Ação dos inibidores de proteases, EcTI e CrataBL, em linhagens de câncer cerebral (glioblastoma multiforme)
Data
2015-11-27
Autores
Bonturi, Camila Ramalho 
Orientadores
Oliva, Maria Luiza Vilela
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Glioblastoma multiforme (GBM) é um câncer cerebral com alta malignidade e agressividade. É o tumor mais comum dentre os que afetam o cérebro e apresenta dificuldade em relação ao diagnóstico e tratamento. A quimioterapia é usualmente adjuvante à radioterapia e em alguns casos, a cirurgia é também requerida. No entanto, a eficácia do tratamento é baixa, com um tempo de vida inferior a 1 ano e com aparecimento de recidivas mesmo após a cirurgia. Devido à importância e estágio avançado deste tumor (grau IV) compostos que apresentam propriedades anti-tumorigênica estão sendo investigados no esforço contra o GBM. Vários estudos têm demonstrado em modelos experimentais (in vitro e in vivo) a ação antitumoral (câncer gástrico, câncer de próstata, fibrosarcoma humano) e antitrombótica dos inibidores de proteases EcTI, Enterolobium contortisiliquum Trypsin Inhibitor e CrataBL, Crataeva tapia Bark Lectin. O presente trabalho propôs avaliar o potencial anti-tumorigênico desses inibidores no câncer cerebral do tipo GBM analisando eventos como a viabilidade, adesão, invasão, vias de sinalização, liberação de cálcio, óxido nítrico, ciclo e morte celular. Os inibidores de proteases foram eficazes na diminuição da viabilidade das células de câncer tanto isoladas quanto em co-cultura. Interessantemente, esses compostos promoveram um aumento do processo adesivo resultando na diminuição da invasão. EcTI e CrataBL também promoveram aumento da liberação de cálcio basal e óxido nítrico, relacionados com eventos anti-proliferativos e de apoptose. Os inibidores causaram parada do ciclo celular na fase G1/S, além de diminuir a expressão de citocinas pro-inflamatórias como IL-6, IL-8, MCP-1, G-CSF e GM-CSF. Com relação a sinalização celular, EcTI inteferiu nas proteínas integrina ?1/FAK/Src, enquanto CrataBL agiu em Src e BR2. Com isso, verifica-se que os inibidores por interferirem na invasão, adesão, viabilidade e vias de sinalização chaves no desenvolvimento do GBM, EcTI e CrataBL são importantes compostos para serem investigados nesse câncer.
Glioblastoma multiforme (GBM) is a brain tumor with high malignancy and aggressiveness. It is the more common tumor among those that affect the brain and presents difficulty in the diagnosis and treatment. Chemotherapy is the most used treatment with adjuvant radiotherapy and in some cases a surgery is also required. However, the effectiveness of these treatments is low, and the lifetime is less than 1 year with relapses of tumor even after surgery. Because of the importance of this tumor and advanced stage (stage IV) compounds that have anti-tumorigenic properties are being investigated in the effort against GBM. Several studies have shown in experimental models (in vitro and in vivo) antitumor action (gastric cancer, prostate cancer, human fibrosarcoma) and antithrombotic action of protease inhibitors, as EcTI (Enterolobium contortisiliquum Trypsin Inhibitor) and CrataBL (Crataeva tapia Bark Lectin). This study proposed to evaluate the anti-tumorigenic potential of these inhibitors on GBM brain cancer analyzing some events, as viability, adhesion, invasion, signaling pathways, calcium and oxide nitric realease, cell cycle and apoptosis. The inhibitors were effective in reducing the viability of cancer cells both isolated and in co-culture. Interestingly these compounds increased on adhesion process resulting in decreased invasion. EcTI CrataBL also promoted and increased basal calcium and nitric oxide release that are related with anti-proliferative and apoptosis events. Inhibitors caused cell cycle arrest at the G1/S phase, and reduce proinflammatory cytokines such as IL-6, IL-8, MCP-1, G-CSF and GM-CSF. With respect to cell signaling, EcTI interfered in integrin ?1/FAK/Src proteins, while CrataBL acted in Src and BR2. It appears that the inhibitors to interfere in invasion, adhesion, viability and key signaling pathways in the development of GBM, EcTI and CrataBL are important compounds to be investigated in cancer.
Glioblastoma multiforme (GBM) is a brain tumor with high malignancy and aggressiveness. It is the more common tumor among those that affect the brain and presents difficulty in the diagnosis and treatment. Chemotherapy is the most used treatment with adjuvant radiotherapy and in some cases a surgery is also required. However, the effectiveness of these treatments is low, and the lifetime is less than 1 year with relapses of tumor even after surgery. Because of the importance of this tumor and advanced stage (stage IV) compounds that have anti-tumorigenic properties are being investigated in the effort against GBM. Several studies have shown in experimental models (in vitro and in vivo) antitumor action (gastric cancer, prostate cancer, human fibrosarcoma) and antithrombotic action of protease inhibitors, as EcTI (Enterolobium contortisiliquum Trypsin Inhibitor) and CrataBL (Crataeva tapia Bark Lectin). This study proposed to evaluate the anti-tumorigenic potential of these inhibitors on GBM brain cancer analyzing some events, as viability, adhesion, invasion, signaling pathways, calcium and oxide nitric realease, cell cycle and apoptosis. The inhibitors were effective in reducing the viability of cancer cells both isolated and in co-culture. Interestingly these compounds increased on adhesion process resulting in decreased invasion. EcTI CrataBL also promoted and increased basal calcium and nitric oxide release that are related with anti-proliferative and apoptosis events. Inhibitors caused cell cycle arrest at the G1/S phase, and reduce proinflammatory cytokines such as IL-6, IL-8, MCP-1, G-CSF and GM-CSF. With respect to cell signaling, EcTI interfered in integrin ?1/FAK/Src proteins, while CrataBL acted in Src and BR2. It appears that the inhibitors to interfere in invasion, adhesion, viability and key signaling pathways in the development of GBM, EcTI and CrataBL are important compounds to be investigated in cancer.
Descrição
Citação
BONTURI, Camila Ramalho. Ação dos inibidores de proteases, EcTI e CrataBL, em linhagens de câncer cerebral (glioblastoma multiforme). 2015. 122 f. Dissertação (Mestrado em Biologia Molecular) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2015.