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1.
Medicine (Baltimore) ; 98(38): e16988, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567935

RESUMO

RATIONALE: Peripherally inserted central catheters (PICC), normally located at the lower 1/3rd of the superior vena cava (SVC) and cavo-atrial junction, are commonly used in cancer patients. Persistent left superior vena cava (PLSVC) is a vascular anomaly, in patients with which seldom research was reported about PICC implanted. After obtaining written informed consent, we present a case where two successful insertions of PICC were performed in a 50-year-old female patient with PLSVC and right SVC. PATIENTS CONCERNS: The patient had ovarian cancer and was admitted for chemotherapy using PICC. DIAGNOSES: Ovarian cancer and PLSVC. INTERVENTIONS AND OUTCOMES: Following insertion of PICC in PLSVC, thrombosis developed. PICC was removed after routine anticoagulation therapy. Owing to tumor recurrence, a second PICC was inserted in the right SVC without any complications. LESSONS: PICC insertion in PLSVC for chemotherapy may be associated with an increased risk of deep venous thrombosis of the upper extremity. A right catheter insertion in patient with PLSVC was preferred.


Assuntos
Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Malformações Vasculares/complicações , Veia Cava Superior/anormalidades , Trombose Venosa/diagnóstico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Braço , Cateterismo Periférico/efeitos adversos , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/complicações , Neoplasias Ovarianas/complicações , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/etiologia
2.
Anticancer Res ; 39(10): 5505-5513, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570444

RESUMO

BACKGROUND/AIM: The potential of the DNA mismatch repair (MMR) system as a prognostic predictor has been evaluated in several cancer types. However, associations between MMR and the prognostic factors of ovarian cancer are poorly understood. PATIENTS AND METHODS: MLH1 expression was evaluated by immunohistochemistry in patients with advanced serous ovarian cancer treated with platinum- and taxane-based chemotherapy. Associations between MLH1 expression and clinicopathological factors as well as claudin-4 expression were examined. RESULTS: Low MLH1 expression was significantly associated with increased progression-free and overall survival, and a normalisation of CA125 levels after chemotherapy. Additionally, low claudin-4 expression was more frequently found among the group with low MLH1 expression. CONCLUSION: Low MLH1 expression was associated with improved prognosis and is a possible predictor of the chemosensitivity of ovarian cancer. Claudin-4 might be involved in the molecular mechanisms underlying how MLH1 influences survival and chemosensitivity in patients with ovarian cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteína 1 Homóloga a MutL/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Taxoides/farmacologia , Idoso , Antígeno Ca-125/metabolismo , Claudina-4/metabolismo , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão
3.
Medicine (Baltimore) ; 98(33): e16771, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415377

RESUMO

The cell wall skeleton of Bacillus Calmette-Guérin (BCG-CWS) is a bioactive component that is a strong immune adjuvant for cancer immunotherapy. BCG-CWS activates the innate immune system through various pattern recognition receptors and is expected to elicit antigen-specific cellular immune responses when co-administered with tumor antigens. To determine the recommended dose (RD) of BCG-CWS based on its safety profile, we conducted a phase I dose-escalation study of BCG-CWS in combination with WT1 peptide for patients with advanced cancer.The primary endpoint was the proportion of treatment-related adverse events (AEs) at each BCG-CWS dose. The secondary endpoints were immune responses and clinical effects. A BCG-CWS dose of 50, 100, or 200 µg/body was administered intradermally on days 0, 7, 21, and 42, followed by 2 mg of WT1 peptide on the next day. For the escalation of a dose level, 3 + 3 design was used.Study subjects were 18 patients with advanced WT1-expressing cancers refractory to standard anti-cancer therapies (7 melanoma, 5 colorectal, 4 hepatobiliary, 1 ovarian, and 1 lung). Dose-limiting toxicity occurred in the form of local skin reactions in 2 patients at a dose of 200 µg although no serious treatment-related systemic AEs were observed. Neutrophils and monocytes transiently increased in response to BCG-CWS. Some patients demonstrated the induction of the CD4 T cell subset and its differentiation from the naïve to memory phenotype, resulting in a tumor response.The RD of BCG-CWS was determined to be 100 µg/body. This dose was well tolerated and showed promising clinical effects with the induction of an appropriate immune response.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Esqueleto da Parede Celular/uso terapêutico , Mycobacterium bovis , Adjuvantes Imunológicos/administração & dosagem , Adulto , Idoso , Vacina BCG/administração & dosagem , Contagem de Linfócito CD4 , Esqueleto da Parede Celular/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento
4.
Anticancer Res ; 39(8): 4023-4030, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366484

