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

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dc.contributor.authorCamargo, Mariana S. de
dc.contributor.authorDe Grandis, Rone A. [UNESP]
dc.contributor.authorSilva, Monize M. da
dc.contributor.authorSilva, Patricia B. da
dc.contributor.authorSantoni, Mariana M. [UNESP]
dc.contributor.authorEismann, Carlos E. [UNESP]
dc.contributor.authorMenegario, Amauri A. [UNESP]
dc.contributor.authorCominetti, Marcia R.
dc.contributor.authorZanelli, Cleslei F. [UNESP]
dc.contributor.authorPavan, Fernando R. [UNESP]
dc.contributor.authorBatista, Alzir A.
dc.contributor.institutionUniversidade Federal de São Carlos (UFSCar)
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniversidade de Brasília (UnB)
dc.date.accessioned2019-10-05T12:40:10Z
dc.date.available2019-10-05T12:40:10Z
dc.date.issued2019-02-01
dc.description.abstractDue 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.en
dc.description.affiliationUniv Fed Sao Carlos, Ctr Exact Sci & Technol, BR-13565905 Sao Carlos, SP, Brazil
dc.description.affiliationSao Paulo State Univ, Sch Pharmaceut Sci, BR-14800903 Araraquara, SP, Brazil
dc.description.affiliationUniv Brasilia, Dept Genet & Morphol, BR-70910970 Brasilia, DF, Brazil
dc.description.affiliationSao Paulo State Univ, Ctr Environm Studies, BR-13506900 Rio Claro, SP, Brazil
dc.description.affiliationUniv Fed Sao Carlos, Dept Gerontol, BR-13565905 Sao Carlos, SP, Brazil
dc.description.affiliationUnespSao Paulo State Univ, Sch Pharmaceut Sci, BR-14800903 Araraquara, SP, Brazil
dc.description.affiliationUnespSao Paulo State Univ, Ctr Environm Studies, BR-13506900 Rio Claro, SP, Brazil
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipIdFAPESP: 2012/21529-7
dc.description.sponsorshipIdFAPESP: 2016/22429-7
dc.description.sponsorshipIdFAPESP: 2016/16312-0
dc.format.extent89-100
dc.identifierhttp://dx.doi.org/10.1007/s10534-018-0160-0
dc.identifier.citationBiometals. Dordrecht: Springer, v. 32, n. 1, p. 89-100, 2019.
dc.identifier.doi10.1007/s10534-018-0160-0
dc.identifier.issn0966-0844
dc.identifier.lattes1525665408900195
dc.identifier.orcid0000-0001-7831-1149
dc.identifier.urihttp://hdl.handle.net/11449/186622
dc.identifier.wosWOS:000457691700008
dc.language.isoeng
dc.publisherSpringer
dc.relation.ispartofBiometals
dc.rights.accessRightsAcesso aberto
dc.sourceWeb of Science
dc.subjectRuthenium compounds
dc.subjectTriple negative breast cancer
dc.subjectTopoisomerase
dc.subjectPARP inhibitor
dc.titleDetermination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitorsen
dc.typeArtigo
dcterms.licensehttp://www.springer.com/open+access/authors+rights?SGWID=0-176704-12-683201-0
dcterms.rightsHolderSpringer
unesp.author.lattes1525665408900195[9]
unesp.author.orcid0000-0001-7831-1149[9]
unesp.departmentCiências Biológicas - FCFpt

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Araraquara - FCF - Faculdade de Ciências Farmacêuticas