Navegando por Palavras-chave "Antitumoral"
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- ItemAcesso aberto (Open Access)Avaliação da segurança e eficácia "in vitro" da Cuscuta racemosa Martius(Universidade Federal de São Paulo, 2017-07-04) Bertoluci, Raquel Silveira [UNIFESP]; Lopes, Patricia Santos [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Cuscuta racemosa, Mart is a parasitic plant belonging to the family Convolvulaceae, known in Brazil for the popular synonymy of "cipó chumbo" and "yarn of eggs". It is popularly used for its anti-inflammatory and healing actions, applied to diuretic and digestive disorders and presents itself as an alternative of biodiversity for use in medicines and cosmetics. The present study verified the in vitro evaluation of the safety and efficacy of the Cuscuta racemosa extract for possible cosmetic and drug applications. Assays were carried out from crude extract and alkaloids fraction from Cuscuta racemosa to evaluate cytotoxicity, and phototoxicity, as well as determination of antimicrobial and antitumor activity. Cytotoxicity and phototoxicity assays were performed according to the standards recommended by the Organization for Economic Co-operation and Development (OECD) using 3T3 BALB cells. Microbiological analyzes were conducted with Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. The evaluation of antimicrobial activity was performed in liquid and solid media. Antitumor activity assays were performed with the HeLa, MDA-DB and Sk-Mel lines. Cytotoxicity tests revealed a cytotoxic effect of the crude extract at concentrations of 34.01 and 50 mg / mL, but at lower concentrations did not present significant action, indicating its safety for possible cosmetic and medicinal applications. Both samples tested showed no phototoxicity. The lethal dose estimated at 50% of the cells calculated for the crude extract was 352.25mg / kg. With respect to the antimicrobial activity, the samples did not present zone of inhibition in solid culture medium in the concentrations tested for none of the tested microorganisms. The crude extract was cytotoxic in all its concentrations in tumor lines. The results indicate the possibility of using the samples in cosmetics, since the alkaloid fraction showed absence of phototoxicity and absence of cytotoxicity, although the samples did not present significant antimicrobial in the concentrations tested. With respect to antitumor activity, complementary studies are necessary directing the active only to the place of action, minimizing the risks of performance of the extract in normal cells.
- ItemSomente MetadadadosCaracterização farmacológica da Crotamina sintética como antitumoral em modelos de melanoma in vivo. Otimização da atividade neoplásica com uso de adjuvantes(Universidade Federal de São Paulo (UNIFESP), 2020-05-28) Porta, Lucas De Carvalho [UNIFESP]; Hayashi, Mirian Akemi Furuie [UNIFESP]; Universidade Federal de São PauloToxins are of great scientific interest, mainly due to their possible use for therapeutic purposes as drugs, or as a structural model for its development. Crotamine, which is one of the most abundant toxins present in the rattlesnake venom, can penetrate cells, with special specificity and cytotoxic activity against active proliferating cells. Daily treatment of animal models of melanoma, with crotamine administered through intraperitoneal or oral routes, showed a significant remission of tumor growth such as an increase in survival of the treated animals. In order to continue and improve the anti-tumor treatment with crotamine, the present work consisted to show the use of crotamine obtained by chemical synthesis, associated with thioridazine or with silica nanoparticles in the therapy of animal models of melanoma, such as the evaluation of treatment-related toxicity through the administration of these associated compounds in isolated skeletal muscle or with high doses injections in vivo. The remission of tumor growth in vivo was evaluated comparing these associations/formulations with the effect of native crotamine alone, suggesting that, although significant toxicity has been observed in the treatment with crotamine associated with thioridazine, which is not due to local effect, it is feasible to decrease the amount of crotamine needed for anti-tumor treatment.
