Polymer “ruthenium-cyclopentadienyl” conjugates - New emerging anti-cancer drugs

In this work, we aimed to understand the biological activity and the mechanism of action of three polymer-‘ruthenium-cyclopentadienyl’ conjugates (RuPMC) and a low molecular weight parental compound (Ru1) in cancer cells. Several biological assays were performed in ovarian (A2780) and breast (MCF7,...

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Published in:European journal of medicinal chemistry 2019-04, Vol.168, p.373-384
Main Authors: Moreira, Tiago, Francisco, Rita, Comsa, Elisabeta, Duban-Deweer, Sophie, Labas, Valérie, Teixeira-Gomes, Ana-Paula, Combes-Soia, Lucie, Marques, Fernanda, Matos, António, Favrelle, Audrey, Rousseau, Cyril, Zinck, Philippe, Falson, Pierre, Garcia, M. Helena, Preto, Ana, Valente, Andreia
Format: Article
Language:English
Subjects:
Cancer
Chemical Sciences
Coordination chemistry
Cytoskeleton
Life Sciences
Medicinal Chemistry
Pharmaceutical sciences
Pharmacology
Polymer-metal conjugates
Proteomic analysis
Ruthenium organometallic compounds
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Summary:In this work, we aimed to understand the biological activity and the mechanism of action of three polymer-‘ruthenium-cyclopentadienyl’ conjugates (RuPMC) and a low molecular weight parental compound (Ru1) in cancer cells. Several biological assays were performed in ovarian (A2780) and breast (MCF7, MDA-MB-231) human cancer derived cell lines as well as in A2780cis, a cisplatin resistant cancer cell line. Our results show that all compounds have high activity towards cancer cells with low IC50 values in the micromolar range. We observed that all Ru-PMC compounds are mainly found inside the cells, in contrast with the parental low molecular weight compound Ru1 that was mainly found at the membrane. All compounds induced mitochondrial alterations. PMC3 and Ru1 caused F-actin cytoskeleton morphology changes and reduced the clonogenic ability of the cells. The conjugate PMC3 induced apoptosis at low concentrations comparing to cisplatin and could overcame the platinum resistance of A2780cis cancer cells. A proteomic analysis showed that these compounds induce alterations in several cellular proteins which are related to the phenotypic disorders induced by them. Our results suggest that PMC3 is foreseen as a lead candidate to future studies and acting through a different mechanism of action than cisplatin. Here we established the potential of these Ru compounds as new metallodrugs for cancer chemotherapy. [Display omitted] •A polymer-ruthenium cyclopentadienyl conjugate (PMC3) is a lead anticancer molecule.•Proteins that regulate the microtubule dynamics are the target for PMC3.•PMC3 is not subject of protein-mediated efflux.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2019.02.061