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1.
Sci Rep ; 10(1): 8542, 2020 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-32444831

RESUMEN

Humanin (HN) is a mitochondrial-derived peptide with cytoprotective effect in many tissues. Administration of HN analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the effect of HN on the progression of experimental triple negative breast cancer (TNBC). The meta-analysis of transcriptomic data from The Cancer Genome Atlas indicated that HN and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of HN in TNBC biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous HN protected TNBC cells from apoptotic stimuli whereas shRNA-mediated HN silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic effect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These findings suggest that HN may exert pro-tumoral effects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias de la Mama Triple Negativas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/cirugía , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven
2.
NOVA publ. cient ; 17(32): 9-24, jul.-dic. 2019.
Artículo en Español | LILACS-Express | LILACS | ID: biblio-1056786

RESUMEN

Resumen La humanina es un péptido derivado de la mitocondria con efectos protectores robustos contra una gran variedad de estímulos citotóxicos en diversos tipos celulares. Esto la convierte en un blanco terapéutico interesante para muchas enfermedades, como el cáncer y enfermedades neurodegenerativas, entre otras. Además, este péptido podría utilizarse como un biomarcador en estas enfermedades. Durante la última década, han sido desarrollados análogos y péptido-miméticos de la humanina que muestran resultados prometedores en modelos preclínicos. A su vez, también se está explorando el potencial terapéutico de vectores de terapia génica que puedan sobreexpresar o silenciar la humanina endógena. Varios puntos importantes a considerar antes de trasladar estas estrategias terapéuticas a la clínica son su posible papel en la progresión del cáncer y la eventual generación de quimiorresistencia. Todos estos temas serán abordados en este artículo de revisión.


Abstract Humanin is a mitochondrial-derived peptide which shows robust protective effects against large series of cytotoxic stimuli in many cell types. This makes it an interesting therapeutic target for many diseases, including cancer and neurodegenerative diseases, among others. Furthermore, this peptide could be used as a biomarker for such diseases. Over the last decade, humanin analogs and peptide mimetics have been developed, which exert highly promising results in preclinical models. Besides, the therapeutic potential of gene therapy vectors that overexpress or silence endogenous humanin is under evaluation. Nonetheless, its possible role in cancer progression and chemoresistance are critical issues to be addressed before translating these therapeutic approaches to the clinic. All these matters will be covered in this review.

3.
Immunology ; 157(3): 198-209, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30866047

RESUMEN

Overcoming the immunosuppressive tumour microenvironment is the major challenge impeding cancer immunotherapy today. Regulatory T-cells (Tregs) are prevalent in nearly all cancers and, as immunosuppressive regulators of immune responses, they are the principal opponents of cancer immunotherapy. However, disabling Tregs systemically causes severe autoimmune toxicity, hastening the need for more selective methods to target intratumoural Tregs. In this review, we discuss a burgeoning new modality to specifically target tumour-infiltrating Tregs (TI-Tregs) by reprogramming their functionality from immunosuppressive to immune stimulatory within tumours. As the basis for therapeutic selectivity of TI-Tregs, we will focus on the defining features of Tregs within cancer: their highly activated state controlled by the engagement of key surface receptors, their distinct metabolic programme, and their unique transcriptional programme. By identifying proteins and pathways that distinguish TI-Tregs from other Tregs in the body, as well as from the beneficial antitumour effector T-cells within tumours, we highlight mechanisms to selectively reprogramme TI-Tregs for the treatment of cancer.


Asunto(s)
Inmunoterapia , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/terapia , Linfocitos T Reguladores/inmunología , Escape del Tumor , Diferenciación Celular , Metabolismo Energético , Humanos , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Fenotipo , Transducción de Señal , Linfocitos T Reguladores/metabolismo , Microambiente Tumoral
4.
PLoS One ; 14(3): e0212911, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30822345

