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1.
Invest New Drugs ; 39(3): 829-835, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33415580

RESUMEN

Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibitors in GCT patients. Here, we present a case series of GCT patients treated with pembrolizumab who were enrolled in a phase II basket trial in advanced, rare solid tumors (ClinicalTrials.gov: NCT02721732). Cases We identified 5 patients with recurrent GCT (4 adult and 1 juvenile type); they had an extensive history of systemic therapy at study enrollment (range, 3-10), with most regimens resulting in less than 12 months of disease control. Pembrolizumab was administered in these patients, as per trial protocol. Although there were no objective responses according to the irRECIST guidelines, 2 patients with adult-type GCT experienced disease control for ≥ 12 months (565 and 453 days). In one, pembrolizumab represented the longest duration of disease control compared to prior lines of systemic therapy (565 days vs. 13 months). In the other, pembrolizumab was the second longest systemic therapy associated with disease control (453 days vs. 22 months) compared to prior lines of therapy. In this patient, pembrolizumab was discontinued following withdrawal of consent. PD-L1 expression was not observed in any baseline tumor samples. Pembrolizumab was well tolerated, with no grade 3 or 4 treatment-related adverse events. Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Tumor de Células de la Granulosa/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Proteínas de la Ataxia Telangiectasia Mutada/genética , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Femenino , Proteína Forkhead Box L2/genética , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Linfocitos Infiltrantes de Tumor/inmunología , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Neurofibromina 1/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética , Adulto Joven
2.
Mol Cancer Ther ; 16(6): 1114-1123, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28265009

RESUMEN

To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N = 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single-dose EPHARNA administration to mice, no gross pathologic or dose-related microscopic findings were observed in either the acute (24 hours) or recovery (14 and 28 days) phases. The no-observed-adverse-effect level (NOAEL) for EPHARNA is considered >225 µg/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the gastrointestinal tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. These data, combined with previously published in vivo validation studies, have led to an ongoing first-in-human phase I clinical trial (NCT01591356). Mol Cancer Ther; 16(6); 1114-23. ©2017 AACR.


Asunto(s)
Liposomas , Nanopartículas , Fosfatidilcolinas , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptor EphA2/genética , Animales , Biomarcadores , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Macaca mulatta , Masculino , Ratones , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/farmacocinética , Distribución Tisular
3.
Mol Cancer Ther ; 16(5): 966-976, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28223424

RESUMEN

Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examination of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH. Genomic analyzes were performed using ovarian cancer cells exposed to MFH for 30 minutes at 43°C, which revealed that heat shock protein (HSP) genes, including HSPA6, were upregulated. HSPA6 encodes the Hsp70, and its expression was confirmed by PCR in HeyA8 and A2780cp20 ovarian cancer cells. Two strategies were investigated to inhibit Hsp70-related genes, siRNA and Hsp70 protein function inhibition by 2-phenylethyenesulfonamide (PES). Both strategies resulted in decreased cell viability following exposure to MFH. Combination index was calculated for PES treatment reporting a synergistic effect. In vivo efficacy experiments with HSPA6 siRNA and MFH were performed using the A2780cp20 and HeyA8 ovarian cancer mouse models. A significantly reduction in tumor growth rate was observed with combination therapy. PES and MFH efficacy were also evaluated in the HeyA8 intraperitoneal tumor model, and resulted in robust antitumor effects. This work demonstrated that HSP70 inhibition combination with MFH generate a synergistic effect and could be a promising target to enhance MFH therapeutic outcomes in ovarian cancer. Mol Cancer Ther; 16(5); 966-76. ©2017 AACR.


