Examinando por Autor "Puga, Renato"
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Ítem Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model(Hindawi, 2020) Vargas, José Eduardo; Puga, Renato; Lenz, Guido; Trindade, Cristiano; Filippi-Chiela, EduardoDoxorubicin (Doxo) is the most effective chemotherapeutic agent for the treatment of breast cancer. However, resistance to Doxo is common. Adjuvant compounds capable of modulating mechanisms involved in Doxo resistance may potentiate the effectiveness of the drug. Resveratrol (Rsv) has been tested as an adjuvant in mammary malignancies. However, the cellular and molecular mechanisms underlying the effects of cotreatment with Doxo and Rsv in breast cancer are poorly understood. Here, we combined in vitro and in silico analysis to characterize these mechanisms. In vitro, we employed a clinically relevant experimental design consisting of acute (24 h) treatment followed by 15 days of analysis. Acute Rsv potentiated the long-lasting effect of Doxo through the induction of apoptosis and senescence. Cells that survived to the cotreatment triggered high levels of autophagy. Autophagy inhibition during its peak of activation but not concomitant with Doxo+Rsv increased the long-term toxicity of the cotreatment. To uncover key proteins potentially associated with in vitro effects, an in silico multistep strategy was implemented. Chemical-protein networks were predicted based on constitutive gene expression of MCF7 cells and interatomic data from breast cancer. Topological analysis, KM survival analysis, and a quantitative model based on the connectivity between apoptosis, senescence, and autophagy were performed. We found seven putative genes predicted to be modulated by Rsv in the context of Doxo treatment: CCND1, CDH1, ESR1, HSP90AA1, MAPK3, PTPN11, and RPS6KB1. Six out of these seven genes have been experimentally proven to be modulated by Rsv in cancer cells, with 4 of the 6 genes in MCF7 cells. In conclusion, acute Rsv potentiated the long-term toxicity of Doxo in breast cancer potentially through the modulation of genes and mechanisms involved in Doxo resistance. Rational autophagy inhibition potentiated the effects of Rsv+Doxo, a strategy that should be further tested in animal models.Ítem Diphenyl Ditelluride: Redox-Modulating and Antiproliferative Properties(Hindawi, 2019) Trindade, Cristiano; Mendes Juchem, André Luiz; Guecheva, Temenouga N.; Oliveira, Iuri M. de; dos Santos Silveira, Priscila; Vargas, José Eduardo; Puga, Renato; Pessoa, Claudia Ó.; Henriques, João A. P.Tellurium is a rare element that has been regarded as a toxic, nonessential element, and its biological role is not clearly established. In addition, the biological effects of elemental tellurium and some of its organic and inorganic derivatives have been studied, leading to a set of interesting and promising applications. Diphenyl ditelluride (DPDT), an organic tellurium derivate, showed antioxidant, antigenotoxic, antimutagenic, and anticancer properties. The antioxidant and prooxidant properties of DPDT are complex and depend on experimental conditions, which may explain the contradictory reports of these properties. In addition, DPDT may exert its effects through different pathways, including distinct ones to those responsible for chemotherapy resistance phenotypes: transcription factors, membrane receptors, adhesion, structural molecules, cell cycle regulatory components, and apoptosis pathways. This review aims to present recent advances in our understanding of the biological effects, therapeutic potential, and safety of DPDT treatment. Moreover, original results demonstrating the cytotoxic effects of DPDT in different mammalian cell lines and systems biology analysis are included, and emerging approaches for possible future applications are inferred.