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| Author(s): |
Rodrigo Lopes Seeger
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2019-09-12 |
| Examining board members: |
Claudiana Lameu;
Luiz Juliano Neto;
Eduardo Moraes Reis;
Marilia Cerqueira Leite Seelaender
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| Advisor: | Claudiana Lameu |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 17/05629-5 - Study of nitric oxide in metastasis and therapeutic potential of BPP-10c (Bj-PRO-10c) on cancer treatment |
| Grantee: | Rodrigo Lopes Seeger |
| Support Opportunities: | Scholarships in Brazil - Master |