RESUMO

Photodynamic therapy has emerged as an effective therapeutic alternative to treat oncological, cardiovascular, dermatological, infectious, and ophthalmic diseases. Photodynamic therapy combines the action of a photosensitizer with light in the presence of oxygen to generate reactive oxygen species, capable of reacting with cellular components, resulting in injury and, consequently, inducing cellular death. Phthalocyanines are considered good photosensitizers, although most of them are lipophilic, difficulting their administration for clinical use. A strategy to overcome the lack of solubility of phthalocyanines in aqueous media is to incorporate them into different delivery systems. The present review aimed to summarize the current status of the main drug delivery systems used for Zn and Al phthalocyanines and their effect in photodynamic therapy, reported in the last five years. Liposomes, polymeric micelles, polymeric nanoparticles, and goldnanoparticles constituted some of the most used carriers and were discussed in this review. The latest studies reported strongly suggest that the application of nanotechnologies as delivery systems allows an increase in photodynamic therapy efficacy and reduces side-effects associated with the phthalocyanine administration, which represents a hope for cancer treatments.

Assuntos

Fotoquimioterapia , Sistemas de Liberação de Medicamentos , Humanos , Indóis , Isoindóis , Micelas , Fármacos Fotossensibilizantes/uso terapêutico

RESUMO

Differentiation of neuronal cells is crucial for the development and function of the nervous system. This process involves high rates of membrane expansion, during which the synthesis of membrane lipids must be tightly regulated. In this work, using a variety of molecular and biochemical assays and approaches, including immunofluorescence microscopy and FRET analyses, we demonstrate that the proto-oncogene c-Fos (c-Fos) activates cytoplasmic lipid synthesis in the central nervous system and thereby supports neuronal differentiation. Specifically, in hippocampal primary cultures, blocking c-Fos expression or its activity impairs neuronal differentiation. When examining its subcellular localization, we found that c-Fos co-localizes with endoplasmic reticulum markers and strongly interacts with lipid-synthesizing enzymes, whose activities were markedly increased in vitro in the presence of recombinant c-Fos. Of note, the expression of c-Fos dominant-negative variants capable of blocking its lipid synthesis-activating activity impaired neuronal differentiation. Moreover, using an in utero electroporation model, we observed that neurons with blocked c-Fos expression or lacking its AP-1-independent activity fail to initiate cortical development. These results highlight the importance of c-Fos-mediated activation of lipid synthesis for proper nervous system development.

Assuntos

Córtex Cerebral/embriologia , Neurogênese , Neurônios/citologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Wistar

RESUMO

Tumor cells require high rates of lipid synthesis to support membrane biogenesis for their exacerbated growth. The only two proteins known that activate phospholipid synthesis are Fra-1 and c-Fos, two members of the AP-1 family of transcription factors. These proteins that are overexpressed in human breast malignant tumors increase the rate of phospholipid synthesis at the endoplasmic reticulum through a mechanism independent of their nuclear function. The aim of this study was to inhibit breast tumor cell proliferation by modulating c-Fos and Fra-1 and regulate membrane biogenesis by controlling lipid synthesis rates. The molecular mechanism by which Fra-1 and c-Fos activate phospholipid synthesis was examined. Both proteins physically associate with the rate limiting enzyme CDP-DAG synthase through their N-terminus domain and activate it through their basic domain; neither protein associates to or activates the enzyme phosphatidylinositol synthase as determined through in vitro enzymatic reactions and FRET experiments. The N-terminus domain of both proteins act as negative dominant peptides that physically associate with CDP-DAG synthase but do not activate it. Proliferation of MDA-MB231 and 4T1 cells was impaired in vitro after inducing them to proliferate in the presence of the negative dominant peptides derived from Fra-1 and c-Fos. When tumors generated in Balb/c mice with the breast tumor cell line 4T1 were treated with these negative dominant peptides, a significant reduction in tumor growth was observed. Consequently, these Fra-1 and c-Fos negative dominant peptides can be exploited as a new therapeutic strategy to impair breast tumor cell proliferation.