Anticancer activity of osmium(VI) nitrido complexes in patient-derived glioblastoma initiating cells and in vivo mouse models

Berger, Gilles; Grauwet, Korneel; Zhang, Hong; Hussey, Amanda Am; Nowicki, Michal O.; Wang, David I.; Chiocca, Antonio; Lawler, Sean E.; Lippard, Stephen Sj

doi:10.1016/j.canlet.2017.11.041

Cited by 31 publications

(18 citation statements)

References 54 publications

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“… 11 Higher oxidation state complexes of osmium also show clinical promise, with potential both in vitro and in vivo . 12 The mechanism of action of Os(VI) nitrido complexes developed by Lippard et al depends greatly on the choice of ligands; structurally similar complexes activate either p53 -dependent or p53 -independent cell death pathways, depending on the nature of the coordinated ligands. 13 …”

Section: Introductionmentioning

confidence: 99%

In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That Circumvent Platinum Resistance

et al. 2018

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Platinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here, we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os(N,N′)], and 18-electron phenylazopyridine complexes [(η6-arene)Os(N,N’)Cl/I]+ (arene = p-cymene, biphenyl, or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency toward cancer cells involves the generation of reactive oxygen species. Evidence of such a mechanism of action has been found both in vitro and in vivo. This work appears to provide the first study of osmium complexes in the zebrafish model, which has been shown to closely model toxicity in humans. A fluorescent osmium complex, derived from a lead compound, was employed to confirm internalization of the complex, visualize in vivo distribution, and confirm colocalization with reactive oxygen species generated in zebrafish.

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Section: Introductionmentioning

confidence: 99%

In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That Circumvent Platinum Resistance

et al. 2018

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“…Relating to this data, it is notable that cisplatin was previously put through several clinical trials for high grade glioma without success, but gives promising cytotoxicity data in 2D and some 3D cultures, including collagen gels and 3D spheroids/neurospheres (Ahmed et al, 2018;Berger et al, 2018;Yuki et al, 1994;Yung et al, 1982). Investigation into the factors which contribute to this cisplatin resistance in 3D bioprinted culture may help inform future 3D culture models of glioblastoma.…”

Section: Discussionmentioning

confidence: 91%

Three dimensional in vitro models of cancer: Bioprinting multilineage glioblastoma models

Hermida

Kumar

Schwarz

et al. 2020

Advances in Biological Regulation

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Three dimensional (3D) bioprinting of multiple cell types within optimised extracellular matrices has the potential to more closely model the 3D environment of human physiology and disease than current alternatives. In this study, we used a multi-nozzle extrusion bioprinter to establish models of glioblastoma made up of cancer and stromal cells printed within matrices comprised of alginate modified with RGDS cell adhesion peptides, hyaluronic acid and collagen-1. Methods were developed using U87MG glioblastoma cells and MM6 monocyte/macrophages, whilst more disease relevant constructs contained glioblastoma stem cells (GSCs), co-printed with glioma associated stromal cells (GASCs) and microglia. Printing parameters were optimised to promote cell-cell interaction, avoiding the 'caging in' of cells due to overly dense cross-linking. Such printing had a negligible effect on cell viability, and cells retained robust metabolic activity and proliferation. Alginate gels allowed the rapid recovery of printed cell protein and RNA, and fluorescent reporters provided analysis of protein kinase activation at the single cell level within printed constructs. GSCs showed more resistance to chemotherapeutic drugs in 3D printed tumour constructs compared to 2D monolayer cultures, reflecting the clinical situation. In summary, a novel 3D bioprinting strategy is developed which allows control over the spatial organisation of tumour constructs for pre-clinical drug sensitivity testing and studies of the tumour microenvironment.

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“…[5a] Further studies with osmium(VI)-nitrido complexes revealed that substitution of the bidentate 1,10-phenanthroline ligand in 2 with at ridentate 2,2':6',2"-terpyridine ligand yields monocationic analogue 5 with enhanced anti-CSC properties. [17] Cytotoxicity studies on monolayera nd three-dimensional patientderived cancer-initiating glioblastoma cells showed that both 2 and 5 cause rapid cell death at low micromolar concentrations, comparable to cisplatin and temozolomide (a clinically approveda nti-glioblastoma agent). Cell-cycle studies revealed no major arrests upon treatment of cancer-initiating glioblastoma cells with 2 or 5,w hich suggests that 2-a nd 5-mediated cell death is non-DNA centred.…”

Section: Third-row Transition Metal Complexesmentioning

confidence: 99%

The Next Generation of Anticancer Metallopharmaceuticals: Cancer Stem Cell‐Active Inorganics

Laws

Suntharalingam

2018

ChemBioChem

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Cancer stem cells (CSCs) are heavily linked to fatal incidences of cancer relapse and metastasis. Conventional cancer therapies such as surgery, chemotherapy and radiation are largely futile against CSCs. Therefore, highly original approaches are needed to overcome CSCs and to provide durable, long-term clinical outcomes. Many academia- and pharmaceutical-led studies aimed at developing chemical or biological anti-CSC agents are ongoing; however, the application of inorganic compounds is rare. In this minireview, we discuss how the chemical diversity and versatility offered by metals has been harnessed to develop an unprecedented, emerging class of metallopharmaceuticals: CSC-active inorganics. A detailed account of their mechanism(s) of action is provided, and possible future directions for exploration are also put forward.

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Anticancer activity of osmium(VI) nitrido complexes in patient-derived glioblastoma initiating cells and in vivo mouse models

Cited by 31 publications

References 54 publications

In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That Circumvent Platinum Resistance

In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That Circumvent Platinum Resistance

Three dimensional in vitro models of cancer: Bioprinting multilineage glioblastoma models

The Next Generation of Anticancer Metallopharmaceuticals: Cancer Stem Cell‐Active Inorganics

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