RESUMO

BACKGROUND: Treatment options for patients with platinum-resistant ovarian cancer are generally palliative in nature and rarely have realistic potential to be curative. Because many patients with recurrent ovarian cancer receive aggressive chemotherapy for prolonged periods, sometimes continuously, therapy-related toxicities are a major factor in treatment decisions. The use of ex vivo drug sensitivity screens has the potential to improve the treatment of patients with platinum-resistant ovarian cancer by providing personalized treatment plans and thus reducing toxicity from unproductive therapy attempts. MATERIALS AND METHODS: We evaluated the treatment responses of a set of six early-passage patient-derived ovarian cancer cell lines towards a set of 30 Food and Drug Administration-approved chemotherapy drugs using drug-sensitivity testing. RESULTS: We observed a wide range of treatment responses of the cell lines. While most compounds displayed vastly different treatment responses between cell lines, we found that some compounds such as docetaxel and cephalomannine reduced cell survival of all cell lines. CONCLUSION: We propose that ex vivo drug-sensitivity screening holds the potential to greatly improve patient outcomes, especially in a population where multiple continuous treatments are not an option due to advanced disease, rapid disease progression, age or poor overall health. This approach may also be useful to identify potential novel therapeutics for patients with ovarian cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Platina/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Platina/efeitos adversos
5.
Medicine (Baltimore) ; 98(31): e16620, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374028

RESUMO

Psychological state of patients with ovarian cancer is worthy of attention. We aimed to investigate the levels of anxiety and depression in patients with ovarian cancer. We also investigated the dynamic changes in anxiety and depression levels after chemotherapy.A total of 228 females were included in this study. Among them, a total of 111 participants had ovarian cancer and 117 females who underwent a physical examination were selected as healthy controls. All patients enrolled were asked to fill in the Self-rating Depression Scale and the Self-rating Anxiety Scale. For patients with ovarian cancer, repeat questionnaires were measured after cycle 1 chemotherapy.The depression score of patients with ovarian cancer was 45.90 ± 10.19, significantly higher than in controls (36.08 ± 9.06, P < .001). Similar results were observed in respect of anxiety score. The score of ovarian cancer patients was 39.53 ± 12.92, significantly higher than of controls (32.15 ±â€Š7.44, P < .001). Multivariate analyses were conducted, and the results showed that young age was the independent risk factor associated with depression among patients with ovarian cancer, while young age and singleness were the independent risk factors associated with anxiety. Repeat questionnaires were measured after chemotherapy. Interestingly, we found depression scores decreased from 45.90 ±â€Š10.19 to 36.29 ±â€Š8.98 after chemotherapy (P < .001), while anxiety score increased from 39.53 ±â€Š12.92 to 42.75 ±â€Š9.96 after chemotherapy (P = .009). Multivariate analysis suggested that only higher income and higher baseline depression score were the independent and most relevant risk factors associated with depression remission after chemotherapy. For patients with anxiety remission, only higher baseline anxiety score was the independent risk factor associated with anxiety remission.This study suggests that for patients with ovarian cancer, timely monitoring of the patient's psychological state, especially before and after chemotherapy treatment, is very important. Assessing the changes in the patient's psychological state, screening the population with risk factors, and prompt intervention by mobilizing social support may be effective in preventing depression and anxiety in such population.


