Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis
Identifieur interne : 000626 ( Ncbi/Merge ); précédent : 000625; suivant : 000627Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis
Auteurs : Gang Cheng [États-Unis] ; Qi Zhang [États-Unis] ; Jing Pan [États-Unis] ; Yongik Lee [États-Unis] ; Olivier Ouari [France] ; Micael Hardy [France] ; Monika Zielonka [États-Unis] ; Charles R. Myers [États-Unis] ; Jacek Zielonka [États-Unis] ; Katherine Weh [États-Unis] ; Andrew C. Chang [États-Unis] ; Guoan Chen [États-Unis] ; Laura Kresty [États-Unis] ; Balaraman Kalyanaraman [États-Unis] ; Ming You [États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2019.
Abstract
Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.
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DOI: 10.1038/s41467-019-10042-1
PubMed: 31101821
PubMed Central: 6525201
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Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation></author><author><name sortKey="Ouari, Olivier" sort="Ouari, Olivier" uniqKey="Ouari O" first="Olivier" last="Ouari">Olivier Ouari</name><affiliation wicri:level="3"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2112 9282</institution-id><institution-id institution-id-type="GRID">grid.4444.0</institution-id><institution>Aix Marseille Univ,</institution><institution>CNRS,</institution></institution-wrap>ICR UMR 7273, 13013 Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>ICR UMR 7273, 13013 Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Hardy, Micael" sort="Hardy, Micael" uniqKey="Hardy M" first="Micael" last="Hardy">Micael Hardy</name><affiliation wicri:level="3"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2112 9282</institution-id><institution-id institution-id-type="GRID">grid.4444.0</institution-id><institution>Aix Marseille Univ,</institution><institution>CNRS,</institution></institution-wrap>ICR UMR 7273, 13013 Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>ICR UMR 7273, 13013 Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Zielonka, Monika" sort="Zielonka, Monika" uniqKey="Zielonka M" first="Monika" last="Zielonka">Monika Zielonka</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Department of Biophysics,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Center for Disease Prevention Research,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation></author><author><name sortKey="Myers, Charles R" sort="Myers, Charles R" uniqKey="Myers C" first="Charles R." last="Myers">Charles R. Myers</name><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Center for Disease Prevention Research,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Department of Pharmacology and Toxicology,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation></author><author><name sortKey="Zielonka, Jacek" sort="Zielonka, Jacek" uniqKey="Zielonka J" first="Jacek" last="Zielonka">Jacek Zielonka</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Free Radical Research Center,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Department of Biophysics,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Center for Disease Prevention Research,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation></author><author><name sortKey="Weh, Katherine" sort="Weh, Katherine" uniqKey="Weh K" first="Katherine" last="Weh">Katherine Weh</name><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000000086837370</institution-id><institution-id institution-id-type="GRID">grid.214458.e</institution-id><institution>Section of Thoracic Surgery, Department of Surgery, Rogel Cancer Center,</institution><institution>University of Michigan,</institution></institution-wrap>1500 East Medical Center Drive, Ann Arbor, MI 48109 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Michigan</region></placeName><wicri:cityArea>1500 East Medical Center Drive, Ann Arbor</wicri:cityArea></affiliation></author><author><name sortKey="Chang, Andrew C" sort="Chang, Andrew C" uniqKey="Chang A" first="Andrew C." last="Chang">Andrew C. Chang</name><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000000086837370</institution-id><institution-id institution-id-type="GRID">grid.214458.e</institution-id><institution>Section of Thoracic Surgery, Department of Surgery, Rogel Cancer Center,</institution><institution>University of Michigan,</institution></institution-wrap>1500 East Medical Center Drive, Ann Arbor, MI 48109 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Michigan</region></placeName><wicri:cityArea>1500 East Medical Center Drive, Ann Arbor</wicri:cityArea></affiliation></author><author><name sortKey="Chen, Guoan" sort="Chen, Guoan" uniqKey="Chen G" first="Guoan" last="Chen">Guoan Chen</name><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000000086837370</institution-id><institution-id institution-id-type="GRID">grid.214458.e</institution-id><institution>Section of Thoracic Surgery, Department of Surgery, Rogel Cancer Center,</institution><institution>University of Michigan,</institution></institution-wrap>1500 East Medical Center Drive, Ann Arbor, MI 48109 