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3.
J Natl Cancer Inst ; 109(7)2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28376174

RESUMEN

Background: The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K. Methods: Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided. Results: MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model ( P < .001). Mice treated with combination MSC2363318A and paclitaxel had the longest overall survival (mean = 104.2 days, 95% confidence interval [CI] = 97.0 to 111.4) compared with those treated with vehicle (mean = 61.9 days, 95% CI = 46.3 to 77.5), MSC2363318A alone (mean = 89.7 days, 95% CI = 83.0 to 96.4), and paclitaxel alone (mean = 73.6 days, 95% CI = 53.4 to 93.8). Regression and stabilization of established tumors in the Ishikawa (endometrioid) uterine cancer model was observed in mice treated with combination MSC2363318A and paclitaxel. Synergy between MSC2363318A and paclitaxel was observed in vitro in cell lines that had an IC50 of 5 µM or greater. RPPA results identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R = 0.54, P = .02). After establishment of a murine ovarian cancer model of adaptive anti-angiogenic resistance (SKOV3ip1-luciferase), we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A, resulting in improved overall survival ( P = .01) using the Kaplan-Meier method. Mice treated with bevacizumab induction followed by MSC2363318A had the longest overall survival (mean = 66.0 days, 95% CI = 53.9 to 78.1) compared with mice treated with control (mean = 42.0 days, 95% CI = 31.4 to 52.6) and bevacizumab-sensitive mice (mean = 47.2 days; 95% CI = 37.5 to 56.9). Conclusions: MSC2363318A has therapeutic efficacy in multiple preclinical models of ovarian and uterine cancer. These findings support clinical development of a dual AKT/P70S6K inhibitor.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Ováricas/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Neoplasias Uterinas/metabolismo , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Bevacizumab/administración & dosificación , Bevacizumab/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Factores de Transcripción , Carga Tumoral/efectos de los fármacos , Neoplasias Uterinas/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP
4.
Biochem J ; 474(5): 731-749, 2017 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-28057718

RESUMEN

The role of reactive oxygen species (ROS) in osmotic stress, dextran sulfate sodium (DSS) and cyclic stretch-induced tight junction (TJ) disruption was investigated in Caco-2 cell monolayers in vitro and restraint stress-induced barrier dysfunction in mouse colon in vivo Live cell imaging showed that osmotic stress, cyclic stretch and DSS triggered rapid production of ROS in Caco-2 cell monolayers, which was blocked by depletion of intracellular Ca2+ by 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Knockdown of CaV1.3 or TRPV6 channels blocked osmotic stress and DSS-induced ROS production and attenuated TJ disruption and barrier dysfunction. N-Acetyl l-cysteine (NAC) and l-NG-Nitroarginine methyl ester (l-NAME) blocked stress-induced TJ disruption and barrier dysfunction. NAC and l-NAME also blocked stress-induced activation of c-Jun N-terminal kinase (JNK) and c-Src. ROS was colocalized with the mitochondrial marker in stressed cells. Cyclosporin A blocked osmotic stress and DSS-induced ROS production, barrier dysfunction, TJ disruption and JNK activation. Mitochondria-targeted Mito-TEMPO blocked osmotic stress and DSS-induced barrier dysfunction and TJ disruption. Chronic restraint stress in mice resulted in the elevation of intracellular Ca2+, activation of JNK and c-Src, and disruption of TJ in the colonic epithelium. Furthermore, corticosterone administration induced JNK and c-Src activation, TJ disruption and protein thiol oxidation in colonic mucosa. The present study demonstrates that oxidative stress is a common signal in the mechanism of TJ disruption in the intestinal epithelium by different types of cellular stress in vitro and bio behavioral stress in vivo.


Asunto(s)
Calcio/metabolismo , Colon/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Estrés Psicológico/metabolismo , Uniones Estrechas/metabolismo , Animales , Proteína Tirosina Quinasa CSK , Células CACO-2 , Canales de Calcio/genética , Canales de Calcio/metabolismo , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Quelantes/farmacología , Colon/citología , Colon/efectos de los fármacos , Corticosterona/farmacología , Ciclosporina/farmacología , Sulfato de Dextran/farmacología , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Regulación de la Expresión Génica , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Mecanotransducción Celular , Ratones , Ratones Endogámicos C57BL , NG-Nitroarginina Metil Éster/farmacología , Presión Osmótica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/agonistas , Estrés Mecánico , Estrés Psicológico/genética , Estrés Psicológico/fisiopatología , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/patología , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismo
5.
Cell Rep ; 17(6): 1621-1631, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27806300

RESUMEN

Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers.


Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Hipertermia Inducida , Neoplasias Ováricas/metabolismo , Neoplasias Uterinas/metabolismo , Animales , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Genes Relacionados con las Neoplasias , Humanos , Ratones , Modelos Biológicos , Neoplasias Ováricas/genética , Proteómica , Neoplasias Uterinas/genética
6.
JCI Insight ; 1(17): e87754, 2016 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-27777972

RESUMEN

Current antiangiogenesis therapy relies on inhibiting newly developed immature tumor blood vessels and starving tumor cells. This strategy has shown transient and modest efficacy. Here, we report a better approach to target cancer-associated endothelial cells (ECs), reverse permeability and leakiness of tumor blood vessels, and improve delivery of chemotherapeutic agents to the tumor. First, we identified deregulated microRNAs (miRs) from patient-derived cancer-associated ECs. Silencing these miRs led to decreased vascular permeability and increased maturation of blood vessels. Next, we screened a thioaptamer (TA) library to identify TAs selective for tumor-associated ECs. An annexin A2-targeted TA was identified and used for delivery of miR106b-5p and miR30c-5p inhibitors, resulting in vascular maturation and antitumor effects without inducing hypoxia. These findings could have implications for improving vascular-targeted therapy.


Asunto(s)
Antineoplásicos/farmacología , Aptámeros de Nucleótidos , Células Endoteliales/citología , MicroARNs/administración & dosificación , Neovascularización Patológica/prevención & control , Línea Celular Tumoral , Humanos , Nanopartículas , Neoplasias/irrigación sanguínea , Neoplasias/terapia , Transfección
7.
Mol Cancer Ther ; 15(12): 2894-2904, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27638860

RESUMEN

To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC versus aspirin on three human (A2780, SKOV3ip1, and HeyA8) and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following antiangiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50% to 90% (depending on the ovarian cell line). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis, and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust antineoplastic action in the presence of VEGF-blocking drugs. Mol Cancer Ther; 15(12); 2894-904. ©2016 AACR.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Aspirina/farmacología , Neovascularización Patológica , Neoplasias Ováricas/patología , Fosfatidilcolinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Tromboxanos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Cell Metab ; 23(2): 388-388.e1, 2016 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-26863488

RESUMEN

Perturbation of an organism's homeostasis by stress can trigger biological or behavioral adaptation and accelerate onset and course of several diseases. Signaling triggered by norepinephrine or epinephrine (via adrenergic receptors) and cortisol (through glucocorticoid receptors) has profound effects on dampening immune responses, accelerating cancer progression and increasing the risk of cardiovascular, metabolic, and colonic diseases. To view this SnapShot, open or download the PDF.


Asunto(s)
Enfermedad , Estrés Psicológico/patología , Humanos , Especificidad de Órganos
9.
Clin Cancer Res ; 22(7): 1713-24, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-26581245

RESUMEN

PURPOSE: Chronic adrenergic activation has been shown to associate with adverse clinical outcomes in cancer patients, but the underlying mechanisms are not well understood. The focus of the current study was to determine the functional and biologic effects of adrenergic pathways on response to chemotherapy in the context of ovarian cancer. EXPERIMENTAL DESIGN: Increased DUSP1 production by sympathetic nervous system mediators (e.g., norepinephrine) was analyzed by real-time quantitative RT-PCR and by Western blotting. In vitro chemotherapy-induced cell apoptosis was examined by flow cytometry. For in vivo therapy, a well-characterized model of chronic stress was used. RESULTS: Catecholamines significantly inhibited paclitaxel- and cisplatin-induced apoptosis in ovarian cancer cells. Genomic analyses of cells treated with norepinephrine identified DUSP1 as a potential mediator. DUSP1 overexpression resulted in reduced paclitaxel-induced apoptosis in ovarian cancer cells compared with control; conversely, DUSP1 gene silencing resulted in increased apoptosis compared with control cells. DUSP1 gene silencing in vivo significantly enhanced response to paclitaxel and increased apoptosis. In vitro analyses indicated that norepinephrine-induced DUSP1 gene expression was mediated through ADRB2 activation of cAMP-PLC-PKC-CREB signaling, which inhibits JNK-mediated phosphorylation of c-Jun and protects ovarian cancer cells from apoptosis. Moreover, analysis of The Cancer Genome Atlas data showed that increased DUSP1 expression was associated with decreased overall (P= 0.049) and progression-free (P= 0.0005) survival. CONCLUSIONS: These findings provide a new understanding of the mechanisms by which adrenergic pathways can impair response to chemotherapy and have implications for cancer management.


Asunto(s)
Adrenérgicos/farmacología , Antineoplásicos/farmacología , Fosfatasa 1 de Especificidad Dual/metabolismo , Neoplasias Ováricas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Catecolaminas/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Fosfatasa 1 de Especificidad Dual/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Modelos Biológicos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosforilación , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-jun/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico , Transcripción Genética , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Mol Cancer Ther ; 14(6): 1466-1475, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25833835

RESUMEN

PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wild-type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAK(Y397) in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAK(Y397) expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAK(Y397) expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAK(Y397) expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development.


Asunto(s)
Aminopiridinas/farmacología , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Ácidos Hidroxámicos/farmacología , Fosfohidrolasa PTEN/metabolismo , Neoplasias Uterinas/tratamiento farmacológico , Animales , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Ratones Desnudos , Mutación , Neovascularización Patológica/metabolismo , Neovascularización Patológica/prevención & control , Fosfohidrolasa PTEN/genética , Fosforilación/efectos de los fármacos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Valor Predictivo de las Pruebas , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Uterinas/irrigación sanguínea , Neoplasias Uterinas/genética , Ensayos Antitumor por Modelo de Xenoinjerto
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