P-mapa, a promisor immunomodulator against tumor cells of colonic tissues: An investigation of the action mechanism over the TLR4 signaling pathway

• Published in: Life sciences (1973) Vol. 242; p. 117185
• Main Authors: Socca, Eduardo Augusto Rabelo, Reis, Sabrina Karen, Genaro, Sandra Cristina, Leite, Stephanie Kussik, Reis, Ianny Brum, Bockëlmann, Petra Karla, Durán, Nelson, Fávaro, Wagner José
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.02.2020; Elsevier BV
• Subjects: 1,2-Dimethylhydrazine; 5-Fluorouracil; Aberrant Crypt Foci - pathology; Animals; Anticancer properties; Antineoplastic Agents - therapeutic use; Biopolymers - therapeutic use; Cell division; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Cytokines; Enzyme-Linked Immunosorbent Assay; Fluorouracil; Fluorouracil - therapeutic use; Fungi; Histopathology; Immune system; Immunohistochemistry; Immunologic Factors - therapeutic use; Immunomodulation; Immunomodulators; Interferon; Interferon regulatory factor 3; Interferon-gamma; Linoleic Acids - therapeutic use; Male; Mucosa; NF-κB protein; Oleic Acids - therapeutic use; Organic chemistry; P-mapa; Rats; Rats, Inbred F344; Signal transduction; Signal Transduction - drug effects; Signaling; Synthesis; TLR4 protein; TLR4 signaling pathway; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Tumor cells; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; γ-Interferon; Interferon-gamma; P-mapa; 1,2-Dimethylhydrazine; TLR4 signaling pathway; Colorectal cancer; Fluorouracil
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.117185

Colorectal cancer (CRC) is a multifactorial syndrome that drives to uncontrollable cell division, genetic alterations, and functional alteration. In the present work, we evaluated the immunomodulatory properties of P-mapa, a compound extracted from Aspergillus oryzae fungus, versus Fluorouracil (5-FU) treatment in chemically induced CRC. CRC was induced by DMH in F344 rats. Animals of treated groups receive weekly 15 mg/Kg of 5-FU or 5 mg/Kg of P-mapa, over 10 weeks. Tissues were stained for aberrant crypt foci (ACF) counting and histopathology evaluation, immunostained for TLR4 pathways and quantified for TNFα Cytokine assay. DMH was efficient to induce hyperplastic lesions and ACF. Both treatments reduced significantly ACF formation and tumor aggressiveness. Immunohistochemistry for TLR4 signaling reveals that both treatments had no effect over the TLR4-NFκB signaling pathway. On the other hand, both succeed in increase interferon signaling, with activation of the TRIF-IRF3 pathway and consequently inducing IFNγ synthesis. The present results show the immunomodulatory properties of P-mapa in chemically induced CRC model. P-mapa induced a significant increase in Type-I IFNs synthesis and subsequently immune cell recruitment, resulting in an increase of IFNγ concentration in colorectal mucosa and its inhibitory effects over tumoral growth. In this scenario, P-mapa showed an interesting antitumoral effect by inhibiting tumor growth.