RESUMEN

In recent years a non-neuronal cholinergic system has been described in immune cells, which is often usually activated during the course of inflammatory processes. To date, it is known that Acetylcholine (ACh), a neurotransmitter extensively expressed in the airways, not only induces bronchoconstriction, but also promotes a set of changes usually associated with the induction of allergic/Th2 responses. We have previously demonstrated that ACh polarizes human dendritic cells (DC) toward a Th2-promoting profile through the activation of muscarinic acetylcholine receptors (mAChR). Here, we showed that ACh promotes the acquisition of an inflammatory profile by murine DC, with the increased MHC II IAd expression and production of two cytokines strongly associated with inflammatory infiltrate and tissue damage, namely TNF-α and MCP-1, which was prevented by blocking mAChR. Moreover, we showed that ACh induces the up-regulation of M3 mAChR expression and the blocking of this receptor with tiotropium bromide prevents the increase of MHC II IAd expression and TNF-α production induced by ACh on DC, suggesting that M3 is the main receptor involved in ACh-induced activation of DC. Then, using a short-term experimental murine model of ovalbumin-induced lung inflammation, we revealed that the intranasal administration of ACh-treated DC, at early stages of the inflammatory response, might be able to exacerbate the recruitment of inflammatory mononuclear cells, promoting profound structural changes in the lung parenchyma characteristic of chronic inflammation and evidenced by elevated systemic levels of inflammatory marker, TNF-α. These results suggest a potential role for ACh in the modulation of immune mechanisms underlying pulmonary inflammatory processes.


Asunto(s)
Acetilcolina/metabolismo , Células Dendríticas/inmunología , Lesión Pulmonar/inmunología , Animales , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/trasplante , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Pulmón/citología , Pulmón/inmunología , Pulmón/patología , Lesión Pulmonar/sangre , Lesión Pulmonar/diagnóstico , Ratones , Ovalbúmina/inmunología , Cultivo Primario de Células , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunología
5.
Expert Opin Ther Targets ; 23(2): 117-126, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30582721

RESUMEN

INTRODUCTION: Mitochondrial-derived peptides (MDPs) are encoded within the mitochondrial genome. They signal within the cell or are released to act as autocrine/paracrine/endocrine cytoprotective factors playing a key role in the cellular stress response. The first reported and better characterized MDP is humanin (HN), which exerts robust protective effects against a myriad of cytotoxic stimuli in many cell types. These effects have led to the evaluation of HN and its analogs as therapeutic targets for several chronic diseases. Areas covered: We describe the latest findings on the mechanism of action of HN and discuss the role of HN as therapeutic target for neurodegenerative and cardiovascular diseases, diabetes, male infertility, and cancer. Since HN can be detected in circulation, we also depict its value as a biomarker for these diseases. Expert opinion: HN analogs and peptide mimetics have been developed over the last decade and show promising results in preclinical models of degenerative diseases. Local administration of gene therapy vectors that overexpress or silence endogenous HN could also hold therapeutic potential. Controversy on the role of HN in cancer progression and chemoresistance should be addressed before the translation of these therapeutic approaches.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Terapia Molecular Dirigida , Neoplasias/terapia , Animales , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/terapia , Modelos Animales de Enfermedad , Terapia Genética/métodos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Mitocondrias/metabolismo , Neoplasias/patología , Enfermedades Neurodegenerativas/fisiopatología , Enfermedades Neurodegenerativas/terapia
6.
Breast Cancer Res Treat ; 166(2): 393-405, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28756536

RESUMEN

PURPOSE: Regulatory T cells (Tregs) impair the clinical benefit of cancer immunotherapy. To optimize the antitumor efficacy of therapeutic dendritic cell (DC) vaccines, we aimed to inhibit Foxp3, a transcription factor required for Treg function. METHODS: Mice bearing established syngeneic LM3 and 4T1 breast tumors were treated with antitumor DC vaccines and a synthetic peptide (P60) that has been shown to inhibit Foxp3. RESULTS: Treatment with P60 improved the therapeutic efficacy of DC vaccines in these experimental models. In addition, monotherapy with P60 inhibited tumor growth in immunocompetent as well as in immuno-compromised animals bearing established tumors. We found expression of Foxp3 in human and murine breast tumor cells. P60 inhibited IL-10 secretion in breast cancer cells that expressed Foxp3. CONCLUSIONS: Our results suggest that Foxp3 blockade improves the therapeutic efficacy of DC vaccines by inhibition of Tregs and through a direct antitumor effect. This strategy could prove useful to neutralize the immunosuppressive microenvironment and to boost antitumor immunity in breast cancer.