Asunto(s)
Proteínas HSP70 de Choque Térmico/genética , Hipertermia Inducida , Neoplasias Ováricas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Supervivencia Celular/genética , Terapia Combinada , Femenino , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Humanos , Fenómenos Magnéticos , Ratones , Neoplasias Ováricas/patología , ARN Interferente Pequeño/genética
4.
Integr Cancer Ther ; 16(1): 3-20, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27903842

RESUMEN

BACKGROUND: Although epidemiological research demonstrates that there is an association between lifestyle factors and risk of breast cancer recurrence, progression of disease, and mortality, no comprehensive lifestyle change clinical trials have been conducted to determine if changing multiple risk factors leads to changes in biobehavioral processes and clinical outcomes in women with breast cancer. This article describes the design, feasibility, adherence to the intervention and data collection, and patient experience of a comprehensive lifestyle change clinical trial (CompLife). METHODS: CompLife is a randomized, controlled trial of a multiple-behavior intervention focusing on diet, exercise, and mind-body practice along with behavioral counseling to support change. The initial exposure to the intervention takes place during the 4 to 6 weeks of radiotherapy (XRT) for women with stage III breast cancer and then across the subsequent 12 months. The intervention group will have 42 hours of in-person lifestyle counseling during XRT (7-10 hours a week) followed by up to 30 hours of counseling via video connection for the subsequent 12 months (weekly sessions for 6 months and then monthly for 6 months). The primary outcome is disease-free survival. Multiple secondary outcomes are being evaluated, including: (1) biological pathways; (2) overall survival; (3) patient-reported outcomes; (4) dietary patterns/fitness levels, anthropometrics, and body composition; and (5) economic outcomes. Qualitative data of the patient experience in the trial is collected from exit interviews, concluding remarks, direct email correspondences, and web postings from patients. RESULTS: Fifty-five patients have been recruited and randomized to the trial to date. Accrual of eligible patients is high (72%) and dropout rates extremely low (5%). Attendance to the in-person sessions is high (95% attending greater than 80% of sessions) as well as to the 30 hours of video counseling (88% attending more than 70% of sessions). Adherence to components of the behavior change intervention is high and compliance with the intensive amount of data collection is exceptional. Qualitative data collected from the participants reveals testimonials supporting the importance of the comprehensive nature of intervention, especially the mind-body/mindfulness component and social support, and meaningful lifestyle transformations. CONCLUSION: Conducting a comprehensive, multicomponent, lifestyle change clinical trial for women with breast was feasible and collection of biobehavioral outcomes successful. Adherence to behavior change was high and patient experience was overwhelmingly positive.


Asunto(s)
Neoplasias de la Mama/psicología , Consejo/métodos , Dieta/psicología , Supervivencia sin Enfermedad , Ejercicio Físico/psicología , Femenino , Humanos , Estilo de Vida , Persona de Mediana Edad , Recurrencia Local de Neoplasia/psicología , Cooperación del Paciente/psicología
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.
EBioMedicine ; 12: 34-42, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27720213

RESUMEN

MicroRNAs (miRNAs) are an evolutionarily conserved class of small, regulatory non-coding RNAs that negatively regulate protein coding gene and other non-coding transcripts expression. miRNAs have been established as master regulators of cellular processes, and they play a vital role in tumor initiation, progression and metastasis. Further, widespread deregulation of microRNAs have been reported in several cancers, with several microRNAs playing oncogenic and tumor suppressive roles. Based on these, miRNAs have emerged as promising therapeutic tools for cancer management. In this review, we have focused on the roles of miRNAs in tumorigenesis, the miRNA-based therapeutic strategies currently being evaluated for use in cancer, and the advantages and current challenges to their use in the clinic.


Asunto(s)
Terapia Genética , MicroARNs/genética , MicroARNs/uso terapéutico , Neoplasias/genética , Neoplasias/terapia , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Terapia Genética/efectos adversos , Terapia Genética/métodos , Humanos , Inmunomodulación/genética , Neoplasias/inmunología , Neoplasias/patología , Interferencia de ARN , Resultado del Tratamiento , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
7.
J Med Imaging (Bellingham) ; 3(3): 036001, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27547777

RESUMEN

Silicon-based nanoparticles are ideally suited for use as biomedical imaging agents due to their biocompatibility, biodegradability, and simple surface chemistry that facilitates drug loading and targeting. A method of hyperpolarizing silicon particles using dynamic nuclear polarization, which increases magnetic resonance imaging signals by several orders-of-magnitude through enhanced nuclear spin alignment, has recently been developed to allow silicon particles to function as contrast agents for in vivo magnetic resonance imaging. The enhanced spin polarization of silicon lasts significantly longer than other hyperpolarized agents (tens of minutes, whereas [Formula: see text] for other species at room temperature), allowing a wide range of potential applications. We report our recent characterizations of hyperpolarized silicon particles, with the ultimate goal of targeted, noninvasive, and nonradioactive molecular imaging of various cancer systems. A variety of particle sizes (20 nm to [Formula: see text]) were found to have hyperpolarized relaxation times ranging from [Formula: see text] to 50 min. The addition of various functional groups to the particle surface had no effect on the hyperpolarization buildup or decay rates and allowed in vivo imaging over long time scales. Additional in vivo studies examined a variety of particle administration routes in mice, including intraperitoneal injection, rectal enema, and oral gavage.

8.
J Nucl Med ; 57(11): 1778-1783, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27283932

RESUMEN

Imaging-based techniques have enabled the direct integration of noninvasive imaging with minimally invasive interventions such as photothermal therapy (PTT) to improve the precision of treatment. METHODS: We investigated the feasibility of PTT for ovarian cancer under the guidance of PET and MR temperature imaging using copper sulfide nanoparticles (CuS NPs). The tumor distribution of the CuS NPs after systemic administration was assessed using highly sensitive, quantifiable PET imaging. Two wavelengths of near-infrared (NIR) lasers-808 and 980 nm-were tested for PTT using noninvasive MR temperature imaging real-time monitoring. RESULTS: The in vivo studies revealed that the 980-nm NIR laser had better photothermal effects than the 808-nm NIR laser. These results were in accord with the histologic findings. In vivo PTT using CuS NPs combined with 980-nm laser irradiation achieved significant tumor ablation compared with no treatment control in both subcutaneous (P = 0.007) and orthotopic (P < 0.001) models of ovarian cancer with regard to the percentage of necrotic damage. CONCLUSION: Our results indicate that real-time monitoring of the accuracy of PTT is a promising approach for future clinical translation of this emerging thermal ablation technique.


Asunto(s)
Terapia por Luz de Baja Intensidad/métodos , Imagen por Resonancia Magnética/métodos , Nanopartículas del Metal , Neoplasias Ováricas/terapia , Tomografía de Emisión de Positrones/métodos , Termografía/métodos , Animales , Línea Celular Tumoral , Cobre , Radioisótopos de Cobre , Femenino , Humanos , Hipertermia Inducida/métodos , Ratones , Ratones Desnudos , Imagen Multimodal/métodos , Neoplasias Ováricas/diagnóstico por imagen , Medicina de Precisión/métodos , Radiofármacos
9.
ACS Nano ; 9(7): 7085-96, 2015 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-26098195

RESUMEN

Translation of nanoparticles (NPs) into clinical practice has been limited by toxic effects induced by nonspecific accumulation of NPs in healthy organs after systemic administration. The ideal NPs should accumulate in the target site, carry out their function, and then ultimately be eliminated from the body. Here, we show a single-compartment, multifunctional ultrasmall copper sulfide nanodot (CuS ND) that is rapidly cleared from the body. These CuS NDs have a hydrodynamic diameter of <6 nm, can efficiently absorb near-infrared light for photothermal ablation therapy, and stably incorporate the copper-64 radioisotope for noninvasive positron emission tomography (PET). Importantly, ∼95% of CuS NDs are excreted intact through the renal-urinary system within 24 h with minimal retention in the liver and the spleen. The ultrasmall CuS NDs accumulate in 4T1 tumors in Balb/c mice, as monitored by PET imaging, and mediate tumor ablation when combined with near-infrared light irradiation. As a first example of PET-visible, renal-clearable inorganic nanomaterials with peak absorption in the near-infrared region, CuS NDs represent a robust platform for cancer imaging and therapy.


