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Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier

BACKGROUND: The new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom BCG (Bacillus Calmette-Guerin) has failed or is contraindicated are recently increasing due to the development of new drugs. Although agents like mitomycin C and BCG are routinely used, ther...

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Autores principales: Garcia, Patrick Vianna, Seiva, Fábio Rodrigues Ferreira, Carniato, Amanda Pocol, de Mello Júnior, Wilson, Duran, Nelson, Macedo, Alda Maria, de Oliveira, Alexandre Gabarra, Romih, Rok, Nunes, Iseu da Silva, Nunes, Odilon da Silva, Fávaro, Wagner José
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937612/
https://www.ncbi.nlm.nih.gov/pubmed/27389279
http://dx.doi.org/10.1186/s12885-016-2474-z
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author Garcia, Patrick Vianna
Seiva, Fábio Rodrigues Ferreira
Carniato, Amanda Pocol
de Mello Júnior, Wilson
Duran, Nelson
Macedo, Alda Maria
de Oliveira, Alexandre Gabarra
Romih, Rok
Nunes, Iseu da Silva
Nunes, Odilon da Silva
Fávaro, Wagner José
author_facet Garcia, Patrick Vianna
Seiva, Fábio Rodrigues Ferreira
Carniato, Amanda Pocol
de Mello Júnior, Wilson
Duran, Nelson
Macedo, Alda Maria
de Oliveira, Alexandre Gabarra
Romih, Rok
Nunes, Iseu da Silva
Nunes, Odilon da Silva
Fávaro, Wagner José
author_sort Garcia, Patrick Vianna
collection PubMed
description BACKGROUND: The new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom BCG (Bacillus Calmette-Guerin) has failed or is contraindicated are recently increasing due to the development of new drugs. Although agents like mitomycin C and BCG are routinely used, there is a need for more potent and/or less-toxic agents. In this scenario, a new perspective is represented by P-MAPA (Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride), developed by Farmabrasilis (non-profit research network). This study detailed and characterized the mechanisms of action of P-MAPA based on activation of mediators of Toll-like Receptors (TLRs) 2 and 4 signaling pathways and p53 in regulating angiogenesis and apoptosis in an animal model of NMIBC, as well as, compared these mechanisms with BCG treatment. RESULTS: Our results demonstrated the activation of the immune system by BCG (MyD88-dependent pathway) resulted in increased inflammatory cytokines. However, P-MAPA intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway (TRIF-dependent pathway), which was more effective in the NMIBC treatment. Interferon signaling pathway activation induced by P-MAPA led to increase of iNOS protein levels, resulting in apoptosis and histopathological recovery. Additionally, P-MAPA immunotherapy increased wild-type p53 protein levels. The increased wild-type p53 protein levels were fundamental to NO-induced apoptosis and the up-regulation of BAX. Furthermore, interferon signaling pathway induction and increased p53 protein levels by P-MAPA led to important antitumor effects, not only suppressing abnormal cell proliferation, but also by preventing continuous expansion of tumor mass through suppression of angiogenesis, which was characterized by decreased VEGF and increased endostatin protein levels. CONCLUSIONS: Thus, P-MAPA immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of patients that are refractory or resistant to BCG intravesical therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2474-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-49376122016-07-09 Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier Garcia, Patrick Vianna Seiva, Fábio Rodrigues Ferreira Carniato, Amanda Pocol de Mello Júnior, Wilson Duran, Nelson Macedo, Alda Maria de Oliveira, Alexandre Gabarra Romih, Rok Nunes, Iseu da Silva Nunes, Odilon da Silva Fávaro, Wagner José BMC Cancer Research Article BACKGROUND: The new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom BCG (Bacillus Calmette-Guerin) has failed or is contraindicated are recently increasing due to the development of new drugs. Although agents like mitomycin C and BCG are routinely used, there is a need for more potent and/or less-toxic agents. In this scenario, a new perspective is represented by P-MAPA (Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride), developed by Farmabrasilis (non-profit research network). This study detailed and characterized the mechanisms of action of P-MAPA based on activation of mediators of Toll-like Receptors (TLRs) 2 and 4 signaling pathways and p53 in regulating angiogenesis and apoptosis in an animal model of NMIBC, as well as, compared these mechanisms with BCG treatment. RESULTS: Our results demonstrated the activation of the immune system by BCG (MyD88-dependent pathway) resulted in increased inflammatory cytokines. However, P-MAPA intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway (TRIF-dependent pathway), which was more effective in the NMIBC treatment. Interferon signaling pathway activation induced by P-MAPA led to increase of iNOS protein levels, resulting in apoptosis and histopathological recovery. Additionally, P-MAPA immunotherapy increased wild-type p53 protein levels. The increased wild-type p53 protein levels were fundamental to NO-induced apoptosis and the up-regulation of BAX. Furthermore, interferon signaling pathway induction and increased p53 protein levels by P-MAPA led to important antitumor effects, not only suppressing abnormal cell proliferation, but also by preventing continuous expansion of tumor mass through suppression of angiogenesis, which was characterized by decreased VEGF and increased endostatin protein levels. CONCLUSIONS: Thus, P-MAPA immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of patients that are refractory or resistant to BCG intravesical therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2474-z) contains supplementary material, which is available to authorized users. BioMed Central 2016-07-07 /pmc/articles/PMC4937612/ /pubmed/27389279 http://dx.doi.org/10.1186/s12885-016-2474-z Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Garcia, Patrick Vianna
Seiva, Fábio Rodrigues Ferreira
Carniato, Amanda Pocol
de Mello Júnior, Wilson
Duran, Nelson
Macedo, Alda Maria
de Oliveira, Alexandre Gabarra
Romih, Rok
Nunes, Iseu da Silva
Nunes, Odilon da Silva
Fávaro, Wagner José
Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier
title Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier
title_full Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier
title_fullStr Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier
title_full_unstemmed Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier
title_short Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier
title_sort increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of p-mapa biological response modifier
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937612/
https://www.ncbi.nlm.nih.gov/pubmed/27389279
http://dx.doi.org/10.1186/s12885-016-2474-z
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