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.
Highlights
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
No further testing of P-MAPA was performed with standard Minimum Inhibitory Concentration (MIC) assays using colorimetric methods
In the bladder cancer (BC) studies presented here, the results demonstrated that P-MAPA immunotherapy was more effective in restoring normal morphological features and alkaline phosphatase activity compared to Bacillus Calmette-Guerin (BCG)
Summary
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. Besides the impairment of the immunological status associated with the main disease, several therapies can often cause additional immunosuppression creating the conditions for the emergence of infections [1,2,3,4]. In this scenario, compounds which can act in the immune system such as new vaccines, vaccine adjuvants and biological response modifiers are considered potential candidates for the treatment of these diseases or conditions. TLRs are transmembrane proteins that recognize pathogen-associated molecular patterns as well as endogenous damageassociated molecular patterns and elicit pathogen-induced and noninfectious inflammatory responses [10,11].TLRs were initially detected only on immune cells, but recent studies demonstrate that tumor cells express functional TLRs and that TLR signaling can promote opposite outcomes: tumor growth and immune evasion or apoptosis and cell cycle arrest [12,13,14]
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