Asunto(s)
Radioisótopos de Cobre/farmacocinética , Nanopartículas/efectos adversos , Fototerapia , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Eliminación Renal , Animales , Radioisótopos de Cobre/efectos adversos , Radioisótopos de Cobre/química , Femenino , Células HEK293 , Células Hep G2 , Humanos , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Radiofármacos/efectos adversos , Radiofármacos/química
10.
PLoS One ; 10(6): e0131095, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26098849

RESUMEN

PURPOSE: To assess whether T1 relaxation time of tumors may be used to assess response to bevacizumab anti-angiogenic therapy. PROCEDURES: 12 female nude mice bearing subcutaneous SKOV3ip1-LC ovarian tumors were administered bevacizumab (6.25ug/g, n=6) or PBS (control, n=6) therapy twice a week for two weeks. T1 maps of tumors were generated before, two days, and 2 weeks after initiating therapy. Tumor weight was assessed by MR and at necropsy. Histology for microvessel density, proliferation, and apoptosis was performed. RESULTS: Bevacizumab treatment resulted in tumor growth inhibition (p<0.04, n=6), confirming therapeutic efficacy. Tumor T1 relaxation times increased in bevacizumab treated mice 2 days and 2 weeks after initiating therapy (p<.05, n=6). Microvessel density decreased 59% and cell proliferation (Ki67+) decreased 50% in the bevacizumab treatment group (p<.001, n=6), but not apoptosis. CONCLUSIONS: Findings suggest that increased tumor T1 relaxation time is associated with response to bevacizumab therapy in ovarian cancer model and might serve as an early indicator of response.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Ováricas/terapia , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Imagen por Resonancia Magnética , Ratones , Ratones Desnudos , Microvasos/patología , Neovascularización Patológica/patología , Neovascularización Patológica/terapia , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Adv Drug Deliv Rev ; 87: 108-19, 2015 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-25666164

RESUMEN

The discovery of RNA interference, first in plants and Caenorhabditis elegans and later in mammalian cells, led to the emergence of a transformative view in biomedical research. Knowledge of the multiple actions of non-coding RNAs has truly allowed viewing DNA, RNA and proteins in novel ways. Small interfering RNAs (siRNAs) can be used as tools to study single gene function both in vitro and in vivo and are an attractive new class of therapeutics, especially against undruggable targets for the treatment of cancer and other diseases. Despite the potential of siRNAs in cancer therapy, many challenges remain, including rapid degradation, poor cellular uptake and off-target effects. Rational design strategies, selection algorithms, chemical modifications and nanocarriers offer significant opportunities to overcome these challenges. Here, we review the development of siRNAs as therapeutic agents from early design to clinical trial, with special emphasis on the development of EphA2-targeting siRNAs for ovarian cancer treatment.


Asunto(s)
Neoplasias Ováricas/tratamiento farmacológico , Interferencia de ARN/efectos de los fármacos , ARN Interferente Pequeño/uso terapéutico , Receptor EphA2/genética , Animales , Ensayos Clínicos como Asunto , Portadores de Fármacos/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Marcación de Gen , Humanos , Nanopartículas/química , Neoplasias Ováricas/genética , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/farmacocinética
12.
Curr Oncol Rep ; 16(12): 417, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25325936

RESUMEN

Being diagnosed with a life-threatening disease such as cancer and undergoing treatment can cause unwanted distress and interferes with quality of life. Uncontrolled stress can have a negative effect on a number of biological systems and processes leading to negative health outcomes. While some distress is normal, it is not benign and must be addressed, as failure to do so may compromise health and QOL outcomes. We present the evidence for the role of stress in cancer biology and mechanisms demonstrating how distress is associated with worse clinical outcomes. The National Comprehensive Cancer Network states that all patients be screened with the single-item distress thermometer and to also indicate the source of distress and to get appropriate referral. In addition to the many conventional approaches for managing distress from the fields of psychology and psychiatry, many patients are seeking strategies to manage their distress that are outside conventional medicine such as mind-body techniques. Mind-body techniques such as meditation, yoga, tai chi, and qigong have been found to lower distress and lead to improvements in different aspects of quality of life. It is essential that the standard of care in oncology include distress screening and the delivery of different techniques to help patients manage the psychosocial challenges of diagnosis and treatment of cancer.


