The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress

Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malar...

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Veröffentlicht in:	Cell death discovery Jg. 6; H. 1; S. 110
Hauptverfasser:	Coates, James T. T., Rodriguez-Berriguete, Gonzalo, Puliyadi, Rathi, Ashton, Thomas, Prevo, Remko, Wing, Archie, Granata, Giovanna, Pirovano, Giacomo, McKenna, Gillies W., Higgins, Geoff S.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 27.10.2020 Springer Nature B.V
Schlagworte:	631/67/1059/99 692/308/2778 Acetylcysteine Apoptosis Atovaquone Biochemistry Biomedical and Life Sciences Cancer Carboplatin Cell Biology Cell Cycle Analysis Cell death Chemotherapy Cisplatin Cytotoxic agents Cytotoxicity Electron transport chain Glutathione Hypoxia Life Sciences Mitochondria Oxidative stress Platinum Reactive oxygen species Spheroids Stem Cells Superoxide dismutase Tumor cell lines Chemotherapy Preclinical research
ISSN:	2058-7716, 2058-7716
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Abstract	Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent.
AbstractList	Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent. Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent.Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent.
ArticleNumber	110
Author	Puliyadi, Rathi Granata, Giovanna Ashton, Thomas Higgins, Geoff S. Coates, James T. T. McKenna, Gillies W. Pirovano, Giacomo Rodriguez-Berriguete, Gonzalo Prevo, Remko Wing, Archie
Author_xml	– sequence: 1 givenname: James T. T. surname: Coates fullname: Coates, James T. T. organization: Department of Oncology, University of Oxford – sequence: 2 givenname: Gonzalo surname: Rodriguez-Berriguete fullname: Rodriguez-Berriguete, Gonzalo organization: Department of Oncology, University of Oxford – sequence: 3 givenname: Rathi surname: Puliyadi fullname: Puliyadi, Rathi organization: Department of Oncology, University of Oxford – sequence: 4 givenname: Thomas surname: Ashton fullname: Ashton, Thomas organization: Department of Oncology, University of Oxford – sequence: 5 givenname: Remko surname: Prevo fullname: Prevo, Remko organization: Department of Oncology, University of Oxford – sequence: 6 givenname: Archie surname: Wing fullname: Wing, Archie organization: Department of Oncology, University of Oxford – sequence: 7 givenname: Giovanna surname: Granata fullname: Granata, Giovanna organization: Department of Oncology, University of Oxford – sequence: 8 givenname: Giacomo surname: Pirovano fullname: Pirovano, Giacomo organization: Department of Oncology, University of Oxford – sequence: 9 givenname: Gillies W. surname: McKenna fullname: McKenna, Gillies W. organization: Department of Oncology, University of Oxford – sequence: 10 givenname: Geoff S. surname: Higgins fullname: Higgins, Geoff S. email: geoffrey.higgins@oncology.ox.ac.uk organization: Department of Oncology, University of Oxford
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Snippet	Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk...
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SubjectTerms	631/67/1059/99 692/308/2778 Acetylcysteine Apoptosis Atovaquone Biochemistry Biomedical and Life Sciences Cancer Carboplatin Cell Biology Cell Cycle Analysis Cell death Chemotherapy Cisplatin Cytotoxic agents Cytotoxicity Electron transport chain Glutathione Hypoxia Life Sciences Mitochondria Oxidative stress Platinum Reactive oxygen species Spheroids Stem Cells Superoxide dismutase Tumor cell lines
Title	The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress
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