ABSTRACT
Glioblastoma is the most common and aggressive glioma, characterized by brain invasion capability. Being very resistant to the current therapies, since even under treatment, surgery, and chemotherapy with temozolomide (TMZ), patients achieve a median survival of one year. In the search for more effective therapies, new molecules have been designed. For nervous system cancers, molecules able to cross the blood-brain barrier are handled with priority. Accordingly, tacrine was chosen for this study and the inclusion of spiro-heterocyclic rings was done in its structure resulting in new compounds. Cytotoxic activity of tacrine derivatives was assayed using glioblastoma cell line (SF295) as well as analyzing cell death mechanism. Increased caspases activities were observed, confirming apoptosis as cell death type. Some derivatives also increased reactive oxygen species formation and decreased the mitochondrial membrane potential. Moreover, compounds acted on several glioblastoma-related proteins including p53, HLA-DR, beta-catenin, Iba-1, MAP2c, Olig-2, and IDH1. Therefore, tacrine derivatives presented promising results for the development of new glioblastoma therapy, particularly to treat those patients resistant to TMZ.
Subject(s)
Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/pathology , Neoplasm Proteins/physiology , Tacrine/pharmacology , Apoptosis/drug effects , Caspases/physiology , Cell Cycle/drug effects , Cell Line, Tumor , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacology , Drug Screening Assays, Antitumor , Humans , Membrane Potential, Mitochondrial/drug effects , Mitosis/drug effects , Molecular Structure , Molecular Targeted Therapy , Necrosis , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Reactive Oxygen Species/metabolism , Tacrine/analogs & derivatives , TemozolomideABSTRACT
Neste trabalho foram estudadas amostras de horizontes A de oito solos representativos da região Campos de Cima da Serra, Rio Grande do Sul, sendo determinados: textura, pH em água, CTC a pH 7, teores de Al trocável e de óxidos de Fe (Fed e Feo). As amostras foram tratadas com peróxido de hidrogênio e, antes e após tratamento, foram determinados teores de C e de N e realizada análise por espectroscopia de infra-vermelho com transformada de Fourier (FTIR). O teor de C foi alto (4 a 23 por cento) e sua variação correlacionou-se com a altitude e com o teor de Al trocável, sugerindo que a menor temperatura e a complexação com Al iônico contribuem para a estabilização da matéria orgânica do solo (MOS). A proporção de carbono do solo resistente à oxidação variou de 1 a 16 por cento e correlacionou-se com a razão Feo/Fed. A estabilização desta fração da MOS foi atribuída à interação de grupos carboxílicos ligados a estruturas alifáticas e aromáticas com óxidos de Fe de baixa cristalinidade.
In this research, texture, soil pH, CEC at pH 7, exchangeable Al, and content of Fe-oxides (Fed and Feo) were determined in A horizons samples of eight representative soils under native pasture from Campos de Cima da Serra, Rio Grande do Sul State, Brazil. The samples were treated with hydrogen peroxide and, before and after the treatment, C and N contents were determined and Fourier Transformed Infra-red (FTIR) spectroscopy was performed. The content of soil C was high (4 to 23 percent) and its variation correlated with the altitude and exchangeable Al indicating that lower temperatures and complexation with ionic Al contribute to soil organic matter (SOM) stabilization. The proportion of oxidation-resistant carbon varied between 1 and 16 percent and correlated with the ratio Feo/Fed. The stabilization of this SOM fraction was assigned to the interaction of carboxylic groups bound to aromatic and aliphatic structures with Fe-oxides of low crystallinity degree.
