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...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Springer Nature
2020
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| _version_ | 1797088940159664128 |
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| author | Coates, JTT Rodriguez-Berriguete, G Puliyadi, R Ashton, T Prevo, R Wing, A Granata, G Pirovano, G McKenna, GW Higgins, GS |
| author_facet | Coates, JTT Rodriguez-Berriguete, G Puliyadi, R Ashton, T Prevo, R Wing, A Granata, G Pirovano, G McKenna, GW Higgins, GS |
| author_sort | Coates, JTT |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:57:18Z |
| format | Journal article |
| id | oxford-uuid:afc0f6e2-3b40-4bae-8b58-0269a742ed16 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:57:18Z |
| publishDate | 2020 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:afc0f6e2-3b40-4bae-8b58-0269a742ed162022-03-27T03:51:39ZThe anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stressJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:afc0f6e2-3b40-4bae-8b58-0269a742ed16ChemotherapyPreclinical researchEnglishSymplectic ElementsSpringer Nature 2020Coates, JTTRodriguez-Berriguete, GPuliyadi, RAshton, TPrevo, RWing, AGranata, GPirovano, GMcKenna, GWHiggins, GSPlatinum 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. |
| spellingShingle | Chemotherapy Preclinical research Coates, JTT Rodriguez-Berriguete, G Puliyadi, R Ashton, T Prevo, R Wing, A Granata, G Pirovano, G McKenna, GW Higgins, GS The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress |
| title | The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress |
| title_full | The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress |
| title_fullStr | The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress |
| title_full_unstemmed | The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress |
| title_short | The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress |
| title_sort | anti malarial drug atovaquone potentiates platinum mediated cancer cell death by increasing oxidative stress |
| topic | Chemotherapy Preclinical research |
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