- ItemSomente MetadadadosCytotoxic effects of dillapiole on MDA-MB-231 cells involve the induction of apoptosis through the mitochondrial pathway by inducing an oxidative stress while altering the cytoskeleton network(Elsevier B.V., 2014-04-01) Ferreira, Adilson Kleber; de-Sa-Junior, Paulo Luiz; Pasqualoto, Kerly Fernanda Mesquita; Azevedo, Ricardo Alexandre de; Dias Camara, Diana Aparecida; Costa, Andre Santos; Figueiredo, Carlos Rogerio [UNIFESP]; Matsuo, Alisson Leonardo [UNIFESP]; Massaoka, Mariana Hiromi [UNIFESP]; Vatti Auada, Aline Vivian; Lebrun, Ivo; Costa Bernstorff Damiao, Mariana Celestina Frojuello; Tavares, Mauricio Temotheo; Motter Magri, Fatima Maria; Kerkis, Irina; Parise Filho, Roberto; Butantan Inst; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP); Univ Prebiteriana MackenzieBreast cancer is the world's leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. the use of natural molecular fingerprints as sources for new bioactive chemical entities has proven to be a quite promising and efficient method. Here, we have demonstrated for the first time that dillapiole has broad cytotoxic effects against a variety tumor cells. for instance, we found that it can act as a pro-oxidant compound through the induction of reactive oxygen species (ROS) release in MDA-MB-231 cells. We also demonstrated that dillapiole exhibits antiproliferative properties, arresting cells at the G0/G1 phase and its antimigration effects can be associated with the disruption of actin filaments, which in turn can prevent tumor cell proliferation. Molecular modeling studies corroborated the biological findings and suggested that dillapiole may present a good pharmacokinetic profile, mainly because its hydrophobic character, which can facilitate its diffusion through tumor cell membranes. All these findings support the fact that dillapiole is a promising anticancer agent. (C) 2013 Elsevier Masson SAS. All rights reserved.
- ItemAcesso aberto (Open Access)Estudo da administração de soluções extrativas de Garcinia brasiliensis nos tumores de Ehrlich ascítico e sólido(Universidade Federal de São Paulo, 2023-11-11) Silva, Lucas Sylvestre [UNIFESP]; Girol, Ana Paula; http://lattes.cnpq.br/1029430934770489; http://lattes.cnpq.br/3224895039553691Introdução: O câncer é uma das principais causas de morte no mundo. Embora exista evidências de progresso nas terapias antitumorigênicas ao longo dos anos, ainda há necessidade de explorar novas abordagens terapêuticas que possam efetivamente inibir a progressão do tumor, garantindo ao mesmo tempo a segurança. Nesse contexto, uma das espécies que tem chamado a atenção por suas propriedades fitoterápicas é a Garcinia brasiliensis, árvore nativa da América do Sul. Um modelo interessante para investigação é o tumor de Ehrlich, que se origina do adenocarcinoma mamário de camundongos fêmeas e compartilha características semelhantes aos tumores humanos. Objetivos: Investigar o efeito de soluções extrativas de folhas de Garcinia brasiliensis (G. brasiliensis) no desenvolvimento do tumor de Ehrlich ascítico e sólido. Materiais e métodos: O extrato bruto (crude extract – CE) e fração acetato de etila (ethil acetate fraction – EAF) foram obtidos de folhas de G. brasiliensis. HPLC foi empregado para identificar compostos bioativos. A pesquisa avaliou a atividade antioxidante por meio do ensaio 2,2-difenil-1-picrilhidrazil (DPPH) e a citotoxicidade por meio de testes de hemólise. O tumor de Ehrlich foi induzido em camundongos BALB/c na forma ascítica (EA) via injeção intraperitoneal e sólida (ES) via injeção subcutânea de 0,5mL (2 x 106 células/ml) de líquido ascítico. Camundongos BALB/c não induzidos a tumores foram tratados por 7 e 14 dias com 0,5mL de solução salina 0,9%, CE e EAF 10%, administrados por via intramuscular. Animais induzidos com tumor ascítico (EA) foram tratados com 0,5mL de CE e 10% EAF por 7 dias, enquanto animais induzidos com tumor sólido (ES) foram tratados com 0,5mL de CE e 10% EAF por 14 dias. A análise bioquímica dos parâmetros de aspartato aminotransferase (AST), alanina aminotransferase (ALT), gama glutamil transferase (Gama GT), creatinina, ureia, albumina, fosfatase alcalina, ácido úrico e níveis de glicose no sangue foi realizada para avaliação da citotoxicidade in vivo. Nos animais induzidos foram avaliados o peso corporal, o volume do tumor, a taxa de inibição do crescimento tumoral. Além disso, foi estudada a composição do líquido ascítico em EA e realizada a análise histopatológica em ES. Os níveis de citocinas IL- 6, IFN-y e TNF-a e as