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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory of Urogenital Carcinogenesis and Immunotherapy, Department of Structural and Functional Biology, University of Campinas (UNICAMP), P.O. BOX 6109, zip code 13083-865, Campinas, São Paulo, Brazil.
authors.forename: Patrick Vianna
authors.initials: PV
authors.lastname: Garcia
authors.affiliation: Institute of Biology, North of Parana State University (UENP), Bandeirantes, PR, Brazil.
authors.forename: Fábio Rodrigues Ferreira
authors.initials: FR
authors.lastname: Seiva
authors.affiliation: Laboratory of Urogenital Carcinogenesis and Immunotherapy, Department of Structural and Functional Biology, University of Campinas (UNICAMP), P.O. BOX 6109, zip code 13083-865, Campinas, São Paulo, Brazil.
authors.forename: Amanda Pocol
authors.initials: AP
authors.lastname: Carniato
authors.affiliation: Department of Anatomy, Institute of Biosciences, UNESP - Univ Estadual Paulista, Botucatu, SP, Brazil.
authors.forename: Wilson
authors.initials: W
authors.lastname: de Mello Júnior
authors.affiliation: Farmabrasilis R&D Division, Campinas, SP, Brazil.|NanoBioss, Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Nelson
authors.initials: N
authors.lastname: Duran
authors.affiliation: Farmabrasilis R&D Division, Campinas, SP, Brazil.
authors.forename: Alda Maria
authors.initials: AM
authors.lastname: Macedo
authors.affiliation: Department of Internal Medicine, University of Campinas (UNICAMP), Campinas, SP, Brazil.|Department of Physical Education, São Paulo State University (UNESP), Rio Claro, SP, Brazil.
authors.forename: Alexandre Gabarra
authors.initials: AG
authors.lastname: de Oliveira
authors.affiliation: Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Rok
authors.initials: R
authors.lastname: Romih
authors.affiliation: Farmabrasilis R&D Division, Campinas, SP, Brazil.
authors.forename: Iseu da Silva
authors.initials: Ida S
authors.lastname: Nunes
authors.affiliation: Farmabrasilis R&D Division, Campinas, SP, Brazil.
authors.forename: Odilon da Silva
authors.initials: Oda S
authors.lastname: Nunes
authors.affiliation: Laboratory of Urogenital Carcinogenesis and Immunotherapy, Department of Structural and Functional Biology, University of Campinas (UNICAMP), P.O. BOX 6109, zip code 13083-865, Campinas, São Paulo, Brazil. wjfavaro@gmail.com.|Farmabrasilis R&D Division, Campinas, SP, Brazil. wjfavaro@gmail.com.|NanoBioss, Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, Brazil. wjfavaro@gmail.com.
authors.forename: Wagner José
authors.initials: WJ
authors.lastname: Fávaro
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D008041:Linoleic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D051193:Toll-Like Receptors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D001500:BCG Vaccine; D007155:Immunologic Factors; D008041:Linoleic Acids; D009943:Organophosphorus Compounds; D051193:Toll-Like Receptors; D016159:Tumor Suppressor Protein p53; C076534:magnesium ammonium phospholinoleate anhydride
keywords: Angiogenesis; Bacillus Calmette–Guerin; Bladder Cancer; Immunotherapy; P-MAPA; Toll-like Receptor; p53