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Michigan</region></placeName><wicri:cityArea>1500 East Medical Center Drive, Ann Arbor</wicri:cityArea></affiliation></author><author><name sortKey="Kresty, Laura" sort="Kresty, Laura" uniqKey="Kresty L" first="Laura" last="Kresty">Laura Kresty</name><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000000086837370</institution-id><institution-id institution-id-type="GRID">grid.214458.e</institution-id><institution>Section of Thoracic Surgery, Department of Surgery, Rogel Cancer Center,</institution><institution>University of Michigan,</institution></institution-wrap>1500 East Medical Center Drive, Ann Arbor, MI 48109 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Michigan</region></placeName><wicri:cityArea>1500 East Medical Center Drive, Ann Arbor</wicri:cityArea></affiliation></author><author><name sortKey="Kalyanaraman, Balaraman" sort="Kalyanaraman, Balaraman" uniqKey="Kalyanaraman B" first="Balaraman" last="Kalyanaraman">Balaraman Kalyanaraman</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Free Radical Research Center,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Department of Biophysics,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Center for Disease Prevention Research,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation></author><author><name sortKey="You, Ming" sort="You, Ming" uniqKey="You M" first="Ming" last="You">Ming You</name><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Center for Disease Prevention Research,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Department of Pharmacology and Toxicology,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>8701 Watertown Plank Road, Milwaukee</wicri:cityArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</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 id="Par1">Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Jemal, A" uniqKey="Jemal A">A Jemal</name></author><author><name sortKey="Siegel, R" uniqKey="Siegel R">R Siegel</name></author><author><name sortKey="Xu, J" uniqKey="Xu J">J Xu</name></author><author><name sortKey="Ward, E" uniqKey="Ward E">E Ward</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kromer, C" uniqKey="Kromer C">C Kromer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goldberg, Sb" uniqKey="Goldberg S">SB Goldberg</name></author><author><name sortKey="Contessa, Jn" uniqKey="Contessa J">JN Contessa</name></author><author><name sortKey="Omay, Sb" uniqKey="Omay S">SB Omay</name></author><author><name 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A">AM James</name></author><author><name sortKey="Murphy, Mp" uniqKey="Murphy M">MP Murphy</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31101821</article-id><article-id pub-id-type="pmc">6525201</article-id><article-id pub-id-type="publisher-id">10042</article-id><article-id pub-id-type="doi">10.1038/s41467-019-10042-1</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Cheng</surname><given-names>Gang</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-0692-1815</contrib-id><name><surname>Zhang</surname><given-names>Qi</given-names></name><xref ref-type="aff" rid="Aff3">3</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Pan</surname><given-names>Jing</given-names></name><xref ref-type="aff" rid="Aff3">3</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-9129-1381</contrib-id><name><surname>Lee</surname><given-names>Yongik</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ouari</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Hardy</surname><given-names>Micael</given-names></name><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Zielonka</surname><given-names>Monika</given-names></name><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Myers</surname><given-names>Charles R.</given-names></name><xref ref-type="aff" rid="Aff3">3</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-2524-0145</contrib-id><name><surname>Zielonka</surname><given-names>Jacek</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Weh</surname><given-names>Katherine</given-names></name><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-9506-0425</contrib-id><name><surname>Chang</surname><given-names>Andrew C.</given-names></name><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Guoan</given-names></name><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Kresty</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Kalyanaraman</surname><given-names>Balaraman</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>You</surname><given-names>Ming</given-names></name><address><email>myou@mcw.edu</email></address><xref ref-type="aff" rid="Aff3">3</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Free Radical Research Center,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Department of Biophysics,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Center for Disease Prevention Research,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2111 8460</institution-id><institution-id institution-id-type="GRID">grid.30760.32</institution-id><institution>Department of Pharmacology and Toxicology,</institution><institution>Medical