Asunto(s)
Neoplasias de la Mama/terapia , Péptidos de Penetración Celular/administración & dosificación , Células Dendríticas/trasplante , Factores de Transcripción Forkhead/antagonistas & inhibidores , Linfocitos T Reguladores/efectos de los fármacos , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/farmacología , Línea Celular Tumoral , Péptidos de Penetración Celular/farmacología , Células Dendríticas/inmunología , Femenino , Humanos , Inmunoterapia , Ratones , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Expert Opin Biol Ther ; 17(8): 945-959, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28604109

RESUMEN

INTRODUCTION: Breast cancer is the most common cancer in women all over the world. Furthermore, up to one third of breast tumors develop metastases that are resistant to standard therapies. Gene therapeutic strategies have been developed in order to specifically target cancer cells either directly or through the stimulation of antitumor immunity. Areas covered: This review describes the therapeutic strategies that are currently under development to treat this disease using engineered viral vectors including: adenovirus, adeno-associated virus, lentivirus, poxvirus, reovirus, baculovirus, herpesvirus and oncolytic viruses. Advantages and disadvantages of these multiple gene therapy platforms are discussed in detail. Expert opinion: Metastatic breast cancer is a perfect candidate for gene therapy approaches due to the presence of several tumor antigens and the aberrant expression of many molecular pathways. Oncolytic vectors are able to attack tumor cells while sparing normal cells and their activity is often enhanced by the administration of chemotherapy. However, more efforts are needed in order to reduce toxicity and to achieve better transduction efficiency. Improved preclinical models and a more critical patient selection for clinical trials, along with advances in gene therapy regulations, will surely facilitate the evolution of gene therapy for the treatment of metastatic breast cancer.


Asunto(s)
Neoplasias de la Mama/terapia , Viroterapia Oncolítica , Adenoviridae/genética , Femenino , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Humanos , Lentivirus/genética , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/virología , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/virología , Virus Oncolíticos/genética , Poxviridae/genética
8.
J Cell Commun Signal ; 11(4): 329-340, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28378125

RESUMEN

Humanin (HN) and Rattin (HNr), its homologous in the rat, are peptides with cytoprotective action in several cell types such as neurons, lymphocytes and testicular germ cells. Previously, we have shown that HNr is expressed in pituitary cells and that HN inhibited the apoptotic effect of TNF-α in both normal and tumor pituitary cells. The aim of the present study was to identify signaling pathways that mediate the antiapoptotic effect of HN in anterior pituitary cells from ovariectomized rats and in GH3 cells, a somatolactotrope cell line. We assessed the role of STAT3, JNK, Akt and MAPKs as well as proteins of the Bcl-2 family, previously implicated in the antiapoptotic effect of HN. We also evaluated the participation of NF-κB in the antiapoptotic action of HN. STAT3 inhibition reversed the inhibitory effect of HN on TNF-α-induced apoptosis in normal and pituitary tumor cells, indicating that STAT3 signaling pathway mediates the antiapoptotic effect of HN on pituitary cells. Inhibition of NF-κB pathway did not affect action of HN on normal anterior pituitary cells but blocked the cytoprotective effect of HN on TNF-α-induced apoptosis of GH3 cells, suggesting that the NF-κB pathway is involved in HN action in tumor pituitary cells. HN also induced NF-κB-p65 nuclear translocation in these cells. In pituitary tumor cells, JNK and MEK inhibitors also impaired HN cytoprotective action. In addition, HN increased Bcl-2 expression and decreased Bax mitochondrial translocation. Since HN expression in GH3 cells is higher than in normal pituitary cells, we may suggest that through multiple pathways HN could be involved in pituitary tumorigenesis.

9.
J Cancer Res Clin Oncol ; 143(9): 1713-1732, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28432455

RESUMEN

PURPOSE: Since combination of Toll-like receptor (TLR) ligands could boost antitumor immunity, we evaluated the efficacy of dendritic cell (DC) vaccines upon dual activation of TLR9 and TLR7 in breast cancer models. METHODS: DCs were generated from mouse bone marrow or peripheral blood from healthy human donors and stimulated with CpG1826 (mouse TLR9 agonist), CpG2006 or IMT504 (human TLR9 agonists) and R848 (TLR7 agonist). Efficacy of antitumor vaccines was evaluated in BALB/c mice bearing metastatic mammary adenocarcinomas. RESULTS: CpG-DCs improved the survival of tumor-bearing mice, reduced the development of lung metastases and generated immunological memory. However, dual activation of TLRs impaired the efficacy of DC vaccines. In vitro, we found that R848 inhibited CpG-mediated maturation of murine DCs. A positive feedback loop in TLR9 mRNA expression was observed upon CpG stimulation that was inhibited in the presence of R848. Impaired activation of NF-κB was detected when TLR9 and TLR7 were simultaneously activated. Blockade of nitric oxide synthase (NOS) and indoleamine-pyrrole-2,3-dioxygenase (IDO) improved the activation of CpG-DCs. When we evaluated the effect of combined activation of TLR9 and TLR7 in human DCs, we found that R848 induced robust DC activation that was inhibited by TLR9 agonists. CONCLUSIONS: These observations provide insight in the biology of TLR9 and TLR7 crosstalk and suggest caution in the selection of agonists for multiple TLR stimulation. Blockade of NOS and IDO could improve the maturation of antitumor DC vaccines. R848 could prove a useful adjuvant for DC vaccines in human patients.


