Induction of ovarian tumor and influence of melatonin on inflammatory signaling pathway mediated by Toll-like receptor 4 in UChB rats

• Grant number: 11/19294-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2012
• End date: March 31, 2012
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Francisco Eduardo Martinez
• Grantee: Luiz Gustavo de Almeida Chuffa
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Ovarian cancer has the highest incidence in peri-and post-menopausal women and, due to its late diagnosis and poor prognosis, is the fourth most common cause of cancer death. Ovarian cancer responds initially to chemotherapy agents, reducing the growth of tumor mass, however, many women timely develop chemoresistance linked to the inflammatory process. It is undisputed that risk factors, such as chronic alcoholism, present co-carcinogenic effects. Interestingly, proinflammatory mechanisms arising from ethanol-induced chemical mediators are similar to those found in ovarian cancer during the chemoresistance process. Since melatonin has immunomodulatory and oncostatic activities, and also seems to alleviate side effects of the disease, especially in hormone-dependent tumors, the study aims to evaluate the effect of ovarian tumor induction and the influence of long-term melatonin on inflammatory process through Toll-like receptor 4 signaling in a model of ethanol-preferring rats (UChB). Thus, the following parameters will be investigated: daily evaluation of the estrous cycle during the trials, frequency and characterization of the types of ovarian tumors by histopathological analysis, mapping and quantification of proteins by proteomic analysis (MALDI-Imaging - matrix-assisted laser desorption/ionization), immunolocalization and quantification of Toll-like receptors (TLR)-4, estradiol receptor (ER)-± and ER-² and immunological factors: nuclear factor kappa ² (NF-k²), inhibitor of NF-k² (Ik²), Ik² kinase complex (IKK²), myeloid differentiation factor (MyD88), mitogen-associated protein kinase (p38MAPK) and kinase receptor associated interleukin 1 (IRAK-1) by immunohistochemistry and Western blot. Furthermore, it will also be assessed the inflammatory process by obtaining the concentration of pro-inflammatory cytokines: interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-± by ELISA in ovarian tissue and the determinations of plasma 17²-estradiol, LH and FSH by radioimmunoassay (RIA). Our results will provide important evidence in clarifying the effects of melatonin during the inflammatory process related to ovarian cancer.

Scientific publications

(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)

CHUFFA, LUIZ GUSTAVO A.; FIORUCI-FONTANELLI, BEATRIZ A.; MENDES, LEONARDO O.; FAVARO, WAGNER J.; PINHEIRO, PATRICIA FERNANDA F.; MARTINEZ, MARCELO; MARTINEZ, FRANCISCO EDUARDO. Characterization of Chemically Induced Ovarian Carcinomas in an Ethanol-Preferring Rat Model: Influence of Long-Term Melatonin Treatment. PLoS One, v. 8, n. 12, DEC 18 2013. (11/19294-9, 13/02466-7)

CHUFFA, LUIZ GUSTAVO A.; FIORUCI-FONTANELLI, BEATRIZ A.; MENDES, LEONARDO O.; FERREIRA SEIVA, FABIO R.; MARTINEZ, MARCELO; FAVARO, WAGNER J.; DOMENICONI, RAQUEL F.; PINHEIRO, PATRICIA F. F.; DOS SANTOS, LUCILENE DELAZARI; MARTINEZ, FRANCISCO EDUARDO. Melatonin attenuates the TLR4-mediated inflammatory response through MyD88-and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer. BMC CANCER, v. 15, FEB 6 2015. (11/19294-9, 13/02466-7)