarcinoma , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Doença Trofoblástica Gestacional , Neoplasias Pulmonares , Metotrexato , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologia , Estudos de Coortes , Feminino , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Gravidez , Recidiva , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Reino Unido/epidemiologia
2.
Anticancer Res ; 39(5): 2377-2383, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092430

RESUMO

BACKGROUND: Human choriocarcinoma is the most aggressive type of gestational trophoblastic neoplasia. The expression of epidermal growth factor receptor (EGFR) in choriocarcinomas is significantly higher than those of trophoblastic cells in healthy placentas. Lapatinib is a potent EGFR and human epidermal growth factor receptor 2 (HER2) inhibitor that inhibits cell proliferation and induces apoptosis in various human cancer cells. Amphiregulin (AREG) is the most abundant EGFR ligand in amniotic fluid during human pregnancy. AIM: To explore the role of AREG in human choriocarcinoma cell proliferation. MATERIALS AND METHODS: The effect of lapatinib and AREG on cell proliferation was examined by the MTT assay. Western blots were used to investigate EGFR and HER2 expression, and the activation of caspase-3, extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT) signaling pathways. RESULTS: Treatment with lapatinib reduced BeWo cell proliferation by inducing apoptosis. Moreover, AREG treatment stimulated BeWo cell proliferation by activating ERK1/2 and PI3K/AKT signaling pathways, which was blocked by lapatinib. CONCLUSION: Targeting EGFR/HER2 might be a useful therapeutic strategy for human choriocarcinoma.


Assuntos
Anfirregulina/genética , Coriocarcinoma/genética , Receptor ErbB-2/genética , Anfirregulina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologia , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Oncogênica v-akt/genética , Receptor ErbB-2/antagonistas & inibidores
3.
Biomater Sci ; 7(3): 1200-1210, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30656300

RESUMO

To investigate whether circulating tumor cells (CTCs) are detectable in patients with gestational choriocarcinoma (GC) and evaluate the prognostic value of CTC enumeration. In this multicenter study, the presence of CTCs was examined in 180 GC patients using a semi-automated NanoVelcro system, among whom 106 patients underwent CTC re-evaluation after one cycle of chemotherapy. Approximately 96% of the GC patients contained ≥2 CTCs in 7.5 mL of blood. The number of CTCs per 7.5 mL of blood was much higher in patients with distant metastases (n = 95; range, 0 to 104) than in patients without distant metastases (n = 85; range, 0 to 6). Applying a 90-patient training and 90-patient validation cohort, a cutoff value of ≥6 CTCs was defined as the prognostic threshold for progression-free survival (PFS) and overall survival (OS). The presence of ≥6 CTCs was significantly associated with worse PFS and OS (both P < 0.001). A multivariate analysis showed that the CTC number (≥6 CTCs) was the strongest predictor of OS (hazard ratio [HR], 15.8; 95% confidence interval [CI], 4.3-57.9; P < 0.001). The number of CTCs decreased after one cycle of chemotherapy; univariate analyses demonstrated that the CTC count after the first chemotherapy cycle was a strong predictor of OS (HR, 36.1; 95% CI, 4.8-271.5; P < 0.001). CTCs are a promising prognostic factor for GC. The absolute CTC count after one cycle of chemotherapy in the context of this disease is a strong predictor of chemotherapy response.


Assuntos
Neoplasias da Mama/patologia , Coriocarcinoma/patologia , Células Neoplásicas Circulantes/química , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Basigina/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/mortalidade , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Fatores de Risco
4.
Int J Clin Oncol ; 24(2): 153-160, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30242539

