Abstract
Conventional chemotherapy is mostly effective in the treatment of rapidly-dividing differentiated tumor cells but has limited application toward eliminating cancer stem cell (CSC) population. The presence of a very small number of CSCs may contribute to the development of therapeutic resistance, metastases, and relapse. Thus, treatment failure by developing novel anticancer drugs capable of effective targeting of CSCs is at present a major challenge for research focused on chemotherapy of cancer. Here, we show that Os(II) complex 2 [Os(η6-pcym)(bphen)(dca)]PF6 (pcym = p-cymene, bphen = bathophenanthroline, and dca = dichloroacetate), is capable of efficient and selective killing CSCs in heterogeneous populations of human breast cancer cells MCF-7 and SKBR-3. Notably, its remarkable submicromolar potency to kill CSCs is considerably higher than that of its Ru analog, [Ru(η6-pcym)(bphen)(dca)]PF6 (complex 1) and salinomycin, one of the most selective CSC-targeting compounds hitherto identified. Furthermore, Os(II) complex 2 reduces the formation, size, and viability of three-dimensional mammospheres which more closely reflect the tumor microenvironment than cells in traditional two-dimensional cultures. The antiproliferation studies and propidium iodide staining using flow cytometry suggest that Os(II) complex 2 induces human breast cancer stem cell death predominantly by necroptosis, a programmed form of necrosis. The results of this study demonstrate the promise of Os(II) complex 2 in treating human breast tumors. They also represent the foundation for further preclinical and clinical studies and applications of Os(II) complex 2 to comply with the emergent need for human breast CSCs-specific chemotherapeutics capable to treat chemotherapy-resistant and relapsed human breast tumors.
Highlights
Many malignancies include a small population of cancer stem cells (CSCs) that self-renew and produce other more differentiated cells which form the bulk of the tumor-cell population
We first decided to prepare, sort and characterize the cancer cell populations enriched with CSCs
CD44+/ CD24− phenotype is commonly used as a reliable phenotype for isolation and characterization of hBCSCs16. human breast CSCs (hBCSCs) overexpress CD4417, a cell-surface glycoprotein associated with invasion, migration, adhesion, cell proliferation and angiogenesis
Summary
Many malignancies include a small population of cancer stem cells (CSCs) that self-renew and produce other more differentiated (non-stem) cells which form the bulk of the tumor-cell population. A number of platinum and other transition metal-based compounds have been shown to exhibit antitumor activity in tumor cells, but their efficacy to attack CSCs have not been mostly tested. None of the clinically used metal-based anticancer agents, such as platinum cytostatics, showed potency against CSCs at their therapeutically administered doses. New half sandwich Ru(II) and Os(II) bathophenanthroline complexes [Ru(η6-pcym)(bphen)(dca)] PF6 (Ru(II) complex 1) and [Os(η6-pcym)(bphen)(dca)]PF6 (Os(II) complex 2) [pcym = 1-methyl-4-(propan2-yl)benzene (p-cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline); dca = dichloroacetate] have been prepared and characterized[9] (Fig. 1) As they have shown superior activity in very aggressive triple negative breast cancer cells MDA-MB-23110, we decided to investigate the in vitro efficacy of these half sandwich Ru(II) and Os(II) complexes using human breast CSCs (hBCSCs). Necroptosis rather than apoptosis or autophagy appears the predominant mode of death of hBCSCs
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