Original ArticlesAnticancer activity of osmium(VI) nitrido complexes in patient-derived glioblastoma initiating cells and in vivo mouse models
Introduction
Gliomas are the most common primary brain tumors [1]. Grade III and IV gliomas are considered high-grade malignancies with a very poor prognosis. Glioblastoma (GBM, grade IV glioma), the most common and malignant form of glioma, is resistant to current treatments [2,3]. The standard of care for GBM relies on surgical resection followed by radiotherapy with adjuvant chemotherapy using temozolomide (TMZ), an orally available DNA alkylating agent [4]. Approximately 10,000 new patients are diagnosed with GBM each year in the USA [1] with a 5-year survival rate of 3% and a median survival of slightly less than 15 months [2,4]. Obstacles to the effective treatment of GBM include molecular heterogeneity, its localization in the brain where it is at least partially protected by the blood brain barrier, its diffuse infiltrative character that prevents complete surgical resection, and glioblastoma initiating cells (GSCs) in the tumor microenvironment that provide a self-renewing population of tumor cells with enhanced tumorigenic properties [5,6]. Chemotherapeutics, such as TMZ, are only partly effective against the tumor mass and the tumor ultimately re-establishes itself from resistant GSCs [4]. These hurdles in GBM treatment warrant the development of new and more effective therapeutics.
One of the most effective achievements in drug development for cancer chemotherapy is the use of cisplatin to treat solid tumors, especially testicular cancer. Cisplatin immediately transformed testis malignancies from a largely incurable to a treatable cancer with a cure rate reaching over 80%, yet it has faced major drawbacks limiting its clinical use [[7], [8], [9]]. Currently, a platinum-based drug is used in up to half of cancer chemotherapeutic regimens but resistance and recurrence following initial tumor regression are still major concerns [10,11]. The success in the clinical application of platinum(II)-based anticancer agents has motivated research to develop new transition metal-based chemotherapeutics. Also, much effort has been spent to elucidate the molecular basis for both the anticancer activity and the resistance to platinum drugs, paving the way for the rational design of new compounds. Consequently, the chemical diversity of platinum derivatives has grown to include trans isomers, orally active platinum(IV) pro-drugs, and di- and tri-nuclear constructs [[12], [13], [14], [15]], research driven by the need to circumvent intrinsic limitations of classical Pt drugs, particularly resistance and toxicity.
Apart from the well-established anticancer properties of platinum salts, other transition metals (Os, Re, Ru, Ti, Pd, Au, Mn, Cu) have shown promising activity [[16], [17], [18], [19], [20], [21], [22]]. Such compounds do not obey the original structure-activity relationship rules of the effective platinum(II) complexes, offering the hope of overcoming the common shortcomings associated with cis-configured, square-planar platinum(II) derivatives, and they provide good efficacy toward platinum non-responsive cancers. Ruthenium and titanium complexes are now in clinical trials and their mechanisms of action have been extensively studied [[23], [24], [25]]. Besides their well-known anticancer properties, metal complexes are broadly applied in medicinal chemistry [26], from Alzheimer's disease [27] to inflammatory or epigenetic modulators [28,29].
On the other hand, not much mechanistic information is available regarding osmium-based anticancer complexes, the biological properties of which remain relatively unexplored. Some of these complexes have proved to be non-cross-resistant to cisplatin [30,31]. Osmium(II) arene complexes containing azopyridine ligand derivatives have nanomolar-range activity toward a large panel of cancer cell lines [32]. A similar type of osmium complex induces apoptosis and S-phase cell cycle arrest through a mitochondria-mediated process in A549 non-small cell lung cancer cells [33]. Anticancer polypyridyl osmium(II) complexes inhibit protein-protein interactions [34,35]. Recently, we discovered breast cancer stem cell (CSC) selective activity for the osmium(VI) nitrido complex [OsCl3N(phen)]. Treatment of CSC-enriched human breast cancer HMLER cultures with this compound diminished by half the proportion of these cancer initiating cells. It also displayed potent inhibition of mammosphere formation. Profiling of its mechanism of action using an shRNA library showed that this osmium complex exhibits a mechanism of action involving DNA damage and endoplasmic reticulum stress. Subsequently, we turned our attention to investigate the in vitro and in vivo efficacy of this neutral phenanthroline compound and a cationic terpyridine complex using GSC and glioblastoma models. The data reveal these compounds to be effective against GBM models, as described in this report.
Section snippets
Synthesis of the osmium complexes
The complexes were prepared following previously published procedures [18,36]. Briefly, a tetrabutylammonium salt of the Os(VI) nitrido chloride starting material was produced, followed by the complexation with the bi- and tridentate heterocyclic ligands in organic solvents, affording the desired compounds by precipitation over the course of the reaction.
Cell lines and culture
Human ovarian carcinoma A2780 and the cisplatin resistant A2780/CP70 derivative, as well as human cervical carcinoma HeLa cells were obtained
Results
To extend our investigation of the anti-cancer properties of osmium(VI) nitrido complexes involving bidentate N-donor ligands [18], we first examined the antiproliferative effects of the tridentate 2,2′:6′,2″-terpyridine congener [36,41], which bears a positive charge and is more soluble in aqueous media. To evaluate the potency of these agents, we first performed MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays on common cancer cell lines (A549, HeLa and A2780) and
Discussion
We disclose the first investigation of in vitro and in vivo activity of osmium(VI) nitrido compounds in the treatment of GBM. A careful in vitro evaluation was first provided by means of conventional cytotoxicity assays on patient-derived GBM models, bolstered by a 3D-growth GILA assay using a transduced fluorescent cell model. The data revealed good potency for the tested osmium compounds, which outperformed clinically utilized TMZ and showed IC50 values ranging between those of cisplatin and
Conflict of interest
None
Acknowledgments
This work was supported in part by NCI grants R01 CA166172 to A.C. and CA034492 to S.J.L.. G.B. performed this study while a recipient of a Fulbright Scholar Grant. G.B. and K.G. were supported by a Fellowship of the Belgian American Educational Foundation. We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically the Flow Cytometry Core supported by Cancer Center Support (core) Grant P30-CA14051. S.E.L., H.Z., M.O.N. and E.A.C. were supported by the DFCI
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2021, BiomaterialsCitation Excerpt :Since the discovery of the antiproliferative activity of cisplatin and its derivatives [1,2], there has been extensive interest in the design of metal-based anticancer drugs [3]. Besides the well-established platinum, other noble metal-based small molecules [4–8], such as those of gold [9], ruthenium [10] and osmium [11], have also been reported as potential anticancer candidates. On the other hand, the anticancer properties of the earth abundant metal-based small molecules are much less explored and the earth abundant metals are usually essential trace elements for the human body [12,13].