RESUMO

OBJECTIVE: To evaluate the survival and functional outcome of patients with brain metastasis due to gestational trophoblastic neoplasia (GTN). METHODS: A 17-year retrospective study based on case review of women with brain metastasis from GTN identified by the electronic databases held in the French Reference Centre. PRIMARY OUTCOME MEASURE: 5-year overall survival calculated with the Kaplan-Meier method. SECONDARY OUTCOME MEASURES: causes of death, prognostic factors and functional outcomes. RESULTS: 21 patients had GTN brain metastasis and were treated with multidrug chemotherapy without concomitant whole-brain radiation therapy. Three patients died early (< 4 weeks) of cerebral hemorrhage, 3 died ≥ 1 months after treatment initiation and 15 were alive at the date of last contact. The overall survival rate at 5 years was 69.8% (95% CI 44.3-85.3). After excluding early deaths, the survival rate at 5 years was 81.5% (95% CI 52.3-93.7). No predictive factor of survival was identified. Although 11 of the 12 (92%) surviving patients contacted still reported sequelae, nine of them (75%) had resumed a normal life. CONCLUSIONS: After excluding early deaths, this study implies a high survival rate in patients with brain metastasis from GTN. These results were achieved in the total absence of whole-brain radiotherapy and almost completely without the need for intrathecal methotrexate.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Coriocarcinoma/patologia , Doença Trofoblástica Gestacional/patologia , Neoplasias Uterinas/patologia , Adolescente , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Coriocarcinoma/tratamento farmacológico , Feminino , Doença Trofoblástica Gestacional/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Gravidez , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Uterinas/tratamento farmacológico , Adulto Jovem
5.
Obstet Gynecol ; 133(1): 163-166, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30531566

RESUMO

BACKGROUND: Gestational trophoblastic neoplasia rarely occurs in term pregnancies. Stage IV choriocarcinoma treated with conventional chemotherapy can result in death as a result of hemorrhagic sequelae at tumor sites. CASE: A 30-year-old woman at 34 weeks of gestation presented with a persistent cough, worsening dyspnea, and vaginal bleeding. Chest radiograph demonstrated innumerable lung nodules, and quantitative ß-hcg concentration exceeded 1.3 million milli-international units/mL. Cesarean delivery was performed for presumed abruption. Placental pathology demonstrated choriocarcinoma, and imaging confirmed stage IV disease with a World Health Organization score of 14. Remission was achieved after two courses of low-dose induction chemotherapy followed by 10 cycles of combination chemotherapy. CONCLUSION: Gestational trophoblastic neoplasia should be considered in a pregnant or postpartum woman presenting with atypical vaginal bleeding. Coexistent pulmonary or neurologic findings may suggest advanced disease.


Assuntos
Coriocarcinoma/diagnóstico , Doença Trofoblástica Gestacional/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Diagnóstico Pré-Natal , Neoplasias Uterinas/diagnóstico , Adulto , Antineoplásicos/uso terapêutico , Coriocarcinoma/complicações , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/secundário , Diagnóstico Diferencial , Feminino , Doença Trofoblástica Gestacional/complicações , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/secundário , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Neoplásica , Gravidez , Terceiro Trimestre da Gravidez , Hemorragia Uterina/etiologia , Neoplasias Uterinas/complicações , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/patologia
6.
Int J Cancer ; 144(6): 1421-1431, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30070688

RESUMO

Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5-mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non-progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with <4 CTCs (P < 0.001). These findings demonstrates the feasibility of CTC detection in cases of GC by adopting EpCAM/CD147 antibodies together as capturing antibodies. The CTC count is a promising indicator in the evaluation of biological activities and the chemotherapy response in GC patients.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Coriocarcinoma/sangue , Resistencia a Medicamentos Antineoplásicos , Células Neoplásicas Circulantes , Adulto , Antineoplásicos/uso terapêutico , Basigina/metabolismo , Biópsia , Contagem de Células , Linhagem Celular Tumoral , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/mortalidade , Coriocarcinoma/patologia , Gonadotropina Coriônica/metabolismo , Progressão da Doença , Molécula de Adesão da Célula Epitelial/metabolismo , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Fatores de Risco , Adulto Jovem
7.
J Cell Physiol ; 234(2): 1803-1815, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30070691

