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Master's Dissertation
DOI
https://doi.org/10.11606/D.46.2019.tde-25112019-172232
Document
Author
Full name
Rodrigo Lopes Seeger
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Lameu, Claudiana (President)
Juliano Neto, Luiz
Reis, Eduardo Moraes
Seelaender, Marilia Cerqueira Leite
Title in Portuguese
O papel do óxido nítrico no potencial terapêutico do BPP-10c para o tratamento de doenças associadas ao câncer
Keywords in Portuguese
Caquexia
Células tronco tumorais
Neuroblastoma
Óxido nítrico
Peptídeo potenciador de bradicinina 10c
Abstract in Portuguese
O óxido nítrico (NO) foi descrito primeiramente como um mensageiro secundário que regula a sinalização vasodilatadora no sistema cardiovascular. No entanto, nos últimos anos tem-se caracterizado outras importantes funções desempenhadas pelo NO, de funções fisiológicas à patológicas. O NO é sintetizado a partir de L-arginina e oxigênio por uma família de enzimas nomeada de óxido nítrico sintases (NOS). As três isoformas encontradas de NOS, induzível (iNOS), endotelial (eNOS) e neuronal (nNOS) são significativamente importantes, pois já foram demonstradas alterações na expressão das isoformas da NOS em diferentes tipos de câncer. Recentemente, foi demonstrado que alguns peptídeos anti-hipertensivos isolados do veneno da serpente Bothrops jararaca, os BPPs, induzem a produção de óxido nítrico (NO) via ciclo citrulina-NO, pois aumentam os níveis de L-arginina devido à ativação da argininosuccinato sintase (ASS), uma enzima passo-limitante na biossíntese de L-arginina. Neste trabalho estudamos o BPP-10c que modulando o ciclo citrulina-NO causou elevação na produção de nitrito e preveniu o aumento da produção de superóxido em células de neuroblastoma metastático (SH-SY5Y). O BPP-10c foi capaz de atenuar a proliferação clonogênica de tumoresferas, sem alterar a viabilidade celular. Além disso, camundongos com xenotumores derivados de tumoresferas de neuroblastomametastático exibiram significativa perda de peso e debilitação sistêmica comparado ao grupo que recebeu as células tratadas com BPP-10c, mostrando que o peptídeo inibiu os efeitos sistêmicos desencadeados pelo tumor. Nossos dados indicam que o BPP- 10c preveniu o desenvolvimento da caquexia nos animais, cujo mecanismo deve estar relacionado a redução na produção de superóxido e na expressão de atrogin-1 e MuRF-1, moléculas envolvidas no desenvolvimento da caquexia do câncer. Embora, os mecanismos envolvidos na caquexia do câncer sejam complexos e multifatoriais, a perda de peso e principalmente, a perda de massa muscular esquelética caracterizam essa síndrome, e esses efeitos não podem ser revertidos unicamente por suplementação nutricional. Assim, nossos dados revelam um potencial terapêutico do BPP-10c, impedindo a manifestação de caquexia, característico de pacientes em estados avançados de câncer e especialmente no neuroblastoma metastático.
Title in English
The role of nitric oxide in the therapeutic potential of BPP-10c for the treatment of cancer-associated diseases
Keywords in English
Bradykinin-potentiating peptide 10c
Cachexia
Cancer stem-like cells
Neuroblastoma
Nitric oxide
Abstract in English
Nitric oxide (NO) was first described as a secondary messenger that regulates vasodilator signaling in the cardiovascular system. However, in recent years other important roles of NO have been characterized, both physiologically and in pathological conditions. NO is synthesized from L-arginine and oxygen in a reaction catalysed by a family of enzymes named nitric oxide synthases (NOS). The three isoforms described for NOS, inducible (iNOS), endothelial (eNOS) and neuronal (nNOS) are significantly important, since alterations in the expression of NOS isoforms in different types of cancer have been demonstrated. Recently, has been described that some antihypertensive peptides isolated from Bothrops jararaca snake venom, the BPPs, induce nitric oxide (NO) production via citrulline-NO cycle because they increase Larginine levels due to activation of argininosuccinate synthase (ASS), the rate-limiting step enzyme in L-arginine biosynthesis. In this work we demonstrated that the BPP-10c modulates the citrulline-NO cycle causing an increase in nitrite production and prevents the increase of superoxide production in metastatic neuroblastoma cells (SH-SY5Y). BPP-10c was able to attenuate clonogenic proliferation of tumorespheres without altering cell viability. In addition, tumor-bearing mice exhibited significant weight loss and systemic debilitation compared to the group receiving BPP-10c-treated cells, showingthat the peptide inhibited tumor-triggered systemic effects. In addition, tumor-bearing mice exhibited significant weight loss and systemic impairment compared to the group receiving BPP-10c-treated cells showing that the peptide inhibited the tumor-triggered cachexia. Our data indicate that BPP-10c prevented the development of the cachetic condition in animals, whose mechanism is related to the decreased production of superoxide and in the expression of atrogin-1 and MuRF-1 which are molecules directly involved in the development of cancer cachexia. Although the mechanisms involved in cancer cachexia are complex and multifactorial, the weight loss and especially, the loss of skeletal muscle mass characterize this syndrome, and most importantly these effects cannot reverted simply by nutritional supplementation. We demonstrated that BPP-10c was able to prevent metastatic neuroblastoma-induced cachexia. Thus, our data reveal a therapeutic potential of BPP-10c, preventing the manifestation of cachexia, characteristic of patients with advanced stages of cancer and especially metastatic neuroblastoma.
 
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Release Date
2019-12-02
Publishing Date
2019-12-06
 
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