Assuntos
Antineoplásicos/uso terapêutico , Ansiedade/epidemiologia , Depressão/epidemiologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/epidemiologia , Adulto , Fatores Etários , Idoso , Antineoplásicos/administração & dosagem , China/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/psicologia , Fatores de Risco , Fatores Socioeconômicos
6.
Anticancer Res ; 39(7): 3803-3808, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262907

RESUMO

BACKGROUND: Platinum-based therapy represents the main pharmacological treatment for ovarian carcinoma. Since molecular targeting of receptor tyrosine kinases (RTK) affects factors that may modulate drug response, the aim of this study was to examine whether downstream targets of AXL RTK could be exploited to improve cell response to cisplatin. MATERIALS AND METHODS: Inhibitors of p38 (SB203580) and of signal transducer and activator of transcription 3 (stattic) were employed in combination with cisplatin in ovarian carcinoma cell lines. Apoptosis assay and western blot analysis were performed to evaluate cell response after treatment. RESULTS: SB203580 produced a synergistic effect in combination with cisplatin in cisplatin-resistant IGROV-1/Pt1 cells. In addition, a favorable drug interaction was observed in A2780 cells when pre-incubated with cisplatin prior to stattic. The analysis of cell response after combined treatment showed down-regulation of the pro-apoptotic protein BCL2-associated agonist of cell death (BAD). CONCLUSION: Our results support the notion that downstream targets of AXL in ovarian carcinoma cells can be exploited to increase cisplatin activity in ovarian carcinoma models.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Imidazóis/farmacologia , Neoplasias Ovarianas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição STAT3
7.
J Surg Oncol ; 120(4): 779-785, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31283034

RESUMO

BACKGROUND: We sought to determine if complete pathologic response (cPR) and cytoreductive status at interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT) are associated with improved clinical outcomes in ovarian cancer. METHODS: We evaluated 91 patients with advanced ovarian cancer who underwent NACT and IDS. Pathologic response, cytoreductive status, and outcomes were determined. Descriptive statistics, bivariate analysis, and Kaplan-Meier survival probabilities were calculated. RESULTS: cPR occurred in 9 (10%), microscopic pathologic response (microPR) in 18 (20%), and macroscopic pathologic response (macroPR) in 64 (70%) patients. Median progression-free survival (PFS) for patients with cPR was significantly improved compared with patients with any pathologic residual disease (microPR/macroPR; undefined vs 10.9 months, P = .01); whereas, microPR was not associated with significantly improved PFS compared with macroPR (16.3 months vs 10 months, P = .08). Cytoreduction to no gross residual disease was associated with improved PFS (undefined vs 7.5 months vs 5.5 months, P < .01) and overall survival (undefined vs 38.7 months vs 12 months, P < .01) compared with visible residual disease less than or equal to 1 cm or suboptimal. CONCLUSIONS: cPR is uncommon (10%) after NACT for advanced ovarian cancer. Better pathologic response and cytoreductive status are associated with improved PFS, emphasizing the importance of both chemotherapy response and surgical effort.


Assuntos
Cistadenocarcinoma Seroso/patologia , Procedimentos Cirúrgicos de Citorredução/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Estudos de Coortes , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Prognóstico , Taxa de Sobrevida
8.
Expert Opin Investig Drugs ; 28(8): 667-673, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31353973

RESUMO

Introduction: A PEGylated form of irinotecan, a topoisomerase I inhibitor, is now available in commerce; its safety and efficacy have been tested in platinum resistant/refractory ovarian cancer (PROC) patients. This novel agent is known as Etirinotecan Pegol (EP). EP, like irinotecan, exerts its action through its principal metabolite SN-38. Areas covered: This drug evaluation article focuses on the most recent investigations and clinical progress regarding EP, a long-acting polymer conjugate of irinotecan for the treatment of PROC. Expert opinion: EP provides prolonged and continuous exposure of SN-38 in tumors, when compared to its parent drug irinotecan. Results from phase II studies are comparable in terms of efficacy to other agents of proven use in PROC. A limitation of the use of EP is the schedule-dependent toxicities (mainly diarrhea and dehydration). In the future, EP could be investigated in association with other agents, even in attempts to restore sensitivity to other treatments. PROC remains a very difficult setting and EP might be a valid agent for patients with good performance status that have exhausted therapeutic options. In such a setting, participation in clinical trials is strongly encouraged.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Inibidores da Topoisomerase I/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/patologia , Polietilenoglicóis/efeitos adversos , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacologia
9.
J Surg Oncol ; 120(3): 550-557, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31267569