RESUMO

Carvacrol is a monoterpenoid phenol present in the oils of various plants including Origanum vulgare (oregano) or Origanum majorana (marjoram). For a long time, it has been used as spice in foods because of its antimicrobial properties. Additionally, it appears to have anticancer effects against some cancer but this has not been well studied. Therefore, we conducted various assays to confirm the effects of carvacrol on choriocarcinoma cell lines (JAR and JEG3). Our results indicate that carvacrol has antiproliferative properties and induces apoptosis, resulting in increased expression of proapoptotic proteins. Additionally, carvacrol disrupted the mitochondrial membrane potential and induced calcium ion overload in the mitochondrial matrix in both JAR and JEG3 cells. Furthermore, carvacrol generated oxidative stress and lipid peroxidation in both JAR and JEG3 cells. Moreover, carvacrol-suppressed phosphoinositide 3-kinase-protein kinase B and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) signal transduction whereas expression of phosphor-P38 and c-Jun N-terminal kinase MAPK was increased. Together, our results indicate that carvacrol may be a possible new therapeutic agent or supplement for the control of human choriocarcinomas.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Coriocarcinoma/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Neoplasias Uterinas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Feminino , Homeostase , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
8.
Phytomedicine ; 50: 238-246, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30466984

RESUMO

BACKGROUND: Human placental choriocarcinoma is a gestational trophoblastic tumor with high rates of metastasis and reoccurrence. However, some patients with choriocarcinoma are chemoresistance to conventional chemotherapeutic agents. HYPOTHESIS: Naringenin increases apoptosis in human placental choriocarcinoma cells. METHODS: We investigated the effects of naringenin on proliferation and migration of JAR and JEG3 cells, and performed TUNEL and Annexin V/PI staining assays to examine apoptotic effects of naringenin on both cells. In addition, we studied the loss of mitochondrial membrane potential (MMP) and the production of mitochondrial reactive oxygen species (ROS) to determine the specific reason for apoptosis of choriocarcinoma cells being mediated via mitochondria. Consistent with the induction of production of ROS by naringenin in both choriocarcinoma cell lines, we investigated lipid peroxidation and glutathione levels in both JAR and JEG3 cells since both are affected by ROS. We next determined dose-dependent effects of naringenin and its pharmacological inhibitors on signal transduction pathways in JAR and JEG3 cells by western blot analyses. RESULTS: Naringenin reduced viability and migratory functions of both cell lines, and increased mitochondria related apoptosis induced by ROS and lipid peroxidation, decreased glutathione and decreased mitochondrial membrane potential MMP in a dose-dependent manner. We also determined naringenin activated phosphorylation of ERK1/2, P38, JNK and P70S6K in JAR and JEG3 cells in a dose-response manner. Although naringenin induced phosphorylation of AKT proteins in JAR cells, it suppressed phosphorylation of the protein in JEG3 cells. In addition, we confirmed the mechanism of naringenin-induced cell signaling by using a combination of naringenin and pharmacological inhibitors of the PI3K and MAPK pathways, as well as a ROS inhibitor in JAR and JEG3 cell lines. CONCLUSIONS: Collectively, results of this study indicate that naringenin is a potential therapeutic molecule with anti-cancer effects on choriocarcinoma cells by inducing generation of ROS and activation of the MAPK pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Coriocarcinoma/patologia , Flavanonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Coriocarcinoma/tratamento farmacológico , Feminino , Humanos , MAP Quinase Quinase 4/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo
9.
Int J Mol Sci ; 19(11)2018 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-30400387

