Abstract

The cytotoxic and immunogenic-activating properties of a cobalt(III)-cyclam complex bearing the non-steroidal anti-inflammatory drug, flufenamic acid is reported within the context of anti-cancer stem cell (CSC) drug discovery. The cobalt(III)-cyclam complex 1 displays sub-micromolar potency towards breast CSCs grown in monolayers, 24-fold and 31-fold greater than salinomycin (an established anti-breast CSC agent) and cisplatin (an anticancer metallopharmaceutical), respectively. Strikingly, the cobalt(III)-cyclam complex 1 is 69-fold and 50-fold more potent than salinomycin and cisplatin towards three-dimensionally cultured breast CSC mammospheres. Mechanistic studies reveal that 1 induces DNA damage, inhibits cyclooxygenase-2 expression, and prompts caspase-dependent apoptosis. Breast CSCs treated with 1 exhibit damage-associated molecular patterns characteristic of immunogenic cell death and are phagocytosed by macrophages. As far as we are aware, 1 is the first cobalt complex of any oxidation state or geometry to display both cytotoxic and immunogenic-activating effects on breast CSCs.

Document Type

Article

Publication Date

2024

Notes/Citation Information

© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH

Digital Object Identifier (DOI)

https://doi.org/10.1002/anie.202317940

Funding Information

This work was supported by a Rosetrees Trust grant (Seedcorn2020\100123) and a R01CA258421-01 grant from the National Cancer Institute (NCI). The authors also acknowledge support of the Center for Pharmaceutical Research and Innovation (NIH P20GM130456). XRD crystallography at the University of Leicester is supported by an EPSRC Core Equipment Award (EP/V034766/1). We also thank the Advanced Imaging Facility (RRID:SCR_020967) at the University of Leicester for support.

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