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Cytotoxicity and photo-cytotoxicity of new ruthenium-phthalocyanines compounds as nitric oxide and oxygen singlet producers in cancer cell lines. an innovative purpose for metal based drug

Grant number: 16/12707-0
Support type:Regular Research Grants
Duration: September 01, 2016 - February 28, 2019
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Roberto Santana da Silva
Grantee:Roberto Santana da Silva
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The discovery that nitric oxide (NO) can be used as a molecule with high cytotoxic potential, has driven researchers in order to prepare compounds that can act as release agents of NO by external stimulus. Several aspects of this feature should be considered in relation to: - rate release of NO; target where NO is released; formation of reactive nitrogen species; metabolism, among other factors. The biochemical mechanism, by which the reactivity of NO occurs, depending on the aspects listed above. Based on this several papers have been published in order to describe the processes related to the biochemical pathway of NO including cytotoxicity against cancer cells. Our group has contributed to this knowledge. Maybe the more relevant one involves the synergistic effect of fragment of ruthenium compounds, which had been used as NO donor. Most recently we have found that a second radical - singlet oxygen - can also increase this action and has been used in our work, as an alternative strategy for Photodynamic Therapy. In this context, the present project aims to contribute to this knowledge and establish the basis for a new class of metal based drugs. The compound to be used in this project has the basic formula [RuL(phthalocyanine)NO]n+. Species of this type are able to produce NO, by reducing process and singlet oxygen by light irradiation. Interaction of this compound with fluorescent and antibody binding, proposed in this project will provide relationship of cytotoxic activity with cell sub-location. The procedures will be followed in B16F10 cell lines, breast adenocarcinoma MCF-7 carcinoma and squamous epidermoid, A-431. Biochemical aspects and molecular biology will be part of these studies. The experiments will be conducted in 2D and 3D cell culture. Proteomics and western blotting will allow us to know the synergistic mechanism between NO, singlet oxygen and ruthenium complex fragment. Quantification of reactive species of nitrogen and oxygen, photophysical and photochemical aspects will compete the description of the biochemical process related to these studies. Cellular sub-location will be addressed by the use of confocal microscopy.The project is of importance to bioinorganic area and lead to bio-molecular description of these compounds, an innovative account of the biological action of these species. Foreign collaborations will be strengthened allowing scientific deepening from these studies. The post graduate training and scientific collaborations between national and international research groups will strengthen the bioinorganic chemistry as a promising area in terms of development of new drugs. (AU)

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)
NEGRI, LAISA BONAFIM; MARTINS, TASSIA JOI; DA SILVA, ROBERTO SANTANA; HAMBLIN, MICHAEL R. Photobiomodulation combined with photodynamic therapy using ruthenium phthalocyanine complexes in A375 melanoma cells: Effects of nitric oxide generation and ATP production. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, v. 198, SEP 2019. Web of Science Citations: 0.
CASTRO, KELLY A. D. F.; FIGUEIRA, FLAVIO; ALMEIDA PAZ, FILIPE A.; TOME, JOAO P. C.; DA SILVA, ROBERTO S.; NAKAGAKI, SHIRLEY; NEVES, M. GRACA P. M. S.; CAVALEIRO, JOSE A. S.; SIMOES, MARIO M. Q. Copper-phthalocyanine coordination polymer as a reusable catechol oxidase biomimetic catalyst. DALTON TRANSACTIONS, v. 48, n. 23, p. 8144-8152, JUN 21 2019. Web of Science Citations: 0.
DOS SANTOS, JOICY SANTAMALVINA; RAMOS, LOYANNE C.; FERREIRA, LUCIMARA P.; CAMPO, VANESSA LEIRA; DE REZENDE, LUCAS C. D.; EMERY, FLAVIO DA SILVA; DA SILVA, ROBERTO SANTANA. Cytotoxicity, cellular uptake, and subcellular localization of a nitrogen oxide and aminopropyl-beta-lactose derivative ruthenium complex used as nitric oxide delivery agent. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 86, p. 38-47, MAY 1 2019. Web of Science Citations: 1.
CRISALLI, MEREDITH A.; FRANCO, LILIAN P.; SILVA, BRUNO R.; HOLANDA, ALDA K. M.; BENDHACK, LUSIANE M.; DA SILVA, ROBERTO S.; FORD, PETER C. Nitric oxide release from a photoactive water-soluble ruthenium nitrosyl. Biologicaleffects. Journal of Coordination Chemistry, v. 71, n. 11-13, SI, p. 1690-1703, 2018. Web of Science Citations: 2.

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