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

Abstract

BackgroundCompounds 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.MethodsFor these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-κB 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.ResultsThe 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.ConclusionsIn 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.

Biogenic Synthesis of Important Environmental Minerals: Magnesium Phosphate Compounds and Perspectives

“…These data suggested that P-MAPA exhibited an immunotherapeutic effect against tuberculosis only in vivo. 73,74,86 Inhibition of tumor growth (e.g., marked inhibition) and concomitant extension of the host's life span after P-MAPA treatment of animals bearing transplantable lymphosarcoma-180, plasmacytoma SP-2/O/ Ag14, Ehrlich solid carcinoma, Walker 256 tumor and spontaneous mammary carcinoma-SP-1 has been observed. 68,77 Myelosuppression has been observed simultaneously with increased numbers of spleen CFU-GM in tumor-bearing mice.…”

“…65,83 A few years ago, P-MAPA appeared as a potential candidate for intravesical therapy for non-muscle invasive bladder cancer (NMIBC). This immunomodulator was found to be important in the treatment of these types of urinary bladder cancer, 76,82,84,86,87 as well as in the prostate cancer 88 and of pancreatic cancer. 89 The most recent results with respect to NMIBC demonstrated that the immune system by BCG activation (MyD88-dependent pathway) leads to an increased inflammatory cytokines production.…”

Immunological Processes in Cancer: A Link Between Inflammation and Immunity

“…BCG for cancer immunotherapy activity may have its function enhanced by addition of IL10 blocking monoclonal antibody (Luo et al, 2012). Favaro et al (2012) published an interesting article where they compared and characterized the effects of intravesical BCG and/or staphylococcal enterotoxin B for non-muscle invasive bladder cancer. The results showed that both therapies presented similar anti-angiogenic effect and they observed additional activity compared to monotherapy.…”

“…They concluded that given the complexity of tumor-stroma-immune system interactions, a mathematical modeling could help researches to evaluate quantitatively these strategies or even the result of their combination. Favaro et al (2012) characterized the effects of P-MAPA (Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride) on TLRs in vitro and in vivo, as well as to assess its potential as adjuvant therapy for infectious diseases and cancer. The results evidenced that P-MAPA acted as TLR ligand in vitro and improved the immunological status in model for bladder cancer, increasing TLR2 and TLR4 protein levels.…”

Antiproliferative and antimicrobial activities of alkylbenzoquinone derivatives fromArdisia kivuensis

“…A substantial number of microbial pathogens have been putatively linked to cancer (Helicobacter pylori, Hepatitis C virus), and in turn, up to 30% of all cancers worldwide have been related to infectious diseases (Buonaguro et al, 2006). In cancer, besides the impairment of the immunological status associated with the main diseases, several chemotherapeutic agents can often cause additional immunosuppression creating conditions for the emergence of opportunistic infections (Fávaro, 2012). This situation emphasizes the urgent need for developing new drugs.…”