Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer

Autor(es)

Favaro, Wagner J. ^{[1, 2]} ; Nunes, Odilon S. ^[1] ; Seiva, Fabio R. F. ^[2] ; Nunes, Iseu S. ^[1] ; Woolhiser, Lisa K. ^[3] ; Duran, Nelson ^{[1, 4, 5]} ; Lenaerts, Anne J. ^[3]

Afiliação do(s) autor(es)

^[1] Farmabrasilis R&D Div, Campinas, SP - Brazil

^[2] Univ Campinas UNICAMP, Inst Biol, Dept Struct & Funct Biol, BR-61091308 Campinas, SP - Brazil

^[3] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 - USA

^[4] Univ Estadual Campinas, UNICAMP, Inst Chem, Biol Chem Lab, Campinas, SP - Brazil

^[5] Univ Fed do ABC, Ctr Nat & Human Sci, Santo Andre, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INFECTIOUS AGENTS AND CANCER; v. 7, JUN 18 2012.
• Citações Web of Science: 21

Resumo

Background: Compounds that can act as agonists for toll-like receptors (TLRs) may be promising candidates for the development of drugs against infectious diseases and cancer. The present study aimed to characterize the immunomodulatory effects of P-MAPA on TLRs in vitro and in vivo, as well as to investigate its potential as adjuvant therapy in infectious diseases and cancer. Methods: For these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-kappa B activation in HEK293 cells expressing a given TLR, and using an in vivo animal model for bladder cancer (BC). The antimicrobial activity of P-MAPA was tested against Mycobacterium tuberculosis (TB) in vitro in an MIC assay, and in vivo using an aerosol infection model of murine tuberculosis. Antitumor effects of P-MAPA were tested in an animal model with experimentally induced BC. Moxifloxacin (MXF) and Bacillus Calmette-Guerin (BCG) were used as positive controls in the animal models. Results: The results showed that P-MAPA, administered alone or in combination with MXF, induced significant responses in vivo against TB. In contrast, the compound did not show antimicrobial activity in vitro. P-MAPA showed a significant stimulatory effect on human TLR2 and TLR4 in vitro. In BC, TLR2, TLR4 and p53 protein levels were significantly higher in the P-MAPA group than in the BCG group. The most common histopathological changes in each group were papillary carcinoma in BC group, low-grade intraepithelial neoplasia in BCG group and simple hyperplasia in P-MAPA group. Concerning the toxicological analysis performed during BC treatment, P-MAPA did not show evidence for hepatotoxicity and nephrotoxicity. Conclusions: In conclusion, P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels. P-MAPA immunotherapy was more effective in restoring p53 and TLRs reactivities and showed significantly greater antitumor activity than BCG. The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases. (AU)

• Processo FAPESP: 11/05726-4 - Análises do Estresse Oxidativo, Enzimas Antioxidantes e Sinalização Via Receptores Toll-Like 2 e 4 na Progressão do Câncer de Bexiga Urinária de Ratos, frente às Imunoterapias Intravesicais com Bacilo Calmette-Guerin e P-MAPA
• Beneficiário: Fábio Rodrigues Ferreira Seiva
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado