P-MAPA immunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling

Author(s)

de Almeida Chuffa, Luiz Gustavo ^[1] ; Ferreira, Grazielle de Moura ^[1] ; Lupi, Luiz Antonio ^[1] ; Nunes, Iseu da Silva ^[2] ; Favaro, Wagner Jose ^{[2, 3]}

Affiliation

^[1] Sao Paulo State Univ, Inst Biosci, Dept Anat, UNESP, Rubiao Jr S-N, POB 18618-970, BR-510 Botucatu, SP - Brazil

^[2] Farmabrasilis R&D Div, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, UNICAMP, Dept Struct & Funct Biol, Lab Urogenital Carcinogenesis & Immunotherapy, Campinas, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF OVARIAN RESEARCH; v. 11, JAN 17 2018.
• Web of Science Citations: 4

Abstract

Background: Toll-like receptors (TLRs) are transmembrane proteins expressed on the surface of ovarian cancer (OC) and immune cells. Identifying the specific roles of the TLR-mediated signaling pathways in OC cells is important to guide new treatments. Because immunotherapies have emerged as the adjuvant treatment for patients with OC, we investigated the effect of a promising immunotherapeutic strategy based on protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4 signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) in an in vivo model of OC. Methods: Tumors were chemically induced by a single injection of 100 mu g of 7,12-dimethylbenz(a)anthracene (DMBA) directly under the left ovarian bursa in Fischer 344 rats. After the rats developed serous papillary OC, they were given P-MAPA, CIS or the combination P-MAPA+CIS as therapies. To understand the effects of the treatments, we assessed the tumor size, histopathology, and the TLR2- and TLR4-mediated inflammatory responses. Results: Although CIS therapy was more effective than P-MAPA in reducing the tumor size, P-MAPA immunotherapy significantly increased the expressions of TLR2 and TLR4. More importantly, the combination of P-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction in tumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels of the following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkB alpha), and nuclear factor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6, it seems to increase interferon-gamma (IFN-gamma), which may induce the Thelper (Th1)-mediated immune response. Conclusion: Collectively, our results suggest that P-MAPA immunotherapy combined with cisplatin could be considered an important therapeutic strategy against OC cells based on signaling pathways activated by TLR4. (AU)

• FAPESP's process: 16/03993-9 - 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
• Grantee: Luiz Gustavo de Almeida Chuffa
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/00423-4 - Induction of ovarian tumor and the influence of the immunomodulator P-MAPA in combination with cisplatin on the Toll-like 2- and 4-signaling pathway in Fischer 344 rats
• Grantee: Grazielle de Moura Ferreira
• Support Opportunities: Scholarships in Brazil - Scientific Initiation