RESUMO

Tripyrrole molecules have received renewed attention due to reports of numerous biological activities, including antifungal, antibacterial, antiprotozoal, antimalarial, immunosuppressive, and anticancer activities. In a screen of bacterial strains with known toxicities to termites, a red pigment-producing strain, HDZK-BYSB107, was isolated from Chamaecyparis lawsoniana, which grows in Oregon, USA. Strain HDZK-BYSB107 was identified as Serratia marcescens subsp. lawsoniana. The red pigment was identified as prodigiosin using ultraviolet absorption, LC-MS, and 1H-NMR spectroscopy. The bacterial prodigiosin had an inhibitory effect on both Gram-negative and Gram-positive bacteria. The main objective of this study was to explore the anticancer activities and mechanism of strain HDZK-BYSB107 prodigiosin by using human choriocarcinoma (JEG3) and prostate cancer cell lines (PC3) in vitro and JEG3 and PC3 tumor-bearing nude mice in vivo. In vitro anticancer activities showed that the bacterial prodigiosin induced apoptosis in JEG3 cells. In vivo anticancer activities indicated that the prodigiosin significantly inhibited the growth of JEG3 and PC3 cells, and the inhibitory activity was dose and time dependent. The anticancer efficacy of the bacterial prodigiosin on JEG3 and PC3 cells, JEG3 and PC3 tumor exhibited a correlation with the down regulation of the inhibitor of IAP family, including XIAP, cIAP-1 and cIAP-2, and the activation of caspase-9 and caspase-3 accompanied by proteolytic degradation of poly (ADP-ribose)-polymerase. The expressions of P53 and Bax/Bcl-2 in JEG3 and PC3 cells were significantly higher than in untreated groups. Our results indicated that the bacterial prodigiosin extracted from C. lawsoniana is a promising molecule due to its potential for therapeutic applications.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Coriocarcinoma/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Prodigiosina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Serratia marcescens/química , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/metabolismo , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Proteína 3 com Repetições IAP de Baculovírus/genética , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Coriocarcinoma/genética , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Camundongos Nus , Testes de Sensibilidade Microbiana , Células PC-3 , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Prodigiosina/biossíntese , Prodigiosina/isolamento & purificação , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serratia marcescens/metabolismo , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
10.
Cell Physiol Biochem ; 50(5): 1815-1831, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30396168

RESUMO

BACKGROUND/AIMS: Choriocarcinoma (CC) is a highly aggressive gestational trophoblastic neoplasia; however, the underlying molecular mechanisms of its invasiveness and metastasis remain poorly understood. Human secreted frizzled-related protein 2 (SFRP2) could function as a tumor promoter or suppressor in different tumors, yet the role it plays in CC's invasion and metastasis is thoroughly unclear. The current study was aimed to explore the function and underlying mechanism of SFRP2 in CC. METHODS: The expression of SFRP2 in CC tissues was examined via immunohistochemistry. The methylation level and expression of SFRP2 in CC cell lines, JEG-3 and JAR were examined via bisulfite sequencing PCR (BSP), western blotting and quantitative RT-PCR. The biological role of increasing expressed SFRP2 through its promoter demethylation with 5-Aza-2'-deoxycytidine (5-Aza) was examined by a series of in vitro functional studies. Furthermore, lentivirus transfection technology was adopted to investigate the biological roles of SFRP2 knockdown in JEG-3 and JAR cells in vitro and in vivo. Moreover, its downstream signaling pathway was investigated. RESULTS: SFRP2 was downregulated in CC tissues, and its expression was inversely related to its promoter hypermethylation frequency in JEG-3 and JAR cells. Increased SFRP2 through its promoter demethylation inhibited cell migration, invasion and colony formation in JEG-3 and JAR cells, whereas decreased SFRP2 reversed the epithelial-mesenchymal transition (EMT) process and stemness in JEG-3 and JAR cells both in vitro and vivo. Mechanistically, SFRP2 regulated the EMT and stemness of CC cell lines via canonical Wnt/ß-catenin signaling, validated by the usage of a Wnt activator and inhibitor. CONCLUSION: The current study indicates that downregulated SFRP2 has potent tumor-promotive effects in CC through the modulation of cancer stemness and the EMT phenotype via activation of Wnt/ß-catenin signaling in vitro and in vivo.


Assuntos
Transição Epitelial-Mesenquimal , Proteínas de Membrana/metabolismo , Via de Sinalização Wnt , Animais , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Metilação de DNA , Decitabina , Proteínas Desgrenhadas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
11.
J Cancer Res Ther ; 14(Supplement): S803-S805, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30249909

RESUMO

Choriocarcinoma syndrome is a life-threatening lysis syndrome caused by blood vessel rupture and subsequent tumor bleeding. We describe a case of pretreatment choriocarcinoma syndrome that developed in a 27-year-old man. He underwent a high orchiectomy at a local hospital and was diagnosed with metastatic testicular tumor given the high serum human chorionic gonadotropin levels (943,601 mIU/mL). Thus, he was referred to our institution. Although he had bulky lung metastases and alveolar bleeding, we were able to administer full-dose chemotherapy with etoposide and cisplatin. On day 3 of chemotherapy, he presented with severe hypoxia and worsening of alveolar bleeding. Thus, he underwent tracheal intubation at the Intensive Care Unit. Full-dose chemotherapy was continued, and the patient was extubated upon improvement. He is currently alive and continuing treatment at another hospital.


