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. Issue 35 (16th August 2018)

• Record Type: Journal Article
• Authors: Pracharova, Jitka; Novohradsky, Vojtech; Kostrhunova, Hana; Štarha, Pavel; Trávníček, Zdeněk; Kasparkova, Jana; Brabec, Viktor
• Is Part Of: Dalton transactions. Volume 47:Issue 35(2018)
• Page Start: 12197
• Page End: 12208
• Publication Date: 2018-08-16
• Subjects: Chemistry, Inorganic -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/c8dt02236d
• Languages: English
• ISSNs: 1477-9226

Abstract

Abstract : A half-sandwich Os(ii ) bathophenanthroline complex is a potent agent against highly progressive, poorly treatable triple-negative breast cancer cells. 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(η 6 -pcym)(bphen)(dca)]PF6 (Os-dca ) and [Ru(η 6 -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 forOs-dca . The lower potency ofRu-dca in comparison withOs-dca is apparently connected with a relatively quick release of the dca ligand due to the hydrolysis ofRu-dca before this complex enters the cells. Remarkably, bothOs-dca andRu-dca reduce successfully metastasis-related properties of the triple-negative breast cancer cells such as migration, invasion, and re-adhesion. The anti-metastatic effects ofOs-dca andRu-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 thatOs-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 ofOs-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.