RESUMO

BACKGROUND AND OBJECTIVES: Hypertherm intraperitoneal chemotherapy (HIPEC) is increasingly used in the treatment of ovarian, tubal, and primary peritoneal cancer (OC). The aim was to evaluate short-term morbidity of cytoreductive surgery (CRS) and carboplatin HIPEC. METHODS: Prospective feasibility study performed from January 2016 to December 2017. Twenty-five patients with primary OC (FIGO III-IV) received upfront or interval CRS combined with carboplatin HIPEC at dose 800 mg/m 2 . Primary outcome measurements: grade 3 to 5 adverse events within 30 days according to Common Terminology Criteria for Adverse Events. Secondary outcome measurements: reoperation rate, length of hospital stay, readmission rate, and time from surgery to systemic chemotherapy administration. RESULTS: No deaths (grade 5) or grade 4 adverse events were observed. Eleven patients (44.0%) experienced at least one grade 3 adverse event, the most common being an infection (28.0%) and neutropenia (12.0%). The reoperation rate was 8.0%. The median hospital stay was 14 days (range 9-25 days), and five patients (25.0%) were readmitted within 30 days after surgery. Median time from surgery to the administration of the first dose of systemic chemotherapy was 41 days (range 24-81 days). CONCLUSION: Our small-scale prospective study supports that CRS and carboplatin HIPEC used for primary advanced-stage OC is feasible with acceptable morbidity.


Assuntos
Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário/terapia , Neoplasias das Tubas Uterinas/terapia , Hipertermia Induzida/métodos , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução/métodos , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Estudos Prospectivos
10.
Biol Res ; 52(1): 37, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319879

RESUMO

BACKGROUND: Berberine (BBR), a compound extracted from a variety of medicinal herbs, has been shown multiple pharmacological effects against cancer cells of different origins. Cisplatin (DDP) is known as an effective chemotherapeutic agent against cancer by inducing DNA damage and cell apoptosis. However, the effect of the combined used of BBR and DDP on cell necroptosis in ovarian cancer has not been reported. METHODS: OVCAR3 and three patient-derived primary ovarian cancer cell lines (POCCLs) were chosen as the experimental objects. To determine the potential anti-cancer activity of BBR and DDP in combination, we firstly treated OVCAR3 and POCCLs cells with BBR and/or DDP. The cell viability of OVCAR3 and POCCLs with treatment of BBR or DDP for different hours was measured by CCK-8 assay. Flow cytometry was used to analyze cell cycle distribution and changes in apoptotic cells after treatment with BBR and/or DDP. The morphological changes of OVCAR3 cells were observed by using Transmission electron microscopy (TEM) analysis. Proliferation, apoptosis and necroptosis related markers of OVCAR3 and POCCLs with treatment of BBR or DDP were measured by RT-qPCR, western blotting and immunofluorescence assay. RESULTS: Our results demonstrated that BBR significantly inhibited the proliferation of OVCAR3 and primary ovarian cancer cells in a dose- and time-dependent manner. The combination treatment of BBR and DDP had a prominent inhibitory effect on cancer cell growth and induced G0/G1 cell cycle arrest. TEM revealed that the majority of cells after BBR or DDP treatment had an increasing tendency of typical apoptotic and necrotic cell death morphology. Besides, BBR and DDP inhibited the expression of PCNA and Ki67 and enhanced the expression and activation of Caspase-3, Caspase-8, RIPK3 and MLKL. CONCLUSION: This study proposed that the combination therapy of BBR and DDP markedly enhanced more ovarian cancer cell death by inducing apoptosis and necroptosis, which may improve the anticancer effect of chemotherapy drugs. The apoptosis involved the caspase-dependent pathway, while the necroptosis involved the activation of the RIPK3-MLKL pathway. We hope our findings might provide a new insight for the potential of BBR as a therapeutic agent in the treatment of ovarian cancer.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Berberina/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Berberina/farmacologia , Caspases , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Necrose
11.
Oncology ; 97(4): 202-205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31288226