Assuntos
Coriocarcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Orquiectomia/efeitos adversos , Neoplasias Testiculares/tratamento farmacológico , Vasos Sanguíneos/patologia , Coriocarcinoma/diagnóstico por imagem , Coriocarcinoma/patologia , Coriocarcinoma/cirurgia , Gonadotropina Coriônica/sangue , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Hemorragia , Humanos , Quimioterapia de Indução , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Masculino , Neoplasias Testiculares/patologia , Neoplasias Testiculares/secundário , Neoplasias Testiculares/cirurgia , Procedimentos Cirúrgicos Vasculares
12.
Biochem Biophys Res Commun ; 503(4): 3155-3161, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30139515

RESUMO

The trophoblast cells which form the placenta, have a high potential for invading other tissues. Owing to certain mechanisms, trophoblast cells may lose their ability to control cell proliferation, and develop into pregnancy-related tumors, known as choriocarcinomas. Choriocarcinomas mostly develop from the hydatidiform mole, which is frequently found in pregnant women. Owing to their ability to rapidly metastasize through the hematogenous route, choriocarcinomas are very hard to cure if not detected at the proper time. Although numerous studies are attempting to identify the major pathways in choriocarcinoma cells, the critical pathway responsible for the origin of choriocarcinomas is still unclear. In this study, we identified that chrysin has inhibitory effects on human choriocarcinoma cells. The study demonstrated that chrysin disrupts intracellular homeostasis by altering the mitochondrial membrane potential (MMP), cytosolic Ca2+ levels, production of reactive oxygen species (ROS), and lipid peroxidation, leading to the death of choriocarcinoma cells (JAR and JEG3). Additionally, the effects of chrysin on choriocarcinoma cells were found to be mediated via the regulation of the AKT, ERK1/2, and JNK signaling pathways. Altogether, the anti-cancer effects of chrysin can aid the development of a novel therapeutic strategy against the progression of human choriocarcinomas.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Morte Celular/efeitos dos fármacos , Coriocarcinoma/tratamento farmacológico , Flavonoides/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias Uterinas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
13.
Medicine (Baltimore) ; 97(22): e10736, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29851778

RESUMO

RATIONALE: Cutaneous metastasis of testicular choriocarcinoma is exceptionally uncommon. To our knowledge, only 14 cases have been reported in the past 10 years in the pubmed. We have an uncommon case of testicular choriocarcinoma who has metastasized to the adjacent skin and organ systems. PATIENT CONCERNS: An 18-year-old male was diagnosed with initial presentation of cutaneous mass at the left back. Followly,biopsy was performed under local anesthesia.Histopathological examination was consistent with the diagnosis of metastatic choriocarcinoma. DIAGNOSES: The histopathological assessment of the biopsied tissue, in combination with elevated serum ß-HCG levels and presentation of testicular mass, indicated primary testicular choriocarcinoma with cutaneous and systemic metastasis. INTERVENTIONS: Subsequently radical orchiectomy was performed. OUTCOMES: Despite the case completed one cycle of cisplatin-based regimen chemotherapy, he died of multiple organ dysfunction syndrome 2 months after surgery. LESSONS: In this report, cutaneous metastasis with testicular choriocarcinoma is extremely rare. It is important to recognize that this unusual variant of testicular choriocarcinoma has the potential to behave aggressively and to metastasize.