Asunto(s)
Meditación , Neoplasias/psicología , Qigong , Calidad de Vida , Estrés Psicológico/terapia , Taichi Chuan , Yoga , Adaptación Psicológica , Medicina Basada en la Evidencia , Humanos , Estrés Psicológico/etiología , Resultado del Tratamiento
13.
Indian J Exp Biol ; 52(8): 825-34, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25141547

RESUMEN

Dendrocalamus hamiltonii plants are slender and tall (15-25 m) thereby, rendering tagging, sampling and tracking the development of flowers difficult. Therefore, a reproducible system of in vitro flowering was established for tracking the stages of flower development. MS medium supplemented with 2.22 microM 6-benzylaminopurine, 1.23 microM indole-3-butyric acid and 2% sucrose was optimized as the flower induction medium (FIM) wherein 28 and 42 days were required for the development of gynoecium and androecium, respectively. Six distinct stages of in vitro flower development were identified, and the flowers were comparable with that of in planta sporadic flowers. Pollen viability of the in vitro flowers was higher than those of in planta ones. The in vitro system developed in the present study facilitates easy tracking of different stages of flower development under controlled environmental conditions. It can also be used for medium- or long-term storage of pollens and manipulation of in vitro fertilization.


Asunto(s)
Flores/crecimiento & desarrollo , Polen/efectos de los fármacos , Reproducción/efectos de los fármacos , Compuestos de Bencilo/farmacología , Flores/efectos de los fármacos , Técnicas In Vitro , Indoles/farmacología , Magnoliopsida/efectos de los fármacos , Magnoliopsida/crecimiento & desarrollo , Purinas/farmacología , Sacarosa/química
14.
Mol Syst Biol ; 10: 728, 2014 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-24799285

RESUMEN

Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine-addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low-invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high-invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients' microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high-invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low-invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.


Asunto(s)
Proliferación Celular , Metabolismo Energético/genética , Glutamina/metabolismo , Neoplasias Ováricas/metabolismo , Ciclo Celular/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Pronóstico , Transducción de Señal/genética
15.
Cancer Biol Ther ; 15(7): 919-29, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24755674

RESUMEN

This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAK(Y397) were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P<0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P<0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P<0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Indoles/uso terapéutico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Sulfonamidas/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Animales , Carcinoma Epitelial de Ovario , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Dosificación de Gen , Humanos , Indoles/farmacología , Ratones Desnudos , Metástasis de la Neoplasia , Neoplasias Glandulares y Epiteliales/irrigación sanguínea , Neoplasias Glandulares y Epiteliales/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/patología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Sulfonamidas/farmacología , Tirosina/metabolismo
16.
PLoS One ; 8(11): e79167, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24236104

RESUMEN

BACKGROUND: Epithelial ovarian cancer is the leading cause of gynecologic cancer deaths. Most patients respond initially to platinum-based chemotherapy after surgical debulking, however relapse is very common and ultimately platinum resistance emerges. Understanding the mechanism of tumor growth, metastasis and drug resistant relapse will profoundly impact the therapeutic management of ovarian cancer. METHODS/PRINCIPAL FINDINGS: Using patient tissue microarray (TMA), in vitro and in vivo studies we report a role of of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme in ovarian carcinoma. We report here that the expression of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme, is common in primary serous ovarian carcinoma. The in vitro effects of CBS silencing can be reversed by exogenous supplementation with the GSH and H2S producing chemical Na2S. Silencing CBS in a cisplatin resistant orthotopic model in vivo by nanoliposomal delivery of CBS siRNA inhibits tumor growth, reduces nodule formation and sensitizes ovarian cancer cells to cisplatin. The effects were further corroborated by immunohistochemistry that demonstrates a reduction of H&E, Ki-67 and CD31 positive cells in si-RNA treated as compared to scrambled-RNA treated animals. Furthermore, CBS also regulates bioenergetics of ovarian cancer cells by regulating mitochondrial ROS production, oxygen consumption and ATP generation. This study reports an important role of CBS in promoting ovarian tumor growth and maintaining drug resistant phenotype by controlling cellular redox behavior and regulating mitochondrial bioenergetics. CONCLUSION: The present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer.