RESUMO

Based on the results of several phase 3 randomized trials, "maintenance therapy" (prolonged treatment after an initial response to cytotoxic chemotherapy) has assumed a critical role in the routine care of advanced epithelial ovarian cancer. While earlier data had provided support for this therapeutic concept in disease management (e.g., multiple cycles of single-agent paclitaxel following a clinical complete response to a platinum/paclitaxel regimen), more recent data has revealed both the efficacy and safety of the anti-angiogenesis agent, bevacizumab, and several PARP inhibitors when employed in this clinical setting.


Assuntos
Tratamento Farmacológico/métodos , Oncologia/tendências , Neoplasias Ovarianas/tratamento farmacológico , Bevacizumab/administração & dosagem , Feminino , Humanos , Neoplasias Ovarianas/imunologia , Paclitaxel/administração & dosagem , Platina/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
12.
Eur J Med Chem ; 178: 177-194, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185410

RESUMO

Microtubule is one of the important targets for cancer treatment. A novel class of diaryl substituted imidazo[4,5-c]pyridin-2-ones and imidazo[4,5-c]pyridines were designed based on combination principles by merging the structures of ß-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo[4,5-c]pyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Katanina/antagonistas & inibidores , Piridinas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Carcinoma Endometrioide/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Katanina/metabolismo , Ligantes , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Bratisl Lek Listy ; 120(6): 468-475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223029

RESUMO

BACKGROUND: Previous studies on the efficacy of platinum-based drugs and selective inhibitors of proteasome have revealed promising outcomes. This study is aimed to evaluate the effects of the combination of cisplatin and carfilzomib on the cell death induction and drug efflux transporters expression in cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) ovarian cancer cells lines. METHODS: MTT cytotoxic assay was conducted to determine the cytotoxicity. Drug interactions were analyzed based on Chou-Talalay's principles and real-time PCR analysis was performed to determine possible alterations in mRNA levels of MRP1 and BCRP. RESULTS: A2780s cells were more susceptible to both cisplatin and carfilzomib while analyses of drug interactions between the two agents showed synergistic effects in all affected fractions of drug-treated A2780s and A2780cp cells (CI<0.9) with the combination indices being significantly lower in A2780cp cells (p < 0.01). We also found that although mRNA levels of BCRP and MRP1 were significantly altered in both cells exposed to each drug alone, only the combination regimen was able to significantly reduce the mRNA levels of these genes in A2780cp cells (p<0.001). CONCLUSION: This combination might be a potential strategy for suppressing cell growth via downregulating the drug efflux transporters expression, especially in cisplatin-resistant ovarian cancer cells (Fig. 3, Ref. 45).


Assuntos
Antineoplásicos , Cisplatino , Oligopeptídeos , Neoplasias Ovarianas , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Oligopeptídeos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia
14.
Gen Physiol Biophys ; 38(4): 353-363, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241042

RESUMO

Intracellular calcium concentration ([Ca2+]i) may have an important role in the development of chemoresistance, which is an essential problem in cancer chemotherapy. Cisplatin (DDP), which modulates the intracellular calcium concentration by different mechanisms, is an antineoplastic agent with high success rate in cancer therapies. We investigated the regulatory role of [Ca2+] in cisplatin resistance in epithelial ovarian cancer cell line, in MDAH-2774, and its chemoresistant subclone MDAH-2774/DDP. The measurement of [Ca2+]i using fluorescence microscope, and flow cytometry revealed that the amount of intracellular calcium decreased in cisplatin resistant cells compared to the amounts in parental cells. mRNA expression profiles of calcium homeostasis-associated major genes (IP3R1/2/3, RYR1/2, SERCA1/2/3, NCX1/2/3, PMCA1/2/3, and PMCA4) decreased in cisplatin resistant cell line in comparison to the expression profiles in parental cells. Owing to the changes in the expression of genes involved in calcium regulation, these results show, drug resistance may be prevented by introducing a new perspective on the use of inhibitors and activators of these genes, and thus of cytostatic treatment strategies, due to changes in the expression of genes involved in calcium regulation.


