Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1007/s10534-018-0160-0 http://hdl.handle.net/11449/186622 |
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. |
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Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitorsRuthenium compoundsTriple negative breast cancerTopoisomerasePARP inhibitorDue 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.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Fed Sao Carlos, Ctr Exact Sci & Technol, BR-13565905 Sao Carlos, SP, BrazilSao Paulo State Univ, Sch Pharmaceut Sci, BR-14800903 Araraquara, SP, BrazilUniv Brasilia, Dept Genet & Morphol, BR-70910970 Brasilia, DF, BrazilSao Paulo State Univ, Ctr Environm Studies, BR-13506900 Rio Claro, SP, BrazilUniv Fed Sao Carlos, Dept Gerontol, BR-13565905 Sao Carlos, SP, BrazilSao Paulo State Univ, Sch Pharmaceut Sci, BR-14800903 Araraquara, SP, BrazilSao Paulo State Univ, Ctr Environm Studies, BR-13506900 Rio Claro, SP, BrazilFAPESP: 2012/21529-7FAPESP: 2016/22429-7FAPESP: 2016/16312-0SpringerUniversidade Federal de São Carlos (UFSCar)Universidade Estadual Paulista (Unesp)Universidade de Brasília (UnB)Camargo, Mariana S. deDe Grandis, Rone A. [UNESP]Silva, Monize M. daSilva, Patricia B. daSantoni, Mariana M. [UNESP]Eismann, Carlos E. [UNESP]Menegario, Amauri A. [UNESP]Cominetti, Marcia R.Zanelli, Cleslei F. [UNESP]Pavan, Fernando R. [UNESP]Batista, Alzir A.2019-10-05T12:40:10Z2019-10-05T12:40:10Z2019-02-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article89-100http://dx.doi.org/10.1007/s10534-018-0160-0Biometals. Dordrecht: Springer, v. 32, n. 1, p. 89-100, 2019.0966-0844http://hdl.handle.net/11449/18662210.1007/s10534-018-0160-0WOS:00045769170000815256654089001950000-0001-7831-1149Web of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBiometalsinfo:eu-repo/semantics/openAccess2022-02-10T13:05:44Zoai:repositorio.unesp.br:11449/186622Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462022-02-10T13:05:44Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors |
title |
Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors |
spellingShingle |
Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors Camargo, Mariana S. de Ruthenium compounds Triple negative breast cancer Topoisomerase PARP inhibitor |
title_short |
Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors |
title_full |
Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors |
title_fullStr |
Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors |
title_full_unstemmed |
Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors |
title_sort |
Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors |
author |
Camargo, Mariana S. de |
author_facet |
Camargo, Mariana S. de De Grandis, Rone A. [UNESP] Silva, Monize M. da Silva, Patricia B. da Santoni, Mariana M. [UNESP] Eismann, Carlos E. [UNESP] Menegario, Amauri A. [UNESP] Cominetti, Marcia R. Zanelli, Cleslei F. [UNESP] Pavan, Fernando R. [UNESP] Batista, Alzir A. |
author_role |
author |
author2 |
De Grandis, Rone A. [UNESP] Silva, Monize M. da Silva, Patricia B. da Santoni, Mariana M. [UNESP] Eismann, Carlos E. [UNESP] Menegario, Amauri A. [UNESP] Cominetti, Marcia R. Zanelli, Cleslei F. [UNESP] Pavan, Fernando R. [UNESP] Batista, Alzir A. |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Federal de São Carlos (UFSCar) Universidade Estadual Paulista (Unesp) Universidade de Brasília (UnB) |
dc.contributor.author.fl_str_mv |
Camargo, Mariana S. de De Grandis, Rone A. [UNESP] Silva, Monize M. da Silva, Patricia B. da Santoni, Mariana M. [UNESP] Eismann, Carlos E. [UNESP] Menegario, Amauri A. [UNESP] Cominetti, Marcia R. Zanelli, Cleslei F. [UNESP] Pavan, Fernando R. [UNESP] Batista, Alzir A. |
dc.subject.por.fl_str_mv |
Ruthenium compounds Triple negative breast cancer Topoisomerase PARP inhibitor |
topic |
Ruthenium compounds Triple negative breast cancer Topoisomerase PARP inhibitor |
description |
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. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-10-05T12:40:10Z 2019-10-05T12:40:10Z 2019-02-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1007/s10534-018-0160-0 Biometals. Dordrecht: Springer, v. 32, n. 1, p. 89-100, 2019. 0966-0844 http://hdl.handle.net/11449/186622 10.1007/s10534-018-0160-0 WOS:000457691700008 1525665408900195 0000-0001-7831-1149 |
url |
http://dx.doi.org/10.1007/s10534-018-0160-0 http://hdl.handle.net/11449/186622 |
identifier_str_mv |
Biometals. Dordrecht: Springer, v. 32, n. 1, p. 89-100, 2019. 0966-0844 10.1007/s10534-018-0160-0 WOS:000457691700008 1525665408900195 0000-0001-7831-1149 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Biometals |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
89-100 |
dc.publisher.none.fl_str_mv |
Springer |
publisher.none.fl_str_mv |
Springer |
dc.source.none.fl_str_mv |
Web of Science reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1799964691769851904 |