Asunto(s)
Cistationina betasintasa/metabolismo , Resistencia a Antineoplásicos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Adenosina Trifosfato/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antioxidantes/metabolismo , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Cistationina betasintasa/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Inmunohistoquímica , Ratones , Persona de Mediana Edad , Mitocondrias/metabolismo , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Ováricas/genética , Fenotipo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Adulto Joven
17.
Indian J Exp Biol ; 51(1): 88-96, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23441484

RESUMEN

An in vitro propagation protocol using mature seeds of D. membranaceus was successfully established. Scarcity of seeds in bamboos because of their long flowering periods and irregular seed set resulting in low viability and germination potential, motivated us to undertake the present study. The effects of sterilants, light conditions, exogenous application of plant growth regulators and temperature in overcoming germination barriers in ageing seeds of bamboo were studied. It was found that HgCl2 (0.1%) along with bleach (15%) was more effective in raising aseptic cultures. Dark conditions, high temperatures around 30 degrees C and soaking of seeds in GA3 solution (50 ppm) overnight stimulated high percent of seed germination with corresponding increase in shoot length (2.7 +/- 0.7 mm) and number of sprouts (2.1 +/- 0.7) per explants during culture initiation. 6-benzylaminopurine acted synergistically with kinetin to give optimum germination rate of 70 +/- 13.9% as compared to 63.13% when used individually. For prolonged maintenance of cultures, 2% sucrose was found to be suitable for promoting photomixotrophic micropropagation. Following this procedure, about 65% survival of plantlets could be achieved during hardening. Biochemically seeds consume starchy endosperm for emergence of radicle which is taken as a sign of germination as also evident from the present study. Loss of viability and vigour after a year was confirmed by Tetrazolium chloride test. Micropropagation protocol developed here will ensure regeneration of large number of plants in a relatively short time. Conclusively, in vitro propagation protocol developed in D. membranaceus using mature seeds as an explants is reported for the first time.


Asunto(s)
Sasa/metabolismo , Semillas/metabolismo , Endospermo/metabolismo , Germinación , Giberelinas/metabolismo , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Cinetina/química , Luz , Fenotipo , Extractos Vegetales/farmacología , Hojas de la Planta/metabolismo , Fenómenos Fisiológicos de las Plantas , Temperatura , Sales de Tetrazolio/farmacología , Factores de Tiempo
18.
Cancer Res ; 72(18): 4777-86, 2012 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-22865457

RESUMEN

Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light-generated heat to destroy tumor cells. However, complete tumor eradication by PTA therapy alone is difficult because heterogeneous heat distribution can lead to sublethal thermal dose in some areas of the tumor. Successful PTA therapy requires selective delivery of photothermal conducting nanoparticles to mediate effective PTA of tumor cells, and the ability to combine PTA with other therapy modalities. Here, we synthesized multifunctional doxorubicin (DOX)-loaded hollow gold nanospheres (DOX@HAuNS) that target EphB4, a member of the Eph family of receptor tyrosine kinases overexpressed on the cell membrane of multiple tumors and angiogenic blood vessels. Increased uptake of targeted nanoparticles T-DOX@HAuNS was observed in three EphB4-positive tumors both in vitro and in vivo. In vivo release of DOX from DOX@HAuNS, triggered by NIR laser, was confirmed by dual-radiotracer technique. Treatment with T-DOX@HAuNS followed by NIR laser irradiation resulted in significantly decreased tumor growth when compared with treatments with nontargeted DOX@HAuNS plus laser or HAuNS plus laser. The tumors in 6 of the 8 mice treated with T-DOX@HAuNS plus laser regressed completely with only residual scar tissue by 22 days following injection, and none of the treatment groups experienced a loss in body weight. Together, our findings show that concerted chemo-photothermal therapy with a single nanodevice capable of mediating simultaneous PTA and local drug release may have promise as a new anticancer therapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Terapia por Luz de Baja Intensidad/métodos , Nanosferas , Neoplasias Experimentales/tratamiento farmacológico , Receptor EphB4/metabolismo , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/efectos adversos , Portadores de Fármacos/farmacocinética , Femenino , Oro , Rayos Infrarrojos , Ratones , Nanosferas/química , Nanosferas/uso terapéutico , Neoplasias Experimentales/metabolismo , Tomografía Computarizada de Emisión de Fotón Único
19.
J Control Release ; 158(2): 319-28, 2012 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-22063003

