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Effect of P-MAPA immunomodulator associated to interleukin-12 on Ovarian Cancer: in vitro and in vivo approaches involving the inflammatory process and immune system

Abstract

Ovarian cancer (OC) has the highest incidence in postmenopausal women and, due to its late diagnosis and poor prognosis, is the fifth most common cause of cancer death. OC is responsive to chemotherapeutic agents, but many women may develop chemoresistance linked to the inflammatory process. Interleukin(IL)-12 has been administered in patients with solid tumors, including OC, in an attempt to stimulate the polarized Th1-type inflammatory response with high production of interferon-gamma (IFN-g). However, their antitumor effects are limited. The P-MAPA immunomodulator is a biopolymer produced by Farmabrasilis, and has shown significant effects on components of the immune system being capable of stimulating Toll-like receptors (TLR2 and TLR4), production of T cells secreting cytokines (IL-2 and IFN-g) as well as promotion of increased activity of natural killer (NK) cells. Therefore, this study will investigate the effects of P-MAPA and IL-12 as functional treatments on inflammatory process related to cisplatin-resistant human SKOV-3 cells and on the immune system associated to chemically induced ovarian carcinomas in Fischer 344 rats. To achieve the proposal, the following parameters will be evaluated: monitoring the effects of different treatment doses and incubation periods through cell count, assessment of cell viability, cytotoxicity, migration/invasion assay and cell cycle arrest, immunolocalization of TLR2 and TLR4 and quantification of TLR2/TLR4 as well as immunological factors: myeloid differentiation factor (MyD88), IFN-g inducing factor associated TIR domain (TRIF), nuclear factor related to interferon (IRF3) and nuclear factor kappaB (NF-kB) involved in the inflammatory process, evaluation of the secreted proteins/peptides through the global proteomics by electrospray technique (LC MS-MS), measurement of the inflammatory process mediators (pro- and anti-inflammatory) in the culture supernatant via multiplex assay, evaluation of the treatments on OC histopatology, immunolocalization and quantification of TLR2/TLR4 as well as immunological factors in OC tissue, quantification of TCD4+, TCD8+, Tregs, and NKs using flow cytometry, and multiplex assay for OC-related inflammatory mediators. These results may assist in the understanding of the combined effects of the P-MAPA and IL-12 in different responses resulting from the inflammatory process and immune system associated with the OC. (AU)

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Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SILVEIRA, HENRIQUE SPAULONCI; LUPI, LUIZ ANTONIO; ROMAGNOLI, GRAZIELA GORETE; KANENO, RAMON; NUNES, ISEU DA SILVA; FAVARO, WAGNER JOSE; DE ALMEIDA CHUFFA, LUIZ GUSTAVO. P-MAPA activates TLR2 and TLR4 signaling while its combination with IL-12 stimulates CD4+and CD8+effector T cells in ovarian cancer. Life Sciences, v. 254, AUG 1 2020. Web of Science Citations: 0.
LUPI, LUIZ ANTONIO; DELELLA, FLAVIA KARINA; CUCIELO, MAIRA SMANIOTTO; ROMAGNOLI, GRAZIELA GORETE; KANENO, RAMON; NUNES, ISEU DA SILVA; DOMENICONI, RAQUEL FANTIN; MARTINEZ, MARCELO; MARTINEZ, FRANCISCO EDUARDO; FAVARO, WAGNER JOSA; DE ALMEIDA CHUFFA, LUIZ GUSTAVO. P-MAPA and Interleukin-12 Reduce Cell Migration/Invasion and Attenuate the Toll-Like Receptor-Mediated Inflammatory Response in Ovarian Cancer SKOV-3 Cells: A Preliminary Study. Molecules, v. 25, n. 1 JAN 2020. Web of Science Citations: 0.
LUPI JUNIOR, LUIZ ANTONIO; CUCIELO, MAIRA SMANIOTTO; DOMENICONI, RAQUEL FANTIN; DOS SANTOS, LUCILENE DELAZARI; SILVEIRA, HENRIQUE SPAULONCI; NUNES, ISEU DA SILVA; MARTINEZ, MARCELO; MARTINEZ, FRANCISCO EDUARDO; FAVARO, WAGNER JOSE; DE ALMEIDA CHUFFA, LUIZ GUSTAVO. P-MAPA and IL-12 Differentially Regulate Proteins Associated with Ovarian Cancer Progression: A Proteomic Study. ACS OMEGA, v. 4, n. 26, p. 21761-21777, DEC 24 2019. Web of Science Citations: 0.
DE ALMEIDA CHUFFA, LUIZ GUSTAVO; FERREIRA SEIVA, FABIO RODRIGUES; CUCIELO, MAIRA SMANIOTTO; SILVEIRA, HENRIQUE SPAULONCI; REITER, RUSSEL J.; LUPI, LUIZ ANTONIO. Mitochondrial functions and melatonin: a tour of the reproductive cancers. CELLULAR AND MOLECULAR LIFE SCIENCES, v. 76, n. 5, p. 837-863, MAR 2019. Web of Science Citations: 2.
DURAN, NELSON; FAVARO, WAGNER J. BIOGENIC SYNTHESIS OF IMPORTANT ENVIRONMENTAL MINERALS: MAGNESIUM PHOSPHATE COMPOUNDS AND PERSPECTIVES. Química Nova, v. 41, n. 5, p. 567-576, MAY 2018. Web of Science Citations: 1.
DE ALMEIDA CHUFFA, LUIZ GUSTAVO; FERREIRA, GRAZIELLE DE MOURA; LUPI, LUIZ ANTONIO; NUNES, ISEU DA SILVA; FAVARO, WAGNER JOSE. P-MAPA immunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling. JOURNAL OF OVARIAN RESEARCH, v. 11, JAN 17 2018. Web of Science Citations: 4.
NELSON DURÁN; WAGNER J. FAVARO. BIOGENIC SYNTHESIS OF IMPORTANT ENVIRONMENTAL MINERALS: MAGNESIUM PHOSPHATE COMPOUNDS AND PERSPECTIVES. Química Nova, v. 41, n. 5, p. -, Maio 2018.
ZONTA, YOHAN RICCI; MARTINEZ, MARCELO; CAMARGO, ISABEL CRISTINA C.; DOMENICONI, RAQUEL F.; LUPI JUNIOR, LUIZ ANTONIO; PINHEIRO, PATRICIA FERNANDA F.; REITER, RUSSEL J.; MARTINEZ, FRANCISCO EDUARDO; CHUFFA, LUIZ GUSTAVO A. Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 18, n. 4 APR 2017. Web of Science Citations: 21.
DE ALMEIDA CHUFFA, LUIZ GUSTAVO; LUPI-JUNIOR, LUIZ ANTONIO; COSTA, ALINE BALANDIS; AMORIM, JOAO PAULO DE ARRUDA; SEIVA, FABIO RODRIGUES FERREIRA. The role of sex hormones and steroid receptors on female reproductive cancers. Steroids, v. 118, p. 93-108, FEB 2017. Web of Science Citations: 51.

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