expressões da proteína Bax e da protease-6 de mastócitos (Mcpt6) também forma avaliados. Resultados: HPLC indicou presença de Fukugetina e Noratiriol nos extratos. CE e EAF apresentam, respectivamente, atividade antioxidante de 85,9% e 80,58% e baixa citotoxicidade. Em animais não induzidos ao tumor, o CE aumentou a ALT em 14 dias em relação ao controle. No tumor ascítico, o CE reduziu ALT, AST e Gamma GT, enquanto o EAF reduziu ALT em comparação ao grupo não tratado. No tumor sólido, o CE também promoveu a redução de AST e Gamma GT, enquanto o EAF reduziu Gamma GT em comparação ao grupo não tratado. Os tratamentos CE e EAF foram eficazes na inibição do crescimento tumoral nas formas ascítica e sólida do tumor de Ehrlich. No modelo ascítico, houve redução da circunferência abdominal, do volume total de líquido ascítico e do número de células tumorais. Além disso, o tratamento aumentou a expressão da citocina IL-6 e da proteína pró-apoptótica bax em comparação aos animais induzidos sem tratamento. No modelo de tumor sólido, houve redução do volume tumoral e dos diâmetros maiores e menores do tumor, bem como redução da expressão da protease-6 dos mastócitos (mcpt6). Ainda, o tratamento aumentou os níveis do fator de necrose TNF-α em comparação com animais não tratados. Conclusão: O estudo indica que tanto o CE quanto EAF de G. brasiliensis apresentam potenciais efeitos antitumorais e hepatoprotetores promissores.
- ItemSomente MetadadadosFuncionalização De Nanopartículas Metálicas Com Diferentes Combinações De Peptídeos Para Aplicações Como Agentes Antimicrobianos E Antitumorais(Universidade Federal de São Paulo (UNIFESP), 2017-11-27) Formaggio, Daniela Maria Ducatti [UNIFESP]; Tada, Dayane Batista [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Metal nanoparticles (NPs) have showing promising applications in the biomedical field. These NPs have unique physicochemical properties, as well as great chemical versatility on their surface, which allows new modifications and incorporations of different molecules. In addition, they have the advantage of accumulating preferentially in tumor tissues due to the enhanced permeability and retention effect, known as EPR. The incorporation of therapeutic peptides to the surface of metallic NPs could be a promising strategy to improve their applications as therapeutic molecules. Peptides are highly selective molecules. However, they are also vulnerable to some in vivo pharmacologic barriers limiting their effective action, including low bioavailability or deactivation by enzymes. In this work, three types of metal NPs were prepared: gold NPs (AuNPs), silver NPs (AgNPs) and bimetallic NPs composed by gold and platinum (AuPtNPs). NPs were characterized by ultraviolet-visible spectroscopy (UV-Vis), dynamic light scattering (DLS), transmission electron microscopy (TEM), inductively coupled plasma optical emission spectroscopy (ICP-OES) and X-ray diffraction (XRD). Aiming at biomedical applications, NPs were firstly evaluated regarding their toxicity by cell viability assays using human fibroblast cells (HS68 cell line) and embryonic toxicity test in zebrafish (Danio rerio). The assays showed better biocompatibility of AuNPs compared to AgNPs and AuPtNPs. Thus, AuNPs were studied as carriers of antitumor and antimicrobial peptides as an alternative approach of overcoming the pharmacokinetic limitations inherent in these molecules. Two peptides derived from complementary monoclonal antibodies (CDRs) with amino acid sequences YISCYNGATSYNQKFK (C7H2) and RASQSVSSYLA (HuAL1) were previously identified by collaborators of this project demonstrating excellent toxicity against tumor cells, antimetastatic activity as well as a potent antimicrobial activity. The peptides were individually conjugated to the AuNPs surface, forming the AuNPsC7H2 and AuNPsHuAL1 NPs. The peptides were also linked together forming the AuNPsC7H2HuAL1. The in vitro results suggested an improved antitumor activity for AuNPsHuAL1 and AuNPsC7H2HuAL1 against metastatic melanoma tumor cell line (B16F10-Nex2) compared to the peptides in solution. In vivo, the peptide combination of HuAL1 and C7H2 was even more efficient when linked to AuNPs. The antimicrobial activity of the three NPs separately as well as the peptide functionalized AuNPs were also evaluated employing microdilution test against strains of Candida Albicans, Pseudomonas aeruginosa and Staphylococcus aureus. The results confirm an intrinsic antimicrobial action of the three metal NPs and an optimal antibiotic action for AuNPsHuAL1.