Asunto(s)
Adenocarcinoma/terapia , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/inmunología , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 9/agonistas , Adyuvantes Inmunológicos/farmacología , Animales , Vacunas contra el Cáncer/farmacología , Células Dendríticas/inmunología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
10.
Expert Opin Biol Ther ; 17(7): 797-812, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28446053

RESUMEN

INTRODUCTION: Breast cancer is the most common cancer as well as the first cause of death by cancer in women worldwide. Although routine treatment improves the outcome of early stage breast cancer patients, there is no effective therapy for the disseminated disease. Immunotherapy has emerged as a powerful therapeutic strategy for the treatment of many cancers. Although traditionally conceived as a non-immunogenic tumor, breast cancer is now considered a potential target for immunotherapy. Areas covered: In this review, the authors discuss different immunotherapeutic strategies that are currently being tested for the treatment of breast cancer: These strategies include: (i) blockade of immunological checkpoints, (ii) antitumor vaccines, (iii) regulatory T cell blockade, (iv) adoptive T cell transfer therapy, (iv) adoptive immunotherapy with monoclonal antibodies, and (v) combination of immunotherapy with chemotherapy. Expert opinion: A growing body of evidence indicates that immunotherapeutic strategies can benefit a larger cohort of breast cancer patients than hitherto anticipated. Since breast tumors entail multiple mechanisms to impair antitumor immunity, the immunological characterization of individual tumors and the selection of suitable combinations of chemotherapeutic and immunotherapeutic approaches are required to achieve significant clinical benefit in these patients.


Asunto(s)
Neoplasias de la Mama/terapia , Inmunoterapia , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Terapia Combinada , Femenino , Humanos , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
11.
Mol Ther ; 25(1): 232-248, 2017 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-28129117

RESUMEN

Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.


Asunto(s)
Terapia Genética , Glioma/genética , Glioma/inmunología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Animales , Antígeno B7-H1/metabolismo , Biomarcadores , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Antígeno CTLA-4/metabolismo , Células Cultivadas , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Femenino , Expresión Génica , Terapia Genética/métodos , Glioma/patología , Glioma/terapia , Humanos , Inmunofenotipificación , Inmunoterapia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timidina Quinasa/genética , Timidina Quinasa/metabolismo , Transgenes
12.
Parasitol Res ; 115(2): 779-85, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26526953

RESUMEN

The inflammatory response in the myocardium is an important aspect of the pathogenesis of Chagas' heart disease raised by Trypanosoma cruzi. CD40, a transmembrane type I receptor belonging to the tumor necrosis factor receptor (TNFR) family, is expressed in a broad spectrum of cell types and is crucial in several inflammatory and autoimmune diseases. Activation of CD40 through ligation to CD40L (CD154) induces multiple effects, including the secretion of proinflammatory molecules. In the present study, we examined the ability of T. cruzi to trigger the expression of CD40 in cardiac myocytes in vitro and in a murine model of chagasic cardiomyopathy. Our results indicate, for the first time, that T. cruzi is able to induce the expression of CD40 in HL-1 murine cardiomyocytes. Moreover, ligation of CD40 receptor upregulated interleukin-6 (IL-6), associated with inflammation. Furthermore, the induction of this costimulatory molecule was demonstrated in vivo in myocardium of mice infected with T. cruzi. This suggests that CD40-bearing cardiac muscle cells could interact with CD40L-expressing lymphocytes infiltrating the heart, thus contributing to inflammatory injury in chagasic cardiomyopathy.


Asunto(s)
Antígenos CD40/metabolismo , Cardiomiopatía Chagásica/parasitología , Interleucina-6/metabolismo , Miocitos Cardíacos/inmunología , Trypanosoma cruzi/fisiología , Animales , Antígenos CD40/genética , Células Cultivadas , Cardiomiopatía Chagásica/patología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Interferón gamma/farmacología , Ratones , Ratones Endogámicos C3H , Miocardio/patología , Miocitos Cardíacos/parasitología , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Trypanosoma cruzi/inmunología
13.
Methods Mol Biol ; 1382: 467-82, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26611605

RESUMEN

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a median survival of 16.2-21.2 months post diagnosis (Stupp et al., N Engl J Med 352(10): 987-996, 2005). Because of its location, complete surgical resection is impossible; additionally because GBM is also resistant to chemotherapeutic and radiotherapy approaches, development of novel therapies is urgently needed. In this chapter we describe the development of preclinical animal models and a conditionally cytotoxic and immune-stimulatory gene therapy strategy that successfully causes tumor regression in several rodent GBM models.


Asunto(s)
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Animales , Línea Celular Tumoral , Terapia Genética , Humanos , Ratones , Neoplasias Experimentales , Ratas
14.
Endocrine ; 51(3): 506-16, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26296379

RESUMEN

Hormones locally synthesized in the anterior pituitary gland are involved in regulation of pituitary cell renewal. In the pituitary, testosterone (T) may exert its actions per se or by conversion to dihydrotestosterone (DHT) or 17ß-estradiol (E2) by 5α-reductase and aromatase activity, which are expressed in this gland. Previous reports from our laboratory showed that estrogens modulate apoptosis of lactotropes and somatotropes from female rats. Now, we examined the in vitro and in vivo effects of gonadal steroids on apoptosis of anterior pituitary cells from adult male rats. T in vitro did not modify apoptosis in anterior pituitary cells from gonadectomized (GNX) male rats. DHT, a non-aromatizable androgen, exerted direct antiapoptotic action on total anterior pituitary cells and folliculo-stellate cells, but not on lactotropes, somatotropes, or gonadotropes. On the contrary, E2 exerted a rapid apoptotic effect on total cells as well as on lactotropes and somatotropes. Incubation of anterior pituitary cells with T in presence of Finasteride, an inhibitor of 5α-reductase, increased the percentage of TUNEL-positive cells. In vivo administration of DHT to GNX rats reduced apoptosis in the anterior pituitary whereas E2 exerted proapoptotic action and reduced cells in G2/M-phase of the cell cycle. In summary, our results indicate that DHT and E2 have opposite effects on apoptosis in the anterior pituitary gland suggesting that local metabolization of T to these steroids could be involved in pituitary cell turnover in males. Changes in expression and/or activity of 5α-reductase and aromatase may play a role in the development of anterior pituitary tumors.


Asunto(s)
Andrógenos/farmacología , Apoptosis/efectos de los fármacos , Dihidrotestosterona/farmacología , Estradiol/farmacología , Estrógenos/farmacología , Adenohipófisis/efectos de los fármacos , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/biosíntesis , Aromatasa/metabolismo , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Finasterida/farmacología , Masculino , Orquiectomía , Ratas , Ratas Wistar , Testosterona/farmacología
16.
PLoS One ; 9(10): e111548, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25360890

RESUMEN

Humanin (HN) is a 24-amino acid peptide with cytoprotective action in several cell types such as neurons and testicular germ cells. Rattin (HNr), a homologous peptide of HN expressed in several adult rat tissues, also has antiapoptotic action. In the present work, we demonstrated by immunocytochemical analysis and flow cytometry the expression of HNr in the anterior pituitary of female and male adult rats as well as in pituitary tumor GH3 cells. HNr was localized in lactotropes and somatotropes. The expression of HNr was lower in females than in males, and was inhibited by estrogens in pituitary cells from both ovariectomized female and orquidectomized male rats. However, the expression of HNr in pituitary tumor cells was not regulated by estrogens. We also evaluated HN action on the proapoptotic effect of TNF-α in anterior pituitary cells assessed by the TUNEL method. HN (0.5 µM) per se did not modify basal apoptosis of anterior pituitary cells but completely blocked the proapoptotic effect of TNF-α in total anterior pituitary cells, lactotropes and somatotropes from both female and male rats [corrected]. Also, HN inhibited the apoptotic effect of TNF-α on pituitary tumor cells. In summary, our results demonstrate that HNr is present in the anterior pituitary gland, its expression showing sexual dimorphism, which suggests that gonadal steroids may be involved in the regulation of HNr expression in this gland. Antiapoptotic action of HN in anterior pituitary cells suggests that this peptide could be involved in the homeostasis of this gland. HNr is present and functional in GH3 cells, but it lacks regulation by estrogens, suggesting that HN could participate in the pathogenesis of pituitary tumors.