Assuntos
Antineoplásicos/farmacologia , Cálcio/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Homeostase , Neoplasias Ovarianas/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Homeostase/efeitos dos fármacos , Humanos , Neoplasias Ovarianas/tratamento farmacológico
15.
Nat Commun ; 10(1): 2556, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186408

RESUMO

Senescence is a tumor suppression mechanism defined by stable proliferation arrest. Here we demonstrate that the known synthetic lethal interaction between poly(ADP-ribose) polymerase 1 inhibitors (PARPi) and DNA repair triggers p53-independent ovarian cancer cell senescence defined by senescence-associated phenotypic hallmarks including DNA-SCARS, inflammatory secretome, Bcl-XL-mediated apoptosis resistance, and proliferation restriction via Chk2 and p21 (CDKN1A). The concept of senescence as irreversible remains controversial and here we show that PARPi-senescent cells re-initiate proliferation upon drug withdrawal, potentially explaining the requirement for sustained PARPi therapy in the clinic. Importantly, PARPi-induced senescence renders ovarian and breast cancer cells transiently susceptible to second-phase synthetic lethal approaches targeting the senescence state using senolytic drugs. The combination of PARPi and a senolytic is effective in preclinical models of ovarian and breast cancer suggesting that coupling these synthetic lethalities provides a rational approach to their clinical use and may together be more effective in limiting resistance.


Assuntos
Proliferação de Células/efeitos dos fármacos , Senescência Celular , Reparo do DNA , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Mutações Sintéticas Letais , Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico
16.
Life Sci ; 232: 116561, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247208

RESUMO

AIMS: The poor prognosis of ovarian cancer is mainly caused by chemotherapy resistance. Studies show that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. However, the mechanism of ABT737 increases sensitivity to cisplatin by regulating mitochondrial function remains unclear in ovarian cancer cells. Sirt3, as a histone deacetylase, is involved in the regulation of mitochondrial function in cancers. In this study, we intend to explore the mechanistic link between Sirt3 and mitochondrial dysfunction induced by ABT737 and cisplatin in ovarian cancer cells. MAIN METHODS: Apoptosis was examined by flow cytometry following Annexin V and PI staining. Sirt3 activity was assessed using Sirt3 deacetylase fluorometric assay. The mitochondrial membrane potential was examined by flow cytometry following JC-1 staining. Overexpression and knock-down of Sirt3 were confirmed by western blot analysis. Mitochondrial fission/fusion dynamics were detected by immunofluorescence staining or western blot analysis. KEY FINDINGS: Cisplatin accompanied with ABT737 promoted apoptosis and decreased mitochondrial membrane potential. ABT737 enhanced the sensitivity of ovarian cancer cells to cisplatin, which was partly achieved by activating Sirt3 to regulate the mitochondrial fission process. SIGNIFICANCE: This study identified the activation of Sirt3 played an important role in increasing sensitivity of ovarian cancer cells to cisplatin induced by ABT737. Furthermore, Sirt3 might represent a potential therapeutic target for ovarian cancer.


Assuntos
Compostos de Bifenilo/farmacologia , Nitrofenóis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Sirtuína 3/metabolismo , Sulfonamidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/metabolismo , Cisplatino/farmacologia , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Neoplasias Ovarianas/fisiopatologia , Ovário/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Int J Oncol ; 55(1): 277-288, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180526

