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Half-sandwich Os(II) and Ru(II) bathophenanthroline complexes: anticancer drug candidates with unusual potency and a cellular activity profile in highly invasive triple-negative breast cancer cells

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Abstract

There is an urgent need to discover new, selective compounds to add to the limited arsenal of chemotherapeutics displaying selective toxicity for aggressive triple-negative breast cancer (TNBC) cells. The effect of two, recently developed metal-based half-sandwich complexes [Os(η6-pcym)(bphen)(dca)]PF6 (Os-dca) and [Ru(η6-pcym)(bphen)(dca)]PF6 (Ru-dca) [pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene); bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline); dca = dichloroacetate] on triple-negative breast cancer cells MDA-MB-231 is reported. The complexes display selective toxicity in several tumor cells (at submicromolar concentrations), and a prominent effect is observed against highly progressive triple negative breast cancer MDA-MB-231 cells for Os-dca. The lower potency of Ru-dca in comparison with Os-dca is apparently connected with a relatively quick release of the dca ligand due to the hydrolysis of Ru-dca before this complex enters the cells. Remarkably, both Os-dca and Ru-dca reduce successfully metastasis-related properties of the triple-negative breast cancer cells such as migration, invasion, and re-adhesion. The anti-metastatic effects of Os-dca and Ru-dca are associated with their ability to suppress matrix metalloproteinase activity and/or production and reduce the expression of aquaporins. Further detailed mechanistic studies reveal that Os-dca reverses Warburg's effect and oncosis seems to be a prominent mode of cell death that predominates over apoptosis. As such, Os-dca can efficiently overcome the resistance of cancer cells to clinically-used apoptotic inducers cisplatin and carboplatin. The cytostatic and anti-metastatic properties of Os-dca in MDA-MB-231 provide a strong impetus for the development of new metal-based compounds to target hardly treatable human TNBC cells and displaying different modes of action compared to the antitumor metallodrugs in clinical use.

Graphical abstract: Half-sandwich Os(ii) and Ru(ii) bathophenanthroline complexes: anticancer drug candidates with unusual potency and a cellular activity profile in highly invasive triple-negative breast cancer cells

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Publication details

The article was received on 31 May 2018, accepted on 26 Jul 2018 and first published on 27 Jul 2018


Article type: Paper
DOI: 10.1039/C8DT02236D
Citation: Dalton Trans., 2018, Advance Article
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    Half-sandwich Os(II) and Ru(II) bathophenanthroline complexes: anticancer drug candidates with unusual potency and a cellular activity profile in highly invasive triple-negative breast cancer cells

    J. Pracharova, V. Novohradsky, H. Kostrhunova, P. Štarha, Z. Trávníček, J. Kasparkova and V. Brabec, Dalton Trans., 2018, Advance Article , DOI: 10.1039/C8DT02236D

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