Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters











Publication year range
1.
Sci Rep ; 10(1): 8542, 2020 05 22.
Article in English | MEDLINE | ID: mdl-32444831

ABSTRACT

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.


Subject(s)
Biomarkers, Tumor/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lung Neoplasms/secondary , Triple Negative Breast Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Apoptosis , Biomarkers, Tumor/genetics , Cell Proliferation , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Intracellular Signaling Peptides and Proteins/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/surgery , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Prognosis , Survival Rate , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/surgery , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Young Adult
2.
Sci Rep ; 9(1): 19578, 2019 12 20.
Article in English | MEDLINE | ID: mdl-31862900

ABSTRACT

Although prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to explore their contribution in GBM pathogenesis. We detected PRL and PRLR in all GBM cell lines tested. PRLR activation or overexpression using plasmid transfection increased proliferation, viability, clonogenicity, chemoresistance and matrix metalloproteinase activity in GBM cells, while PRLR antagonist ∆1-9-G129R-hPRL reduced their proliferation, viability, chemoresistance and migration. Meta-analysis of transcriptomic data indicated that PRLR was expressed in all grade II-III glioma (GII-III) and GBM samples. PRL was upregulated in GBM biopsies when compared to GII-III. While in the general population tumour PRL/PRLR expression did not correlate with patient survival, biological sex-stratified analyses revealed that male patients with PRL+/PRLRHIGH GBM performed worse than PRL+/PRLRLOW GBM. In contrast, all male PRL+/PRLRHIGH GII-III patients were alive whereas only 30% of PRL+/PRLRLOW GII-III patients survived after 100 months. Our study suggests that PRLR may be involved in GBM pathogenesis and could constitute a therapeutic target for its treatment. Our findings also support the notion that sexual dimorphism should be taken into account to improve the care of GBM patients.


Subject(s)
Glioblastoma/metabolism , Glioma/metabolism , Prolactin/metabolism , Receptors, Prolactin/metabolism , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Movement/genetics , Cell Movement/physiology , Cell Proliferation/genetics , Cell Proliferation/physiology , Female , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioma/genetics , Humans , Male , Plasmids/genetics , Prolactin/genetics , Protein Binding/genetics , Rats , Receptors, Prolactin/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Treatment Outcome
3.
NOVA publ. cient ; 17(32): 9-24, jul.-dic. 2019.
Article in Spanish | LILACS | ID: biblio-1056786

ABSTRACT

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.


Subject(s)
Neurodegenerative Diseases , Volition , Disease , Neoplasms
4.
Expert Opin Ther Targets ; 23(2): 117-126, 2019 02.
Article in English | MEDLINE | ID: mdl-30582721

ABSTRACT

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.


Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Molecular Targeted Therapy , Neoplasms/therapy , Animals , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/therapy , Disease Models, Animal , Genetic Therapy/methods , Humans , Intracellular Signaling Peptides and Proteins/genetics , Mitochondria/metabolism , Neoplasms/pathology , Neurodegenerative Diseases/physiopathology , Neurodegenerative Diseases/therapy
5.
Expert Opin Biol Ther ; 17(8): 945-959, 2017 08.
Article in English | MEDLINE | ID: mdl-28604109

ABSTRACT

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.


Subject(s)
Breast Neoplasms/therapy , Oncolytic Virotherapy , Adenoviridae/genetics , Female , Genetic Vectors/genetics , Genetic Vectors/metabolism , Humans , Lentivirus/genetics , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/virology , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Neural Stem Cells/virology , Oncolytic Viruses/genetics , Poxviridae/genetics
6.
J Cancer Res Clin Oncol ; 143(9): 1713-1732, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28432455

ABSTRACT

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.


Subject(s)
Adenocarcinoma/therapy , Breast Neoplasms/therapy , Cancer Vaccines/immunology , Toll-Like Receptor 7/agonists , Toll-Like Receptor 9/agonists , Adjuvants, Immunologic/pharmacology , Animals , Cancer Vaccines/pharmacology , Dendritic Cells/immunology , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
SELECTION OF CITATIONS
SEARCH DETAIL