RESUMO

Ubiquitin­specific protease 39 (USP39), as one of the deubiquitinating enzymes (DUBs), exhibits aberrant an expression and has oncogenic functions in several types of cancer. However, the function and underlying molecular mechanisms of action of USP39 in ovarian cancer remain largely undetermined. The present study thus aimed to investigate whether USP39 is a promising tumor­associated gene and whether it could be a viable target for overcoming chemotherapeutic resistance in ovarian cancer. The present study identified that USP39 was highly expressed in ovarian cancer samples with carboplatin resistance. A series of functional assays revealed that the knockdown of USP39 in ES2 and SKOV3 cells significantly decreased cell proliferation, induced cell cycle arrest at the G2/M phase and impaired the cell colony formation ability. USP39 deficiency enhanced the carboplatin­induced apoptosis of the SKOV3 cells via the activation of poly­ADP ribose polymerase and caspase­3. USP39 knockdown led to the inhibition of cell migration and invasion. The opposite effects were observed when USP39 was overexpressed in the ES2 and SKOV3 cells. In vivo animal models revealed that the subcutaneous transplantation and intraperitoneal injection of USP39­overexpressing ES2 cells increased tumor burden with or without treatment with carboplatin. However, the knockdown of USP39 suppressed SKOV3 cell growth in vivo. Mechanistic analyses also demonstrated that USP39 induced the phosphorylation of extracellular signal­regulated kinase and AKT and increased the expression of epidermal growth factor receptor and cyclin B1. Collectively, the findings of this study suggest that USP39 may paly a vital role in regulating ovarian cancer malignant phenotypes and carboplatin resistance. Therefore, USP39 may prove to be a promising therapeutic target for patients with ovarian cancer.


Assuntos
Carboplatina/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Proteases Específicas de Ubiquitina/metabolismo , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Distribuição Aleatória , Proteases Específicas de Ubiquitina/biossíntese
19.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(1): 116-120, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31102366

RESUMO

Chemotherapy resistance is one of the biggest challenges in treatment of ovarian cancer. Mounting evidence shows that the exosomes shedding from tumor cells are considered to be involved in chemotherapy resistance of ovarian cancer by enhanced exosomal export of drugs, transferring RNAs or proteins and interfering with the bioactivity of therapeutic anti-tumor antibodies. In this review, we display the correlation between exosomes and chemotherapy resistance of ovarian cancer, the mechanism of exosomes involved in chemotherapy resistance of ovarian cancer, and discuss the potential clinical values of exosomes in chemotherapy resistance of ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário , Exossomos , Neoplasias Ovarianas , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/fisiopatologia , Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/fisiopatologia
20.
Med Sci Monit ; 25: 3231-3237, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31043579

RESUMO

BACKGROUND Worldwide, ovarian cancer has a high mortality rate due to the difficulty in diagnosing early-stage disease and resistance to chemotherapy agents. Costunolide is a plant-derived sesquiterpene lactone with anti-oxidant properties. This study aimed to investigate the effects of costunolide on cell growth, apoptosis, autophagy, the production of reactive oxygen species (ROS), cleaved caspase-3, and cleaved caspase-9 on the multidrug-resistant ovarian cancer cell line, OAW42-A. MATERIAL AND METHODS The MTT assay determined the proliferation rate of OAW42-A multidrug-resistant ovarian cancer cells and the apoptosis rate was determined using propidium iodide (PI) staining. Autophagy was detected by measuring the expression of LC3 II. Fluorescence flow cytometry was used to measure the levels of reactive oxygen species (ROS) and the mitochondrial membrane potential. Protein expression of LC3 II, beclin 1, cleaved caspase-3, and cleaved caspase-9 were measured by Western blot. RESULTS Costunolide treatment inhibited the growth of OAW42-A cells with an IC50 of 25 µM, resulted in apoptotic cell death, increased the expression of Bax, and decreased the expression of Bcl-2. Confocal electron microscopy showed that costunolide induced autophagy in the OAW42-A cells. Western blot showed that costunolide treatment of OAW42-A cells increased the expression of the LC3 II, beclin 1, cleaved caspase-3, and cleaved caspase-9. Costunolide treatment significantly increased the levels of ROS and reduced the OAW42-A cell mitochondrial membrane potential. CONCLUSIONS Costunolide inhibited growth, apoptosis, ROS generation, and was associated with loss of mitochondrial membrane potential of OAW42-A multidrug-resistant ovarian cancer cells.


Assuntos
Caspase 3/metabolismo , Caspase 9/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Metástase Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia
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