Toxicogenetics evaluation and study of antiproliferative response mechanisms of ruthenium-based metallodrugs containing naphthoquinones ligands in tumor cells growing in conventional and 3D systems

• Grant number: 16/22429-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2018
• End date: December 31, 2019
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Fernando Rogério Pavan
• Grantee: Rone Aparecido de Grandis
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Recently, ruthenium complexes have occupied a prominent position in the search for new anti-cancer therapies due their potential of action, selectivity in tumor tissues and less toxicity compared to current platinum complexes in clinical use. The diversity of ligands has been shown to be crucial for these complexes reach multiple biological targets and thus overcome the limitation of current therapies. One approach for multi-target molecules is the combination of bioactive ligands with recognized antitumor properties, such as naphthoquinone derivatives. Thus, the aims of this study are based on the evaluation and characterization of toxicogenetics and antitumor properties of eight new ruthenium complexes containing the bioligands lapachol and lawsone. An initial screening will be performed by cell viability in prostate, lung, breast, colon and liver cancer. The complexes which show promising activity will be evaluated for their ability to interact to DNA by physico-chemical tests and the evaluation of genotoxicity in conventional and three-dimensional cell culture systems (3D). The possible mechanisms by which these complexes induce cell death will be evaluated on apoptosis and necrosis, generation of Reactive Oxygen Species (ROS) and expression of genes involved in key cellular growth pathways, epigenetics and drug metabolism. Finally, it is expected that the data achieved, allow to report any correlation between the structure and activity, in order to elucidate the possible mechanisms of action of these complexes. (AU)

Scientific publications

(5)

(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)

DE SOUZA, P. C.; FERNANDES, G. F. S.; MARINO, L. B.; RIBEIRO, C. M.; DA SILVA, P. B.; CHORILLI, M.; SILVA, C. S. P.; RESENDE, F. A.; SOLCIA, M. C.; DE GRANDIS, R. A.; et al. Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection. BIOMEDICINE & PHARMACOTHERAPY, v. 130, OCT 2020. (18/11079-0, 18/00163-0, 14/03920-6, 17/12419-7, 16/09502-7, 14/02240-1, 13/14957-5, 16/02860-5, 14/24811-0, 16/24633-0, 18/17739-2, 15/19531-1, 16/22429-7, 14/11586-9)

DE GRANDIS, RONE APARECIDO; DA SILVA DOS SANTOS, PATRICK WELLINGTON; DE OLIVEIRA, KATIA MARA; TOMAZELA MACHADO, ANA RITA; AISSA, ALEXANDRE FERRO; BATISTA, ALZIR AZEVEDO; GREGGI ANTUNES, LUSANIA MARIA; PAVAN, FERNANDO ROGERIO. Novel lawsone-containing ruthenium(II) complexes: Synthesis, characterization and anticancer activity on 2D and 3D spheroid models of prostate cancer cells. BIOORGANIC CHEMISTRY, v. 85, p. 455-468, APR 2019. (18/00163-0, 16/22429-7, 16/16312-0)

DE GRANDIS, RONE A.; OLIVEIRA, KATIA M.; GUEDES, ADRIANA P. M.; DOS SANTOS, PATRICK W. S.; AISSA, ALEXANDRE F.; BATISTA, ALZIR A.; PAVAN, FERNANDO R.. A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells. FRONTIERS IN ONCOLOGY, v. 11, JUN 24 2021. (17/15850-0, 16/22429-7, 18/00163-0)

DE CAMARGO, MARIANA S.; DE GRANDIS, RONE A.; DA SILVA, MONIZE M.; DA SILVA, PATRICIA B.; SANTONI, MARIANA M.; EISMANN, CARLOS E.; MENEGARIO, AMAURI A.; COMINETTI, MARCIA R.; ZANELLI, CLESLEI F.; PAVAN, FERNANDO R.; et al. Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors. BIOMETALS, v. 32, n. 1, p. 89-100, FEB 2019. (12/21529-7, 16/22429-7, 16/16312-0)

DE GRANDIS, RONE APARECIDO; COSTA, ANALU ROCHA; FERREIRA MORAES, CARLOS ANDRE; SAMPAIO, NATALIA ZANETI; CERQUEIRA, IGOR HENRIQUE; MARQUES, WELLINGTON GARCIA; MUNDIN GUEDES, ADRIANA PEREIRA; DE ARAUJO-NETO, JOAO HONORATO; PAVAN, FERNANDO ROGERIO; DEMIDOFF, FELIPE CERQUEIRA; et al. Novel Ru(II)-bipyridine/phenanthroline-lapachol complexes as potential anti-cancer agents. Journal of Inorganic Biochemistry, v. 237, p. 12-pg., 2022-12-01. (16/22429-7, 17/15850-0, 17/16278-9, 20/14561-8, 21/04876-4)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

GRANDIS, Rone Aparecido de. Toxicogenetic evaluation and study of antiproliferative response mechanisms of ruthenium-based metallodrugs containing naphthoquinones ligands in tumor cells growing in conventional and 3D systems. 2020. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara Araraquara.