Mecanismo de ação do inibidor de planta EcTI e de um peptídeo derivado em melanoma

• Ano de defesa: 2020
• Autor(a) principal: Bonturi, Camila Ramalho [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: EcTI; Melanoma; Proteases; Skin Cancer; Câncer De Pele
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=9132344; https://hdl.handle.net/11600/64286

Melanoma is a highly malignant cancer and the treatment commonly used is surgical remotion. The available treatments have several side effects and many of them show low efficacy due to the lack of specificity of the compounds. As a result, finding target molecules is a major challenge in oncology. Given that proteases play an important role in tumor development and progression, the purpose of this paper is to investigate the antitumor properties of the purified and isolated EcTI inhibitor of Enterolobium contortisiliquum seeds and a structurally related peptide in cell lines (B16F10- nex2, SK-MEL-28, CHL-1 and HUVEC), with subsequent evaluation in vivo. EcTI and its peptide fragment blocked several important processes of carcinogenesis. Cellular responses did not follow a single pattern; however, the final event was blockade of proliferation, migration and invasion of all tumor cells analyzed, accompanied by decreased membrane potential and intracellular calcium release. In general, EcTI reduced the expression of cell migration, adhesion, and invasion-related proteins, such as FAK and Src, as well as cell death-associated proteins, especially increased BAX and reduced BCL-2. Cell adhesion was mainly influenced by fibronectin and laminin molecules. Autophagy induction was observed, which also interrelates with the cellular apoptosis event, due to the increase of the LC3 protein, an important marker of autophagolysosomes. All of these events were confirmed by cellular changes observed in transmission electron microscopy, with increased apoptotic bodies, invaginations, changing in mitochondria. The peptide, on the other hand, caused endoplasmic reticular swelling, with no apparent mitochondrial morphological alteration. In addition, the in vivo results indicated that the EcTI decreased the tumor mass of mice at dose of 8 mg/kg, while the peptide decreases tumor volume by 4 mg/kg. Results indicate that these compounds are promising in reducing melanoma progression.