Assuntos
Coriocarcinoma/patologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundário , Pele/patologia , Abdome/diagnóstico por imagem , Abdome/patologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Coriocarcinoma/sangue , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/cirurgia , Gonadotropina Coriônica Humana Subunidade beta/sangue , Cisplatino/uso terapêutico , Evolução Fatal , Humanos , Masculino , Insuficiência de Múltiplos Órgãos/complicações , Orquiectomia/métodos , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Neoplasias Testiculares/ultraestrutura , Tórax/diagnóstico por imagem , Tórax/patologia , Tomografia Computadorizada por Raios X
14.
J Obstet Gynaecol Res ; 44(8): 1476-1481, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845692

RESUMO

Gestational trophoblastic neoplasm (GTN) is a serious morbidity of complete hydatidiform mole with coexistent fetus (CHMCF) and usually develops after termination of pregnancy. Here we report a case of choriocarcinoma derived from CHMCF during pregnancy. A 33-year-old multiparous woman with suspected CHMCF was admitted with a severe cough. Computed tomography revealed multiple lung metastases. Cesarean section and hysterectomy were performed at 31 weeks of gestation on diagnosis of high-risk GTN from International Federation of Gynecology and Obstetrics (FIGO) scoring. A live female infant weighing 1390 g was delivered. Choriocarcinoma was diagnosed from pathological findings. The patient received multi-agent chemotherapy and was discharged on the 40th postoperative day. In conclusion, CHMCF can result in high-risk GTN during pregnancy. For a suspected GTN, diagnosis from FIGO scoring should determine treatment strategy. If patients with CHMCF wish to continue their pregnancy, careful follow-up, including regular chest radiography and ultrasonography, is warranted.


Assuntos
Coriocarcinoma/diagnóstico , Mola Hidatiforme/diagnóstico , Neoplasias Pulmonares/diagnóstico , Complicações Neoplásicas na Gravidez/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Cesárea , Coriocarcinoma/tratamento farmacológico , Feminino , Humanos , Mola Hidatiforme/tratamento farmacológico , Recém-Nascido , Nascimento Vivo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Metástase Neoplásica , Gravidez , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico
15.
J Cutan Pathol ; 45(7): 535-538, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29665032

RESUMO

A 19-year-old man suffering from testicular choriocarcinoma presented to the dermatology department with a cutaneous metastasis on his head. This metastasis was the first sign of disease that led to medical consultation. Histopathology revealed cytotrophoblasts and syncytiotrophoblasts, the later expressing human chorionic gonadotropin antigen. Whole body computed tomography showed multiple metastases of the brain, lung, liver, bone, paraaortic lymph nodes and left uvea; the primary was found in the left testicle. Despite neurosurgical intervention and chemotherapy the patient died 9 days after the biopsy of the cutaneous metastasis. Cutaneous metastases of testicular choriocarcinoma are exceptionally rare, with fewer than a dozen cases reported in the English-language literature. The present case highlights that testicular choriocarcinoma metastatic to the skin should be included in the differential of cutaneous scalp tumors.


Assuntos
Coriocarcinoma , Neoplasias de Cabeça e Pescoço , Neoplasias Cutâneas , Neoplasias Testiculares , Adulto , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/secundário , Humanos , Masculino , Metástase Neoplásica , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundário , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia
16.
Medicine (Baltimore) ; 97(14): e9977, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29620671

RESUMO

RATIONALE: Near-term intraplacental choriocarcinoma (IC) coexisting with massive fetomaternal hemorrhage (FMH) is rare, and its clinical course is poorly understood. Here, we report a new case from our hospital, with detailed discussion and literature review. PATIENT CONCERNS: A 21-year-old Chinese female at 35 weeks gestation was admitted to our hospital due to reduced fetal movement. Near-term IC coexisting with massive FMH was diagnosed after delivery. INTERVENTION: The mother and infant were followed 3 months after delivery. Beta-human chorionic gonadotropin (ß-HCG), pathological examination of the placenta, and computed tomography scans were performed for the mother and ß-HCG was performed for the infant. OUTCOMES: The mother's ß-HCG serum level increased from 31,280 IU/L (6 days postdelivery) to 192,070 IU/L (49 days postdelivery), and then steadily fell to 42,468 IU/L (3 months postdelivery) without chemotherapy. The mother died from metastasis and cerebral hemorrhage. The infant survived and his ß-HCG serum level fell to within the normal range without chemotherapy. LESSONS: FMH associated with near-term IC is a rare disease. Measurement of maternal ß-HCG may therefore represent a useful parameter when IC is a possible differential diagnosis. A pathological examination of the placenta should be performed in all cases of FMH to better identify cases of IC. Future research should aim to develop methods of identifying which patients with IC should receive chemotherapy, whether we should use single- or multiagent chemotherapies, and whether there is a positive correlation between chemotherapy regimen and ß-HCG serum levels.