RESUMEN

Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light-generated heat to destroy tumor cells. However, complete eradication of tumor cells with PTA is difficult because of uneven heat distribution in the treatment volume. We hypothesized that combining PTA with chemotherapy using a single multifunctional nanoconstruct that mediates simultaneous photothermal cell killing and drug release (photothermal-chemotherapy) would result in enhanced antitumor activity and reduced toxicity compared to chemotherapy alone. Doxorubicin (DOX) was loaded to hollow gold nanospheres (HAuNS) coated with polyethylene glycol (PEG). The pharmacokinetics and biodistribution of both DOX and HAuNS in the resulting nanoconstruct, DOX@PEG-HAuNS having different DOX:PEG:HAuNS ratios, were evaluated using dual isotope labeling techniques. The antitumor activity of DOX@PEG-HAuNS with DOX:PEG:HAuNS weight ratio of 1:3:1 (NP3) in combination with NIR laser was studied in vitro and in vivo using human MDA-MB-231 breast cancer and A2780 ovarian cancer cells. In vitro, NP3 mediated PTA of both cancer cells and DOX release upon NIR laser treatment. In vivo, NP3 showed slower clearance in blood and greater accumulation in tumors than free DOX. NP3-plus-NIR laser demonstrated greater antitumor activity than free DOX, NP3, or liposomal DOX. Moreover, NP3 displayed significantly decreased systemic toxicity compared to free DOX or liposomal DOX. Enhanced antitumor effect with NP3-plus-laser can be attributed to both the cytotoxic effect of DOX released from NP3 and the photothermal effect mediated by HAuNS. Slow release of DOX from NP3 in normal tissues contributed to reduced systemic toxicity. Photothermal-chemotherapy exemplified by a single-agent nanoconstruct NP3 is a promising approach to anticancer therapy.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Oro/administración & dosificación , Nanosferas/administración & dosificación , Neoplasias/terapia , Animales , Antibióticos Antineoplásicos/farmacocinética , Línea Celular Tumoral , Doxorrubicina/farmacocinética , Portadores de Fármacos/farmacocinética , Femenino , Oro/farmacocinética , Humanos , Hipertermia Inducida , Rayos Láser , Ratones , Ratones Desnudos , Neoplasias/patología , Fototerapia , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
20.
J Nanosci Nanotechnol ; 11(5): 4153-7, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21780419

RESUMEN

The cytotoxic enhancement of cisplatin by magnetic fluid hyperthermia (MFH) was investigated in human colon adenocarcinoma cells (Caco-2). A nanoparticle platform based on iron oxide functionalized with carboxymethyl dextran was employed to produce heat at the nanoscale. To assess the synergistic effect of hyperthermia and the anticancer drug cis-Diamminedichloroplatinum, commonly known as cisplatin (CIS), cell viability was measured 24, 48, and 72 hours after three different combined hyperthermia and CIS exposure sequences. These included CIS incubation prior to hyperthermia or magnetic fluid hyperthermia, CIS exposure only during hyperthermia or MFH, and additional CIS incubation following hyperthermia or MFH. Additional incubation of CIS after hyperthermia treatment appears to be more effective than prior CIS incubation for both hyperthermia treatments. Viability data also indicated that MFH combined with CIS is significantly more effective than hot water hyperthermia at the same temperature. A CIS concentration an order of magnitude lower than the calculated IC50 was found to be very effective in reducing cell viability. Such dramatic differences suggest that MFH may enhance the passive transport of CIS.


Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Hipertermia Inducida , Magnetismo , Nanopartículas , Células CACO-2 , Humanos
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