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.

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.

• Authors: Jitka Pracharova , Vojtech Novohradsky , Hana Kostrhunova , Pavel Štarha , Zdeněk Trávníček , Jana Kasparkova , Viktor Brabec
• Journal: Dalton transactions (Cambridge, England : 2003) (Dalton Trans) Vol. 47 Issue 35 Pg. 12197-12208 (Sep 11 2018) ISSN: 1477-9234 [Electronic] England
• PMID: 30112527 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Phenanthrolines
• Osmium
• bathophenanthroline
• Ruthenium

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Coordination Complexes (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Molecular Structure
• Osmium (chemistry, pharmacology)
• Phenanthrolines (chemistry, pharmacology)
• Ruthenium (chemistry, pharmacology)
• Triple Negative Breast Neoplasms (drug therapy, pathology)