- ItemSomente MetadadadosGrowth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor(Elsevier B.V., 2010-06-07) Bromberg, Natalia; Dreyfuss, Juliana L. [UNIFESP]; Regatieri, Caio V. [UNIFESP]; Palladino, Marcelly V. [UNIFESP]; Duran, Nelson; Nader, Helena B. [UNIFESP]; Haun, Marcela; Justo, Giselle Z. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Universidade Estadual de Campinas (UNICAMP)The continuing threat to biodiversity lends urgency to the need of identification of sustainable source of natural products. This is not so much trouble if there is a microbial source of the compound. Herein, violacein, a natural indolic pigment extracted from Chromobacterium violaceum, was evaluated for its antitumoral potential against the Ehrlich ascites tumor (EAT) in vivo and in vitro. Evaluation of violacein cytotoxicity using different endpoints indicated that EAT cells were twofold (IC(50) = 5.0 mM) more sensitive to the compound than normal human peripheral blood lymphocytes. in vitro studies indicated that violacein cytotoxicity to EAT cells is mediated by a rapid (8-12 h) production of reactive oxygen species (ROS) and a decrease in intracellular GSH levels, probably due to oxidative stress. Additionally, apoptosis was primarily induced, as demonstrated by an increase in Annexin-V positive cells, concurrently with increased levels of DNA fragmentation and increased caspase-2. caspase-9 and caspase-3 activities up to 4.5-, 6.0- and 5.5-fold, respectively, after 72 h of treatment. Moreover, doses of 0.1 and 1.0 mu g kg(-1) violacein, administered intraperitoneally (i.p.) to EAT-bearing mice throughout the lifespan of the animals significantly inhibited tumor growth and increased survival of mice. in view of these results, a 35-day toxicity study was conducted in vivo. Complete hematology, biochemistry (ALT, AST and creatinine levels) and histopathological analysis of liver and kidney indicated that daily doses of violacein up to 1000 mg kg(-1) for 35 days are well tolerated and did not cause hematotoxicity not renal or hepatotoxicity when administered i.p. to mice. Altogether, these results indicate that violacein causes oxidative stress and an imbalance in the antioxidant defense machinery of cells culminating in apoptotic cell death. Furthermore, this is the first report of its antitumor activity in vivo, which occurs in the absence of toxicity to major organs. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
- ItemSomente MetadadadosModulação do eixo PLCγ1, Ca2+/CAMKII e PKC em células de leucemia mieloide crônica tratadas com violaceína(Universidade Federal de São Paulo (UNIFESP), 2020-07-30) Miura, Natalia Tamagusko [UNIFESP]; Justo, Giselle Zenker [UNIFESP]; Universidade Federal de São PauloViolacein is an indole derivative isolated from Chromobacterium violaceum with potential antitumor activity and specific mechanisms of action in vitro and in vivo. This compound was evaluated in vitro in cultures of chronic myeloid leukemia (CML), which is a myeloproliferative disease associated with a genetic translocation that leads to the formation of the BCR-ABL oncoprotein. BCR-ABL is capable of inducing multiple signal transduction pathways responsible for the leukemogenic process. Moreover, BCR-ABL acts with additional mechanisms, dependent or independent of BCR-ABL, to induce resistance, leading to an unfavorable prognosis in the treatment of the disease and the search for alternative drug therapies. One of the factors that lead to the phenotype of multiple drug resistance (MDR) is related to the increase in the expression of efflux pumps, among them, the P glycoproteins (Pgp), which is one of the most studied mechanisms of chemoresistance in CML. Hence, we compared the phosphoproteomic profile of K562 cells and