A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential

Jiaxin Fang; Owamagbe N. Orobator; Chibuzor Olelewe; Ginevra Passeri; Kuldip Singh; Samuel G. Awuah; Kogularamanan Suntharalingam

doi:10.1002/anie.202317940

A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential

Jiaxin Fang
, Owamagbe N. Orobator
, Chibuzor Olelewe
, Ginevra Passeri
, Kuldip Singh
, Samuel G. Awuah
, Kogularamanan Suntharalingam

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English
Article number	e202317940
Journal	Angewandte Chemie - International Edition
Volume	63
Issue number	6
DOIs	https://doi.org/10.1002/anie.202317940
State	Published - Feb 5 2024

Bibliographical note

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

Funding

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. 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.

Funders	Funder number
Center for Pharmaceutical Research and Innovation, University of Kentucky
University of Leicester
National Childhood Cancer Registry – National Cancer Institute
UK Medical Research Council, Engineering and Physical Sciences Research Council	SCR_020967, EP/V034766/1
Rosetrees Trust	Seedcorn2020\100123, R01CA258421-01
National Institutes of Health (NIH)	P20GM130456

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cancer Stem Cells
Cobalt
Damage-Associated Molecular Patterns
Immunotherapeutics
Non-Steroidal Anti-Inflammatory Drugs

ASJC Scopus subject areas

Catalysis
General Chemistry

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10.1002/anie.202317940

Cite this

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title = "A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential",

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.",

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AB - 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.

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A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

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