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BioMetals

, Volume 32, Issue 1, pp 89–100 | Cite as

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

  • Mariana S. de CamargoEmail author
  • Rone A. De Grandis
  • Monize M. da Silva
  • Patricia B. da Silva
  • Mariana M. Santoni
  • Carlos E. Eismann
  • Amauri A. Menegário
  • Marcia R. Cominetti
  • Cleslei F. Zanelli
  • Fernando R. Pavan
  • Alzir A. Batista
Article
  • 77 Downloads

Abstract

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[(SpymMe2)(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 120 min, respectively. Complexes 2 and 3 fully inhibited Topo II relaxation activity at 125 µM. 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.

Keywords

Ruthenium compounds Triple negative breast cancer Topoisomerase PARP inhibitor 

Notes

Acknowledgements

The authors gratefully acknowledge the financial support from the São Paulo Research Foundation (FAPESP Grants 2012/21529-7, 2016/22429-7 and 2016/16312-0), Coordinating Committee for Advancement of Higher Education Staff in Brazil (CAPES) and the Brazilian National Council of Technological and Scientific Development (CNPq).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflicts of interest regarding the contents of this article.

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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Mariana S. de Camargo
    • 1
    Email author
  • Rone A. De Grandis
    • 2
  • Monize M. da Silva
    • 1
  • Patricia B. da Silva
    • 3
  • Mariana M. Santoni
    • 2
  • Carlos E. Eismann
    • 4
  • Amauri A. Menegário
    • 4
  • Marcia R. Cominetti
    • 5
  • Cleslei F. Zanelli
    • 2
  • Fernando R. Pavan
    • 2
  • Alzir A. Batista
    • 1
  1. 1.Center of Exact Sciences and TechnologyFederal University of São CarlosSão CarlosBrazil
  2. 2.School of Pharmaceutical SciencesSão Paulo State UniversityAraraquaraBrazil
  3. 3.Department of Genetics and MorphologyUniversity of BrasiliaFederal DistrictBrazil
  4. 4.Center of Environmental StudiesSão Paulo State UniversityRio ClaroBrazil
  5. 5.Department of GerontologyFederal University of São CarlosSão CarlosBrazil

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