Asunto(s)
Apoptosis/efectos de los fármacos , Citoprotección/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Hipófisis/metabolismo , Neoplasias Hipofisarias/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Línea Celular Tumoral , Estradiol/farmacología , Estrógenos/farmacología , Femenino , Masculino , Orquiectomía , Ovariectomía , Hipófisis/efectos de los fármacos , Hipófisis/patología , Adenohipófisis/efectos de los fármacos , Adenohipófisis/metabolismo , Adenohipófisis/patología , Neoplasias Hipofisarias/patología , Proteínas/metabolismo , Ratas Wistar
17.
Expert Opin Biol Ther ; 14(9): 1241-57, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24773178

RESUMEN

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and it carries a dismal prognosis. Adenoviral vector (Ad)-mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates' brain. Importantly, Ads have been safely administered within the tumor resection cavity in humans. AREAS COVERED: This review gives background on GBM and Ads; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally, we discuss the results of the human clinical trials for GBM that have used Ads. EXPERT OPINION: The transduction characteristics of Ads, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases encourage the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although, it is the large randomized Phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM.


Asunto(s)
Adenoviridae , Neoplasias Encefálicas/terapia , Terapia Genética/métodos , Vectores Genéticos , Glioma/terapia , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Glioblastoma/terapia , Humanos , Inmunomodulación/genética , Transgenes
18.
Medisan ; 14(3)mar.-abr. 2010. tab, graf
Artículo en Español | CUMED | ID: cum-43146

RESUMEN

Se efectuó un estudio prospectivo y longitudinal de 77 pacientes con enfermedad renal crónica dependientes de hemodiálisis, atendidos en el Servicio de Nefrología del Hospital General Docente Dr Juan Bruno Zayas Alfonso de Santiago de Cuba desde octubre de 2007 hasta abril de 2008, a fin de evaluar su estado nutricional según el método de Chang y brindar soporte nutricional con suplementos de producción nacional (nutrial 1-2) y ADN hiperproteico. Los resultados evidenciaron una mejoría en el índice de riesgo nutricional y se modificaron los parámetros antropométricos e inmunológicos, lo cual posibilitó que se incrementara la calidad de vida de los integrantes de la serie(AU)


A prospective and longitudinal study was carried out in 77 patients with renal chronic disease dependent on hemodialysis, attended in the Nephrology Service of Dr Juan Bruno Zayas Alfonso Teaching General Hospital of Santiago de Cuba, from October, 2007 to April, 2008, in order to evaluate their nutritional state according to Chang's method and to provide nutritional support with national production supplements (nutrial 1-2) and hyperproteic DNA. Results showed an improvement in nutritional risk index and immunologic and anthropometric parameters were modified, contributing to the increase of the life quality in patients of the series(AU)


Asunto(s)
Humanos , Masculino , Femenino , Diálisis Renal , Evaluación Nutricional , Estado Nutricional , Calidad de Vida , Insuficiencia Renal Crónica , Desnutrición , Atención Secundaria de Salud , Estudios Prospectivos , Estudios Longitudinales
19.
Medisan ; 14(3)mar.-abr. 2010. tab, graf
Artículo en Español | LILACS | ID: lil-576591

RESUMEN

Se efectuó un estudio prospectivo y longitudinal de 77 pacientes con enfermedad renal crónica dependientes de hemodiálisis, atendidos en el Servicio de Nefrología del Hospital General Docente Dr Juan Bruno Zayas Alfonso de Santiago de Cuba desde octubre de 2007 hasta abril de 2008, a fin de evaluar su estado nutricional según el método de Chang y brindar soporte nutricional con suplementos de producción nacional (nutrial 1-2) y ADN hiperproteico. Los resultados evidenciaron una mejoría en el índice de riesgo nutricional y se modificaron los parámetros antropométricos e inmunológicos, lo cual posibilitó que se incrementara la calidad de vida de los integrantes de la serie.


A prospective and longitudinal study was carried out in 77 patients with renal chronic disease dependent on hemodialysis, attended in the Nephrology Service of Dr Juan Bruno Zayas Alfonso Teaching General Hospital of Santiago de Cuba, from October, 2007 to April, 2008, in order to evaluate their nutritional state according to Chang's method and to provide nutritional support with national production supplements (nutrial 1-2) and hyperproteic DNA. Results showed an improvement in nutritional risk index and immunologic and anthropometric parameters were modified, contributing to the increase of the life quality in patients of the series.


Asunto(s)
Humanos , Masculino , Femenino , Desnutrición , Evaluación Nutricional , Estado Nutricional , Calidad de Vida , Diálisis Renal , Insuficiencia Renal Crónica , Atención Secundaria de Salud , Estudios Longitudinales , Estudios Prospectivos
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