SIMULTANEOUS BLOCK OF ANGIOGENESIS THROUGH THE SIGNALING PATHWAYS PI3K AND AMPK/AKT/ mTOR AFTER TREATMENT WITH METFORMIN AND LY294002 IN MAMMARY TUMOR

• Grant number: 13/19862-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2013
• End date: November 30, 2016
• Field of knowledge: Agronomical Sciences - Veterinary Medicine - Animal Pathology
• Principal Investigator: Debora Aparecida Pires de Campos Zuccari
• Grantee: Marina Gobbe Moschetta
• Host Institution: Faculdade de Medicina de São José do Rio Preto (FAMERP). Secretaria de Desenvolvimento Econômico (São Paulo - Estado). São José do Rio Preto , SP, Brazil

Abstract

Hypoxia is a known adverse factor in cancer treatment, able to activate signaling pathways MAPK and PI3K / Akt / mTOR, the two major pathways involved in the process of angiogenesis which is regulated by numerous factors, the most significant is the Hypoxia-Inducible Factor - 1 (HIF-1) and Vascular Endothelial Growth Factor (VEGF). The transcription factor HIF-1± is the major regulator of pathophysiological response of cells to conditions of hypoxia, capable of activating transcription of the VEGF, which promotes angiogenesis through its ability to stimulate the growth, migration and invasion of endothelial cells. Therefore, many studies have focused on developing treatment strategies that may be involved in signaling pathways PI3K-MAPK/Akt/mTOR in attempt to inhibit tumor progression. Some studies have shown that treatment with metformin inhibits cell growth through signaling pathway of MAPK/Akt/mTOR and that LY294002 has anti-angiogenic features, able to block the PI3K/Akt signaling pathway in hypoxia, decreasing the release of factors growth such as VEGF. However, little is known about the influence of treatment with metformin in combination with LY294002 in angiogenesis, particularly in mammary tumor. The objective of this study is to evaluate treatment with metformin and LY294002 in tumor angiogenesis as a therapeutic strategy in mammary tumors, an in vitro and in vivo study. The gene and protein expression of HIF-1± and VEGF will be verified by qPCR and immunohistochemistry, respectively. The cell distribution in the phases of the cell cycle and apoptosis by flow cytometry, the expression of proteins involved in signaling pathways of MAPK, PI3K / Akt / mTOR by Antibody Array and the angiogenesis by immunostaining of endothelial cell marker CD31. The results obtained may provide evidence for the use of metformin with or without the inhibitor LY294002 as therapeutic agents in mammary tumor.

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)

MOSCHETTA, MARINA G.; LEONEL, CAMILA; MASCHIO-SIGNORINI, LARISSA B.; BORIN, THAIZ F.; GELALETI, GABRIELA B.; JARDIM-PERASSI, BRUNA V.; FERREIRA, LIVIA C.; SONEHARA, NATHALIA M.; CARVALHO, LIVIA G. S.; HELLMEN, EVA; et al. Evaluation of Angiogenesis Process after Metformin and LY294002 Treatment in Mammary Tumor. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 19, n. 5, p. 655-666, 2019. (13/19862-2)