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

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dc.contributor.authorGarcia, Patrick Vianna
dc.contributor.authorSeiva, Fábio Rodrigues Ferreira
dc.contributor.authorCarniato, Amanda Pocol
dc.contributor.authorde Mello Júnior, Wilson [UNESP]
dc.contributor.authorDuran, Nelson
dc.contributor.authorMacedo, Alda Maria
dc.contributor.authorde Oliveira, Alexandre Gabarra [UNESP]
dc.contributor.authorRomih, Rok
dc.contributor.authorNunes, Iseu da Silva
dc.contributor.authorNunes, Odilon da Silva
dc.contributor.authorFávaro, Wagner José
dc.contributor.institutionUniversidade Estadual de Campinas (UNICAMP)
dc.contributor.institutionInstitute of Biology
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionFarmabrasilis R and D Division
dc.contributor.institutionFaculty of Medicine
dc.date.accessioned2018-12-11T17:28:59Z
dc.date.available2018-12-11T17:28:59Z
dc.date.issued2016-07-07
dc.description.abstractBackground: 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.en
dc.description.affiliationUniversity of Campinas (UNICAMP) Laboratory of Urogenital Carcinogenesis and Immunotherapy Department of Structural and Functional Biology, P.O. BOX 6109
dc.description.affiliationNorth of Parana State University (UENP) Institute of Biology
dc.description.affiliationUNESP - Univ Estadual Paulista Department of Anatomy Institute of Biosciences
dc.description.affiliationFarmabrasilis R and D Division
dc.description.affiliationUniversity of Campinas (UNICAMP) NanoBioss Institute of Chemistry
dc.description.affiliationUniversity of Campinas (UNICAMP) Department of Internal Medicine
dc.description.affiliationSão Paulo State University (UNESP) Department of Physical Education
dc.description.affiliationUniversity of Ljubljana Institute of Cell Biology Faculty of Medicine
dc.description.affiliationUnespUNESP - Univ Estadual Paulista Department of Anatomy Institute of Biosciences
dc.description.affiliationUnespSão Paulo State University (UNESP) Department of Physical Education
dc.identifierhttp://dx.doi.org/10.1186/s12885-016-2474-z
dc.identifier.citationBMC Cancer, v. 16, n. 1, 2016.
dc.identifier.doi10.1186/s12885-016-2474-z
dc.identifier.file2-s2.0-84978378755.pdf
dc.identifier.issn1471-2407
dc.identifier.scopus2-s2.0-84978378755
dc.identifier.urihttp://hdl.handle.net/11449/178149
dc.language.isoeng
dc.relation.ispartofBMC Cancer
dc.relation.ispartofsjr1,464
dc.rights.accessRightsAcesso aberto
dc.sourceScopus
dc.subjectAngiogenesis
dc.subjectBacillus Calmette-Guerin
dc.subjectBladder Cancer
dc.subjectImmunotherapy
dc.subjectP-MAPA
dc.subjectP53
dc.subjectToll-like Receptor
dc.titleIncreased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: Mechanism of action of P-MAPA biological response modifieren
dc.typeArtigo
unesp.author.lattes6249449004253286[7]
unesp.author.orcid0000-0002-6620-5477[7]

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Artigos - Anatomia - IBB