Assuntos
Antineoplásicos/uso terapêutico , Coriocarcinoma/tratamento farmacológico , Transfusão Feto-Materna/tratamento farmacológico , Doenças Placentárias/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Coriocarcinoma/complicações , Coriocarcinoma/patologia , Gonadotropina Coriônica Humana Subunidade beta/sangue , Evolução Fatal , Feminino , Transfusão Feto-Materna/complicações , Humanos , Recém-Nascido , Masculino , Placenta/patologia , Doenças Placentárias/etiologia , Doenças Placentárias/patologia , Gravidez , Nascimento a Termo , Neoplasias Uterinas/complicações , Neoplasias Uterinas/patologia , Adulto Jovem
17.
Drug Deliv ; 25(1): 461-471, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29426237

RESUMO

Gestational trophoblastic neoplasia (GTN) can result from the over-proliferation of trophoblasts. Treatment of choriocarcinoma, the most aggressive GTN, currently requires high doses of systemic chemotherapeutic agents, which result in indiscriminate drug distribution and severe toxicity. To overcome these disadvantages and enhance the chemotherapeutic efficacy, chondroitin sulfate A (CSA)-binding nanoparticles were developed for the targeted delivery of doxorubicin (DOX) to choriocarcinoma cells using a synthetic CSA-binding peptide (CSA-BP), derived from malarial protein, which specifically binds to the CSA exclusively expressed in the placental trophoblast. CSA-BP-conjugated nanoparticles rapidly bonded to choriocarcinoma (JEG3) cells and were efficiently internalized into the lysosomes. Moreover, CSA-BP modification significantly increased the anti-cancer activity of the DOX-loaded nanoparticles in vitro. Intravenous injections of CSA-BP-conjugated nanoparticles loaded with indocyanine green (CSA-INPs) were rapidly localized to the tumor. The CSA-targeted nanoparticles loaded with DOX (CSA-DNPs) strongly inhibited primary tumor growth and, more importantly, significantly suppressed metastasis in vivo. Collectively, our results highlight the potential of the CSA-BP-decorated nanoparticles as an alternative targeted delivery system of chemotherapeutic agents for treating choriocarcinoma and for developing new GTN therapies based on drug targeting.


Assuntos
Sulfatos de Condroitina/administração & dosagem , Coriocarcinoma/tratamento farmacológico , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Neoplasias Uterinas/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/metabolismo , Sítios de Ligação/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Sulfatos de Condroitina/metabolismo , Coriocarcinoma/metabolismo , Relação Dose-Resposta a Droga , Doxorrubicina/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/metabolismo , Gravidez , Resultado do Tratamento , Neoplasias Uterinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
Reprod Sci ; 25(6): 830-836, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28322131

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis and is overexpressed in many kinds of malignant tumors. Soluble VEGF receptor 1 (sVEGFR-1/ soluble fms-like tyrosine kinase 1 [sFlt-1]) plays a role as an inhibitor of VEGF, and an antitumor effect has been shown in several studies using sFlt-1. Recently, in addition to its antiangiogenic effect, it was reported that sFlt-1 has direct cytotoxicity. MATERIALS AND METHODS: Transfection of sFlt-1 plasmid DNA was performed in the BeWo choriocarcinoma cell line. Overexpression of sFlt-1 in BeWo cells was confirmed by ELISA. In order to evaluate cell proliferation, cell counting and BrdU uptake assay were performed. Cytotoxicity was tested by LDH assay. TdT-Mediated dUTP Nick end Labeling (TUNEL) staining and quantitative analysis of caspase-cleaved keratin 18 (ccK18) level were done to evaluate cell apoptosis. RESULTS: The cell number was significantly less, and the ratio of cytotoxicity was significantly higher in sFlt-1 group compared to the control group. TUNEL staining and ccK18 level suggested nonapoptotic cell death. CONCLUSION: Soluble Flt-1 showed a cytotoxic effect on BeWo cells. Our results suggest that sFLT-1 could be therapeutic for malignant tumors.