their variant that overexpresses the Pgp and, therefore, presents the MDR phenotype, the Lucena 1 cell line, using a microarray approach of peptides that allows to analyze the activity of different cell kinases. Data analysis showed that the exposure of K562 cells to violacein significantly modulated 13 kinases, whereas the activity of 6 kinases in Lucena 1 cells showed significant changes after treatment. The results showed a reduction in the activity of Axl and c-Met in K562 cells, while p38MAPK and JNK stimulation were observed in Lucena 1 cells. Of particular importance, the quinoma analysis indicated significant modulation in protein kinase C (PKC) activity after treatment of cells of both strains with violacein. In this sense, a reduction in phosphorylation of PKCα(Ser657) by immunoblotting was also observed. On the other hand, the pretreatment of cells with the specific classic PKC inhibitor, chelerythrine, inhibited about 80% of cell death induced by violacein, corroborating the increase in intracellular Ca2+ concentration. In addition, a significant increase in CAMKII(Thr286) activity was observed, suggesting that stimulation of the Ca2+/CAMKII axis and PKCs is important for cell death induced by violacein. In addition, the results also demonstrated the inhibition of PLCγ1(Tyr783), suggesting that this effect is also involved in inducing cell death. Together, the results indicate an important role for Ca2+ signaling and PLCγ1 inhibition in violacein-induced CML cell death. They also open perspectives for investigating new targets of action of this naturally derived compound.
- ItemAcesso aberto (Open Access)Reações de bromoaminociclização enantiosseletivas visando a síntese de bases esfingóides(Universidade Federal de São Paulo, 2022-03-04) Ohira, Bianca Yumi [UNIFESP]; Rodrigues, Alessandro [UNIFESP]; http://lattes.cnpq.br/5134320818291591; http://lattes.cnpq.br/1702146113386742A porção aminoálcool é um constituinte estrutural presente em diversas moléculas, sejam elas de ocorrência natural ou não, que apresentam diversas atividades biológicas relevantes. Dentre elas, existem os aminoálcoois de cadeia longa, conhecidos como bases esfingóides e que são subunidades presentes em um vasto número de moléculas de ocorrência natural e que são biologicamente ativos, como a esfingosina, esfinganina, xestoaminol C e os clavaminóis. Estes compostos desempenham diversos papéis, seja na sinalização celular, inibição da proteína quinase C, atividade antineoplásica, atividade antifúngica, atividade anti-helmíntica, dentre outras. Devido à importância biológica desses compostos houve o desenvolvimento de inúmeras metodologias, sendo que a maioria envolve a aplicação “chiral pool”. Este trabalho propôs uma rota sintética que não foi descrita até o presente momento, que possui como materiais de partida ácidos carboxílicos ou álcoois. O ácido hexadecanóico foi reduzido ao álcool correspondente (rendimento de 51%), os álcoois foram oxidados a aldeídos (rendimentos entre 37-95%). Estes foram submetidos a uma reação de Horner-Wadsworth-Emmons para a obtenção dos respectivos ésteres (rendimentos entre 16-92%), que sofreram redução na presença de DIBAL-H para formação dos álcoois alílicos (rendimento entre 52-79%) e posterior reação com o isocianato selecionado, levando à formação dos carbamatos alílicos que foram obtidos com rendimento entre 92-100%. Para a reação de bromoaminociclização dos carbamatos, nos inspiramos no trabalho de Shi e colaboradores que fazem uso do fosfinóxido quiral complexado ao Sc(OTf)3. Os produtos ciclizados foram obtidos com rendimento variando de 43-100% e excessos enantioméricos 43-96%. Esses produtos de ciclização podem ser submetidos à hidrólise alcalina a fim de obter-se as bases esfingóides relevantes.