College of Wisconsin,</institution></institution-wrap>8701 Watertown Plank Road, Milwaukee, WI 53226 USA</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2112 9282</institution-id><institution-id institution-id-type="GRID">grid.4444.0</institution-id><institution>Aix Marseille Univ,</institution><institution>CNRS,</institution></institution-wrap>ICR UMR 7273, 13013 Marseille, France</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="ISNI">0000000086837370</institution-id><institution-id institution-id-type="GRID">grid.214458.e</institution-id><institution>Section of Thoracic Surgery, Department of Surgery, Rogel Cancer Center,</institution><institution>University of Michigan,</institution></institution-wrap>1500 East Medical Center Drive, Ann Arbor, MI 48109 USA</aff></contrib-group><pub-date pub-type="epub"><day>17</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>17</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>2205</elocation-id><history><date date-type="received"><day>14</day><month>6</month><year>2018</year></date><date date-type="accepted"><day>9</day><month>4</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.</p></abstract><abstract id="Abs2" abstract-type="web-summary"><p id="Par2">Brain metastases are a major reason for lung cancer mortality. Here, the authors modify lonidamine to target mitochondria, and show its therapeutic efficacy in inhibiting lung cancer brain metastasis by inducing autophagic cell death in cancer cells.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Cancer</kwd><kwd>Oncology</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>France</li><li>États-Unis</li></country><region><li>Michigan</li><li>Provence-Alpes-Côte d'Azur</li><li>Wisconsin</li></region><settlement><li>Marseille</li></settlement></list><tree><country name="États-Unis"><region name="Wisconsin"><name sortKey="Cheng, Gang" sort="Cheng, Gang" uniqKey="Cheng G" first="Gang" last="Cheng">Gang Cheng</name></region><name sortKey="Chang, Andrew C" sort="Chang, Andrew C" uniqKey="Chang A" first="Andrew C." last="Chang">Andrew C. Chang</name><name sortKey="Chen, Guoan" sort="Chen, Guoan" uniqKey="Chen G" first="Guoan" last="Chen">Guoan Chen</name><name sortKey="Cheng, Gang" sort="Cheng, Gang" uniqKey="Cheng G" first="Gang" last="Cheng">Gang Cheng</name><name sortKey="Cheng, Gang" sort="Cheng, Gang" uniqKey="Cheng G" first="Gang" last="Cheng">Gang Cheng</name><name sortKey="Kalyanaraman, Balaraman" sort="Kalyanaraman, Balaraman" uniqKey="Kalyanaraman B" first="Balaraman" last="Kalyanaraman">Balaraman Kalyanaraman</name><name sortKey="Kalyanaraman, Balaraman" sort="Kalyanaraman, Balaraman" uniqKey="Kalyanaraman B" first="Balaraman" last="Kalyanaraman">Balaraman Kalyanaraman</name><name sortKey="Kalyanaraman, Balaraman" sort="Kalyanaraman, Balaraman" uniqKey="Kalyanaraman B" first="Balaraman" last="Kalyanaraman">Balaraman Kalyanaraman</name><name sortKey="Kresty, Laura" sort="Kresty, Laura" uniqKey="Kresty L" first="Laura" last="Kresty">Laura Kresty</name><name sortKey="Lee, Yongik" sort="Lee, Yongik" uniqKey="Lee Y" first="Yongik" last="Lee">Yongik Lee</name><name sortKey="Myers, Charles R" sort="Myers, Charles R" uniqKey="Myers C" first="Charles R." last="Myers">Charles R. Myers</name><name sortKey="Myers, Charles R" sort="Myers, Charles R" uniqKey="Myers C" first="Charles R." last="Myers">Charles R. Myers</name><name sortKey="Pan, Jing" sort="Pan, Jing" uniqKey="Pan J" first="Jing" last="Pan">Jing Pan</name><name sortKey="Pan, Jing" sort="Pan, Jing" uniqKey="Pan J" first="Jing" last="Pan">Jing Pan</name><name sortKey="Weh, Katherine" sort="Weh, Katherine" uniqKey="Weh K" first="Katherine" last="Weh">Katherine Weh</name><name sortKey="You, Ming" sort="You, Ming" uniqKey="You M" first="Ming" last="You">Ming You</name><name sortKey="You, Ming" sort="You, Ming" uniqKey="You M" first="Ming" last="You">Ming You</name><name sortKey="Zhang, Qi" sort="Zhang, Qi" uniqKey="Zhang Q" first="Qi" last="Zhang">Qi Zhang</name><name sortKey="Zhang, Qi" sort="Zhang, Qi" uniqKey="Zhang Q" first="Qi" last="Zhang">Qi Zhang</name><name sortKey="Zielonka, Jacek" sort="Zielonka, Jacek" uniqKey="Zielonka J" first="Jacek" last="Zielonka">Jacek Zielonka</name><name sortKey="Zielonka, Jacek" sort="Zielonka, Jacek" uniqKey="Zielonka J" first="Jacek" last="Zielonka">Jacek Zielonka</name><name sortKey="Zielonka, Jacek" sort="Zielonka, Jacek" uniqKey="Zielonka J" first="Jacek" last="Zielonka">Jacek Zielonka</name><name sortKey="Zielonka, Monika" sort="Zielonka, Monika" uniqKey="Zielonka M" first="Monika" last="Zielonka">Monika Zielonka</name><name sortKey="Zielonka, Monika" sort="Zielonka, Monika" uniqKey="Zielonka M" first="Monika" last="Zielonka">Monika Zielonka</name></country><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Ouari, Olivier" sort="Ouari, Olivier" uniqKey="Ouari O" first="Olivier" last="Ouari">Olivier Ouari</name></region><name sortKey="Hardy, Micael" sort="Hardy, Micael" uniqKey="Hardy M" first="Micael" last="Hardy">Micael Hardy</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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