Assuntos
Antineoplásicos/farmacologia , Coriocarcinoma/enzimologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Coriocarcinoma/tratamento farmacológico , Humanos , L-Lactato Desidrogenase/análise , Proteínas de Membrana/análise , Transfecção , Fator A de Crescimento do Endotélio Vascular/análise , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
J Cell Physiol ; 233(2): 1638-1649, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28657208

RESUMO

Silibinin is a flavonolignan extracted from seeds of milk thistles. Traditionally, it has been used as a therapeutic agent for liver disorders, and now it is well-known for its anti-cancer effects. However, studies on anti-cancer effects of silibinin on choriocarcinoma are very limited. Therefore, we performed proliferation and apoptosis assays to determine effects of silibinin on the viability of human choriocarcinoma (JAR and JEG3) cells. Our results showed that silibinin significantly inhibited proliferation and induced apoptosis in both JAR and JEG3 cells, and significantly increased reactive oxygen species (ROS) and lipid peroxidation. Moreover, silibinin disrupted mitochondrial function by inducing permeabilization of mitochondrial membrane potential and calcium ion efflux in JAR and JEG3 cells. Furthermore, silibinin-induced apoptosis in choriocarcinoma cells via AKT, mitogen-activated protein kinases (MAPK) and unfolded protein response (UPR) signal transduction. Collectively, our results suggest that silibinin is a novel therapeutic agent or dietary supplement for management of human placental choriocarcinomas.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Coriocarcinoma/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Silimarina/farmacologia , Neoplasias Uterinas/tratamento farmacológico , Sinalização do Cálcio/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Silibina , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
20.
Menopause ; 25(2): 239-241, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28816932

RESUMO

OBJECTIVE: Choriocarcinoma is rare in postmenopausal women, and an early diagnosis contributes to a potential cure. METHODS: We report a rare case of a postmenopausal woman with choriocarcinoma. The 61-year-old patient presented with irregular vaginal bleeding, 11 years after menopause and 30 years after the birth of the last child. RESULTS: Radiological investigation found a 3-cm mass on the lower left part of the vaginal wall, and also bilateral lung nodules. Gynecological examination found 3-4 cm blue and purple nodules in the lower left part of the vaginal wall. Her serum CA125 and serum ß-hCG levels were 10.2 and 9273.9 mIU/mL, respectively. The early diagnosis was a choriocarcinoma, and combination chemotherapy (etoposide, kengshengmycin, methotrexate, leucovorin, vincristine, and cyclophosphamide [EMACO]) was administered. After the sixth chemotherapy session, her serum ß-hCG level was <2 mIU/mL, and two additional consolidation chemotherapy sessions were performed. She achieved serological remission, but 4 months after completion of the chemotherapy, a rise in serum ß-hCG level was observed. Therefore, she was subjected to a second treatment with EMACO and fluorouracil (5-Fu) local injection chemotherapy. After nine chemotherapy sessions and three local 5-Fu injections, she showed a normal ß-hCG level, with negative radiological results, and negative pigmentation in the lower left part of the vaginal wall. After a 4-year follow-up period, no local recurrence or distant metastases was found. CONCLUSIONS: This patient has shown a mild response to chemotherapy when compared with patients in reproductive age, and the combination of standard chemotherapy with local injection chemotherapy may be helpful for treating similar clinical cases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Coriocarcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Vaginais/tratamento farmacológico , Coriocarcinoma/diagnóstico por imagem , Coriocarcinoma/secundário , Gonadotropina Coriônica Humana Subunidade beta/sangue , Ciclofosfamida/uso terapêutico , Dactinomicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Pós-Menopausa , Neoplasias Vaginais/diagnóstico por imagem , Neoplasias Vaginais/patologia , Vincristina/uso terapêutico
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