Navegando por Autor "Barbosa, Éverton de Almeida Alves"
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Item Antimetastatic effect of the pharmacological inhibition of serine/arginine-rich protein kinases (SRPK) in murine melanoma(Toxicology and Applied Pharmacology, 2018-10-01) Moreira, Gabriela Alves; Lima, Graziela Domingues de Almeida; Siqueira, Raoni Pais; Barros, Marcus Vinícius de Andrade; Adjanohoun, Abraham Landry Mahuvi; Santos, Viviane Corrêa; Barbosa, Éverton de Almeida Alves; Loterio, Robson Kriiger; Paiva, Janine Cerqueira de; Gonçalves, Victor Hugo Sousa; Viol, Lívia Cristina de Souza; Marques-da-Silva, Eduardo de Almeida; Silva Júnior, Abelardo; Almeida, Márcia Rogéria; Fietto, Juliana Lopes Rangel; Machado-Neves, Mariana; Ferreira, Rafaela Salgado; et al.The Serine/arginine-rich protein kinases (SRPK) are involved in pre-mRNA splicing control through the phosphorylation of the SR protein family of splicing factors. Over the last years, several studies have shown the relevance of SRPK for human cancers and their potential as promising drug targets. In this context, we have previously selected three trifluoromethyl arylamides (named here as SRVIC24, SRVIC30 and SRVIC36) with improved in vitro antileukemia effect and ability of impairing the cellular activity of SRPK. Given the increasing amount of reports on the implication of these kinases in metastatic cancers, in this study, we have evaluated the antimetastatic effect of these compounds and the known SRPK inhibitor (SRPIN340) on a murine model of metastatic melanoma. The compounds were able to impact the melanoma cell metastatic behavior by decreasing migration, invasion, adhesion, and colony formation in in vitro assays. Also, they presented antimetastatic in vivo activity, without apparent signs of systemic toxicity after treatments, as revealed by the histology of organs and analysis of key serum biochemical markers. Moreover, the effect of the treatments on SRPK1 nuclear translocation and SR protein phosphorylation was observed. Finally, molecular docking studies were carried out to gain structural information on the SRPK-compound complexes. Together, these data suggest that SRPK pharmacological inhibition should be considered as an interesting therapeutic strategy against metastatic cancers.Item Formation and characterization of supramolecular structures of β-lactoglobulin and lactoferrin proteins(Food Research International, 2017-07-29) Saraiva, Camila Santiago; Coimbra, Jane Sélia dos Reis; Teixeira, Alvaro Vianna Novaes de Carvalho; Oliveira, Eduardo Basílio de; Teófílo, Reinaldo Francisco; Costa, Angélica Ribeiro da; Barbosa, Éverton de Almeida AlvesCombination of β-lactoglobulin (β-Lg) and lactoferrin (Lf), biomacromolecules derived from bovine whey, was used in the formation of supramolecular structures by thermal gelation technique to adjust the pH. Furthermore, the influence of the molar ratio, temperature, pH, and heating time in the formation of supramolecular structures were also studied. The characterization of the protein supramolecular structures was performed using dynamic light scattering, zeta potential measurements, molecular spectrofluorimetry, and circular dichroism spectroscopy. The thermal behavior of the pure proteins was investigated by differential scanning calorimetry. The protein denaturation temperatures were of around 85 °C for the β-Lg and around 52 °C and 85 °C (a small portion) for the Lf. The protein molar ratio of 2:1 Lf/β-Lg was used to form the structures, whose characterization showed that the best conditions of supramolecular structure formation occurred at pH 6.5 and at temperatures of 62.5 °C. In those conditions, more stable systems with reduced hydrophobic surface and average sizes between 30 and 100 nm were generated. The correlation between pH and temperature suggests that the method of preparation of the supramolecular structure affects its size during storage.Item Potential antileukemia effect and structural analyses of SRPK inhibition by N-(2- (Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl) isonicotinamide (SRPIN340)(Plos One, 2014-04-08) Siqueira, Raoni Pais; Barbosa, Éverton de Almeida Alves; Polêto, Marcelo Depólo; Righetto, Germanna Lima; Seraphim, Thiago Vargas; Salgado, Rafael Locatelli; Ferreira, Joana Gasperazzo; Oliveira, Leandro Licursi de; Laranjeira, Angelo Brunelli Albertoni; Almeida, Márcia Rogéria; Fietto, Juliana Lopes Rangel; Kobarg, Jörg; Oliveira, Eduardo Basílio de; Teixeira, Robson Ricardo; Borges, Júlio César; Silva Júnior, Abelardo; Bressan, Gustavo Costa; et al.Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates.Item Splicing regulators and their roles in cancer biology and therapy(BioMed Research International, 2015-04-01) Silva, Maria Roméria da; Moreira, Gabriela Alves; Silva, Ronni Anderson Gonçalves da; Barbosa, Éverton de Almeida Alves; Siqueira, Raoni Pais; Teixera, Róbson Ricardo; Almeida, Márcia Rogéria; Silva Júnior, Abelardo; Fietto, Juliana Lopes Rangel; Bressan, Gustavo CostaAlternative splicing allows cells to expand the encoding potential of their genomes. In this elegant mechanism, a single gene can yield protein isoforms with even antagonistic functions depending on the cellular physiological context. Alterations in splicing regulatory factors activity in cancer cells, however, can generate an abnormal protein expression pattern that promotes growth, survival, and other processes, which are relevant to tumor biology. In this review, we discuss dysregulated alternative splicing events and regulatory factors that impact pathways related to cancer. The SR proteins and their regulatory kinases SRPKs and CLKs have been frequently found altered in tumors and are examined in more detail. Finally, perspectives that support splicing machinery as target for the development of novel anticancer therapies are discussed.Item Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)(European Journal of Medicinal Chemistry, 2017-03-31) Siqueira, Raoni Pais; Barros, Marcus Vinícius de Andrade; Barbosa, Éverton de Almeida Alves; Onofre, Thiago Souza; Gonçalves, Victor Hugo Sousa; Pereira, Higor Sette; Silva Júnior, Abelardo; Oliveira, Leandro Licursi de; Almeida, Márcia Rogéria; Fietto, Juliana Lopes Rangel; Teixeira, Róbson Ricardo; Bressan, Gustavo CostaThe serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC50 values ranging between 6.0 and 35.7 μM. In addition, these three compounds were able to trigger apoptosis and autophagy, and to exhibit synergistic effects with the chemotherapeutic agent vincristine. Furthermore, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms. Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents.