Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors

Autor(es):Mostrar menos -

de Camargo, Mariana S. ^[1] ; De Grandis, Rone A. ^[2] ; da Silva, Monize M. ^[1] ; da Silva, Patricia B. ^[3] ; Santoni, Mariana M. ^[2] ; Eismann, Carlos E. ^[4] ; Menegario, Amauri A. ^[4] ; Cominetti, Marcia R. ^[5] ; Zanelli, Cleslei F. ^[2] ; Pavan, Fernando R. ^[2] ; Batista, Alzir A. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Carlos, Ctr Exact Sci & Technol, BR-13565905 Sao Carlos, SP - Brazil

^[2] Sao Paulo State Univ, Sch Pharmaceut Sci, BR-14800903 Araraquara, SP - Brazil

^[3] Univ Brasilia, Dept Genet & Morphol, BR-70910970 Brasilia, DF - Brazil

^[4] Sao Paulo State Univ, Ctr Environm Studies, BR-13506900 Rio Claro, SP - Brazil

^[5] Univ Fed Sao Carlos, Dept Gerontol, BR-13565905 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BIOMETALS; v. 32, n. 1, p. 89-100, FEB 2019.
• Citações Web of Science: 3

Resumo

Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anticancer agents. Previous studies showed that three ruthenium(II) compounds: {[}Ru(pySH)(bipy)(dppb)]PF6 (1), {[}Ru(HSpym)(bipy)(dppb)]PF6 (2) and Ru{[}(SpymMe(2))(bipy)(dppb)]PF6 (3) presented anticancer properties higher than doxorubicin and cisplatin and acted as human topoisomerase IB (Topo I) inhibitors. Here, we focused our studies on in vitro intestinal permeability and anticancer mechanisms of these three complexes. Caco-2 permeation studies showed that 1 did not permeate the monolayer of intestinal cells, suggesting a lack of absorption on oral administration, while 2 and 3 permeated the cells after 60 and 120min, respectively. Complexes 2 and 3 fully inhibited Topo II relaxation activity at 125 mu M. In previously studies, 3 was the most potent inhibitor of Topo I, here, we concluded that it is a dual topoisomerase inhibitor. Moreover, it presented selectivity to cancer cells when evaluated by clonogenic assay. Thus, 3 was selected to gene expression assay front MDA-MB-231 cells from triple-negative breast cancer (TNBC), which represents the highly aggressive subgroup of breast cancers with poor prognosis. The analyses revealed changes of 27 out of 84 sought target genes. PARP1 and PARP2 were 5.29 and 1.83 times down-regulated after treatment with 3, respectively. PARPs have been attractive antitumor drug targets, considering PARP inhibition could suppress DNA damage repair and sensitize tumor cells to DNA damage agents. Recent advances in DNA repair studies have shown that an approach that causes cell lethality using synthetic PARP-inhibiting drugs has produced promising results in TNBC. (AU)

• Processo FAPESP: 12/21529-7 - "avaliação da atividade antitumoral de compostos de rutênio: estudo do potencial mutagênico, citotóxico, inibição de topoisomerases e alterações sobre a expressão gênica"
• Beneficiário: Mariana Santoro de Camargo
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/22429-7 - Avaliação toxicogenética e estudo dos mecanismos de resposta antiproliferativa de metalofármacos de rutênio contendo bioligantes naftoquinônicos em modelos celulares tumorais convencionais e em 3D
• Beneficiário: Rone Aparecido de Grandis
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/16312-0 - Citotoxidade e mecanismo de ação de complexos de rutênio contendo produtos naturais ou derivados
• Beneficiário: Alzir Azevedo Batista
• Modalidade de apoio: Auxílio à Pesquisa - Regular