Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma
Identifieur interne : 000468 ( Main/Exploration ); précédent : 000467; suivant : 000469Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma
Auteurs : Jennifer Bryant [Royaume-Uni] ; Nikolaos Batis [Royaume-Uni] ; Anna Clara Franke [Royaume-Uni] ; Gabriella Clancey [Royaume-Uni] ; Margaret Hartley [Royaume-Uni] ; Gordon Ryan [Royaume-Uni] ; Jill Brooks [Royaume-Uni] ; Andrew D. Southam [Royaume-Uni] ; Nicholas Barnes [Royaume-Uni] ; Joanna Parish [Royaume-Uni] ; Sally Roberts [Royaume-Uni] ; Farhat Khanim [Royaume-Uni] ; Rachel Spruce [Royaume-Uni] ; Hisham Mehanna [Royaume-Uni]Source :
- Oncotarget [ 1949-2553 ] ; 2019.
Abstract
Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need.
We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using
Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63–1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/– irradiation) alone.
Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.
Url:
DOI: 10.18632/oncotarget.27156
PubMed: 31497252
PubMed Central: 6718257
Affiliations:
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Le document en format XML
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<author><name sortKey="Roberts, Sally" sort="Roberts, Sally" uniqKey="Roberts S" first="Sally" last="Roberts">Sally Roberts</name>
<affiliation wicri:level="4"><nlm:aff id="A2">Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham</wicri:regionArea>
<placeName><settlement type="city">Birmingham</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Midlands de l'Ouest</region>
</placeName>
<orgName type="university">Université de Birmingham</orgName>
</affiliation>
</author>
<author><name sortKey="Khanim, Farhat" sort="Khanim, Farhat" uniqKey="Khanim F" first="Farhat" last="Khanim">Farhat Khanim</name>
<affiliation wicri:level="4"><nlm:aff id="A6">School of Biomedical Sciences, Institute of Clinical Sciences, University of Birmingham, Birmingham, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>School of Biomedical Sciences, Institute of Clinical Sciences, University of Birmingham, Birmingham</wicri:regionArea>
<placeName><settlement type="city">Birmingham</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Midlands de l'Ouest</region>
</placeName>
<orgName type="university">Université de Birmingham</orgName>
</affiliation>
</author>
<author><name sortKey="Spruce, Rachel" sort="Spruce, Rachel" uniqKey="Spruce R" first="Rachel" last="Spruce">Rachel Spruce</name>
<affiliation wicri:level="4"><nlm:aff id="A1">Institute of Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham</wicri:regionArea>
<placeName><settlement type="city">Birmingham</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Midlands de l'Ouest</region>
</placeName>
<orgName type="university">Université de Birmingham</orgName>
</affiliation>
<affiliation><nlm:aff id="A9">Joint senior authors</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mehanna, Hisham" sort="Mehanna, Hisham" uniqKey="Mehanna H" first="Hisham" last="Mehanna">Hisham Mehanna</name>
<affiliation wicri:level="4"><nlm:aff id="A1">Institute of Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute of Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham</wicri:regionArea>
<placeName><settlement type="city">Birmingham</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Midlands de l'Ouest</region>
</placeName>
<orgName type="university">Université de Birmingham</orgName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="A3">University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>University Hospitals Birmingham NHS Foundation Trust, Birmingham</wicri:regionArea>
<placeName><settlement type="city">Birmingham</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Midlands de l'Ouest</region>
</placeName>
</affiliation>
<affiliation><nlm:aff id="A9">Joint senior authors</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Oncotarget</title>
<idno type="eISSN">1949-2553</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need.</p>
<p>We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using <italic>in vitro</italic>
assays (cell viability, clonogenic survival, apoptosis) and <italic>in vivo</italic>
models (xenograft tumors in NOD/SCID/gamma mice).</p>
<p>Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63–1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/– irradiation) alone. <italic>In vivo</italic>
, daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days (<italic>p</italic>
< 0.0001) versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone. Importantly, combination therapy enabled the dose of cisplatin to be halved to 1 mg/kg, whilst maintaining the same impairment of tumor growth. Treatment was well tolerated; murine plasma levels reached a steady concentration of 0.5 μg/mL, comparable to levels achievable and tolerated in humans.</p>
<p>Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.
</p>
</div>
</front>
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</back>
</TEI>
<affiliations><list><country><li>Royaume-Uni</li>
</country>
<region><li>Angleterre</li>
<li>Midlands de l'Ouest</li>
</region>
<settlement><li>Birmingham</li>
</settlement>
<orgName><li>Université de Birmingham</li>
</orgName>
</list>
<tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Bryant, Jennifer" sort="Bryant, Jennifer" uniqKey="Bryant J" first="Jennifer" last="Bryant">Jennifer Bryant</name>
</region>
<name sortKey="Barnes, Nicholas" sort="Barnes, Nicholas" uniqKey="Barnes N" first="Nicholas" last="Barnes">Nicholas Barnes</name>
<name sortKey="Barnes, Nicholas" sort="Barnes, Nicholas" uniqKey="Barnes N" first="Nicholas" last="Barnes">Nicholas Barnes</name>
<name sortKey="Batis, Nikolaos" sort="Batis, Nikolaos" uniqKey="Batis N" first="Nikolaos" last="Batis">Nikolaos Batis</name>
<name sortKey="Brooks, Jill" sort="Brooks, Jill" uniqKey="Brooks J" first="Jill" last="Brooks">Jill Brooks</name>
<name sortKey="Clancey, Gabriella" sort="Clancey, Gabriella" uniqKey="Clancey G" first="Gabriella" last="Clancey">Gabriella Clancey</name>
<name sortKey="Franke, Anna Clara" sort="Franke, Anna Clara" uniqKey="Franke A" first="Anna Clara" last="Franke">Anna Clara Franke</name>
<name sortKey="Hartley, Margaret" sort="Hartley, Margaret" uniqKey="Hartley M" first="Margaret" last="Hartley">Margaret Hartley</name>
<name sortKey="Khanim, Farhat" sort="Khanim, Farhat" uniqKey="Khanim F" first="Farhat" last="Khanim">Farhat Khanim</name>
<name sortKey="Mehanna, Hisham" sort="Mehanna, Hisham" uniqKey="Mehanna H" first="Hisham" last="Mehanna">Hisham Mehanna</name>
<name sortKey="Mehanna, Hisham" sort="Mehanna, Hisham" uniqKey="Mehanna H" first="Hisham" last="Mehanna">Hisham Mehanna</name>
<name sortKey="Parish, Joanna" sort="Parish, Joanna" uniqKey="Parish J" first="Joanna" last="Parish">Joanna Parish</name>
<name sortKey="Roberts, Sally" sort="Roberts, Sally" uniqKey="Roberts S" first="Sally" last="Roberts">Sally Roberts</name>
<name sortKey="Ryan, Gordon" sort="Ryan, Gordon" uniqKey="Ryan G" first="Gordon" last="Ryan">Gordon Ryan</name>
<name sortKey="Southam, Andrew D" sort="Southam, Andrew D" uniqKey="Southam A" first="Andrew D." last="Southam">Andrew D. Southam</name>
<name sortKey="Southam, Andrew D" sort="Southam, Andrew D" uniqKey="Southam A" first="Andrew D." last="Southam">Andrew D. Southam</name>
<name sortKey="Spruce, Rachel" sort="Spruce, Rachel" uniqKey="Spruce R" first="Rachel" last="Spruce">Rachel Spruce</name>
</country>
</tree>
</affiliations>
</record>
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