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 Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2017
• End date: October 31, 2020
• Field of knowledge: Agronomical Sciences - Veterinary Medicine - Animal Pathology
• Principal Investigator: Maria Lucia Zaidan Dagli
• Grantee: Ivone Izabel Mackowiak da Fonseca
• Host 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.

Scientific publications

(4)

(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)

NISHIYA, ADRIANA TOMOKO; NAGAMINE, MARCIA KAZUMI; MACKOWIAK DA FONSECA, IVONE IZABEL; MIRALDO, ANDREA CARINGI; SCATTONE, NAYRA VILLAR; GUERRA, JOSE LUIZ; XAVIER, JOSE GUILHERME; SANTOS, MARIO; MASSOCO DE SALLES GOMES, CRISTINA OLIVEIRA; WARD, JERROLD MICHAEL; et al. Inhibitory Effects of a Reengineered Anthrax Toxin on Canine Oral Mucosal Melanomas. TOXINS, v. 12, n. 3, MAR 2020. (16/20479-7, 15/25158-1, 15/16776-3, 17/12855-1)

SATO, AYAMI; DA FONSECA, IVONE IZABEL MACKOWIAK; NAGAMINE, MARCIA KAZUMI; DE TOLEDO, GABRIELA FERNANDES; OLIO, RENNAN; HERNANDEZ-BLAZQUEZ, FRANCISCO JAVIER; YANO, TOMOHIRO; YEH, ELIZABETH SHINMAY; DAGLI, MARIA LUCIA ZAIDAN. Effects of Alpha-Connexin Carboxyl-Terminal Peptide (aCT1) and Bowman-Birk Protease Inhibitor (BBI) on Canine Oral Mucosal Melanoma (OMM) Cells. FRONTIERS IN VETERINARY SCIENCE, v. 8, JUN 10 2021. (16/20479-7, 18/11202-7, 17/12855-1, 18/16515-3)

DA FONSECA, JONATHAN MACKOWIAK; MACKOWIAK DA FONSECA, IVONE IZABEL; NAGAMINE, MARCIA KAZUMI; MASSOCO, CRISTINA DE OLIVEIRA; NISHIYA, ADRIANA TOMOKO; WARD, JERROLD MICHAEL; LIU, SHIHUI; LEPPLA, STEPHEN HOWARD; BUGGE, THOMAS HENRIK; ZAIDAN DAGLI, MARIA LUCIA. Inhibitory Effects of a Reengineered Anthrax Toxin on Canine and Human Osteosarcoma Cells. TOXINS, v. 12, n. 10, OCT 2020. (16/20479-7, 17/12855-1, 15/16776-3)

DO NASCIMENTO, RODRIGO S.; NAGAMINE, MARCIA K.; DE TOLEDO, GABRIELA F.; CHAIBLE, LUCAS M.; TEDARDI, V, MARCELLO; DEL-GRANDE, MURILO P.; DA FONSECA, IVONE I. M.; DAGLI, MARIA L. Z.. Sodium dichloroacetate attenuates the growth of B16-F10 melanoma in vitro and in vivo: an opportunity for drug repurposing. ANTI-CANCER DRUGS, v. 32, n. 2, p. 111-116, FEB 2021. (16/20479-7, 17/12855-1, 14/04819-7, 15/01836-0, 18/16515-3)