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Investigation of the carboxyl-terminal Q-connexin peptide (ACT1) activity associated with the inhibitor of histone deacetylases sodium butyrate, and conventional chemotherapeutic agents, on the treatment of canine mammary tumors: in vitro assays

Grant number: 17/12855-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2017
Effective date (End): August 31, 2020
Field of knowledge:Agronomical Sciences - Veterinary Medicine
Principal Investigator:Maria Lucia Zaidan Dagli
Grantee:Ivone Izabel Mackowiak da Fonseca
Home Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Nowadays, cancer represents one of the greatest challenges to science and medical practice in man. As for animals, the problem is no different: there is a need to intensify research in Veterinary Oncology, in all its aspects, particularly with regard to new treatments for animal neoplasms. The effectiveness of an antineoplastic agent for the treatment of a specific cancer can definitely be determined by clinical trials. However, due to ethical reasons, research has to start in experimental systems. The present project aims to investigate the activity of carboxy-terminal Q-connexin peptide (ACT1) as a possible new antineoplastic therapy for canine mammary tumors by performing pre-clinical in vitro tests. The ACT1 peptide allows to specifically examine the endogenous activity of connexin 43 (Cx43) in communicating junctions, without altering the expression levels of Cx43, this peptide consisting of 25 amino acids (ACT1) that mimics the normal Cx43 cytoplasmic domain. In this project, the ACT1 peptide will be tested in canine mammary tumor cultures and these compared to human tumor mammary cell lines. Primary lineages of canine mammary tumors, belonging to the Experimental and Comparative Oncology Laboratory of FMVZ, and the commercial canine mammary tumor line called CF41 will be used. The human cell lines to be used are MCF10a, MCF-7. Treatment with the ACT1 peptide at doses reported in the literature (50, 100 and 200 ¼M) associated or not with the histone desacetylase inhibitor sodium butyrate-NaB (0.1, 0.5, 0.75 mM) and different combinations will be followed, combining these substances among themselves and their associations with classical antineoplastic drugs such as tamoxifen citrate (10µM) and lapatinib (10 and 50nM). Both cell proliferation and death will be quantified. Studies have proven that the ACT1 peptide improves the activity of the chemotherapeutic agents tamoxifen and lapatinib, we hope with this study of the association of a histone desacetylase inhibitor to further improve the action of these drugs used in the treatment of breast tumors. In this way, to advance in new antineoplastic therapies, obtaining important results that will allow, in a timely manner, the conduction of pre-clinical and clinical trials in dogs.