The combination of thioxodihydroquinazolinones and platinum drugs reverses platinum resistance in tumor cells by inducing mitochondrial apoptosis independent of Bax and Bak
Identifieur interne : 000E02 ( Main/Exploration ); précédent : 000E01; suivant : 000E03The combination of thioxodihydroquinazolinones and platinum drugs reverses platinum resistance in tumor cells by inducing mitochondrial apoptosis independent of Bax and Bak
Auteurs : Wei Qian [États-Unis] ; Joseph Salamoun [États-Unis] ; Jingnan Wang [République populaire de Chine] ; Vera Roginskaya [États-Unis] ; Bennett Van Houten [États-Unis] ; Peter Wipf [États-Unis]Source :
- Bioorganic & medicinal chemistry letters [ 0960-894X ] ; 2014.
Descripteurs français
- KwdFr :
- Apoptose (), Composés organiques du platine (), Composés organiques du platine (pharmacologie), Humains, Mitochondries (), Protéine Bak (métabolisme), Protéine Bax (métabolisme), Quinazolinones (), Quinazolinones (pharmacologie), Relation structure-activité, Résistance aux médicaments antinéoplasiques ().
- MESH :
English descriptors
- KwdEn :
- Apoptosis (drug effects), Drug Resistance, Neoplasm (drug effects), Humans, Mitochondria (drug effects), Organoplatinum Compounds (chemistry), Organoplatinum Compounds (pharmacology), Quinazolinones (chemistry), Quinazolinones (pharmacology), Structure-Activity Relationship, bcl-2 Homologous Antagonist-Killer Protein (metabolism), bcl-2-Associated X Protein (metabolism).
- MESH :
- chemical , chemistry : Organoplatinum Compounds, Quinazolinones.
- drug effects : Apoptosis, Drug Resistance, Neoplasm, Mitochondria.
- chemical , metabolism : bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein.
- chemical , pharmacology : Organoplatinum Compounds, Quinazolinones.
- Humans, Structure-Activity Relationship.
Abstract
The effective management of tumors resistant to platinum drugs-based anticancer therapies is a critical challenge in current clinical practices. The proapoptotic Bcl-2 family proteins Bax and Bak are essential for cisplatin-induced apoptosis. Unfortunately, Bax and its related upstream endogenous apoptotic signaling pathways are often dysregulated in cancer cells. Strategies that are able to bypass Bax- and Bak-dependent apoptotic pathways will thus provide opportunities to overcome platinum drug resistance. We have identified the thioxodihydroquinazolinone mdivi-1 as a member of a novel class of small molecules that are able to induce Bax- and Bak-independent mitochondrial outer membrane permeabilization when combined with cisplatin, thereby efficiently triggering apoptosis in platinum resistant tumor cells. In the present structure activity relationship (SAR) study of a computationally selected library of mdivi-1 related small molecules, we established a pharmacophore model that can lead to the enhancement of platinum drug efficacy and Bax/Bak-independent mitochondrial apoptosis. Specifically, we found that a thiourea function is necessary but not sufficient for the synergism of this class of thioxodihydroquinazolinones with cisplatin. We were also able to identify more potent mdivi-1 analogs through this SAR study, which will guide future designs with the goal to develop novel combination regimens for the treatment of platinum and multidrug resistant tumors.
Url:
DOI: 10.1016/j.bmcl.2014.12.072
PubMed: 25582599
PubMed Central: 4318771
Affiliations:
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and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Salamoun, Joseph" sort="Salamoun, Joseph" uniqKey="Salamoun J" first="Joseph" last="Salamoun">Joseph Salamoun</name><affiliation wicri:level="4"><nlm:aff id="A2">Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Wang, Jingnan" sort="Wang, Jingnan" uniqKey="Wang J" first="Jingnan" last="Wang">Jingnan Wang</name><affiliation wicri:level="1"><nlm:aff id="A3">Tsinghua University School of Medicine, Tsinghua University, Haidian District, Beijing 100084, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tsinghua University School of Medicine, Tsinghua University, Haidian District, Beijing 100084</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Roginskaya, Vera" sort="Roginskaya, Vera" uniqKey="Roginskaya V" first="Vera" last="Roginskaya">Vera Roginskaya</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Van Houten, Bennett" sort="Van Houten, Bennett" uniqKey="Van Houten B" first="Bennett" last="Van Houten">Bennett Van Houten</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name><affiliation wicri:level="4"><nlm:aff id="A2">Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university" n="3">Université de Pittsburgh</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="A4">Center for Chemical Methodologies and Library Development, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Chemical Methodologies and Library Development, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university" n="3">Université de Pittsburgh</orgName></affiliation></author></analytic><series><title level="j">Bioorganic & medicinal chemistry letters</title><idno type="ISSN">0960-894X</idno><idno type="eISSN">1464-3405</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Apoptosis (drug effects)</term><term>Drug Resistance, Neoplasm (drug effects)</term><term>Humans</term><term>Mitochondria (drug effects)</term><term>Organoplatinum Compounds (chemistry)</term><term>Organoplatinum Compounds (pharmacology)</term><term>Quinazolinones (chemistry)</term><term>Quinazolinones (pharmacology)</term><term>Structure-Activity Relationship</term><term>bcl-2 Homologous Antagonist-Killer Protein (metabolism)</term><term>bcl-2-Associated X Protein (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Apoptose ()</term><term>Composés organiques du platine ()</term><term>Composés organiques du platine (pharmacologie)</term><term>Humains</term><term>Mitochondries ()</term><term>Protéine Bak (métabolisme)</term><term>Protéine Bax (métabolisme)</term><term>Quinazolinones ()</term><term>Quinazolinones (pharmacologie)</term><term>Relation structure-activité</term><term>Résistance aux médicaments antinéoplasiques ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Organoplatinum Compounds</term><term>Quinazolinones</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Drug Resistance, Neoplasm</term><term>Mitochondria</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>bcl-2 Homologous Antagonist-Killer Protein</term><term>bcl-2-Associated X Protein</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéine Bak</term><term>Protéine Bax</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Composés organiques du platine</term><term>Quinazolinones</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Organoplatinum Compounds</term><term>Quinazolinones</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Apoptose</term><term>Composés organiques du platine</term><term>Humains</term><term>Mitochondries</term><term>Quinazolinones</term><term>Relation structure-activité</term><term>Résistance aux médicaments antinéoplasiques</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">The effective management of tumors resistant to platinum drugs-based anticancer therapies is a critical challenge in current clinical practices. The proapoptotic Bcl-2 family proteins Bax and Bak are essential for cisplatin-induced apoptosis. Unfortunately, Bax and its related upstream endogenous apoptotic signaling pathways are often dysregulated in cancer cells. Strategies that are able to bypass Bax- and Bak-dependent apoptotic pathways will thus provide opportunities to overcome platinum drug resistance. We have identified the thioxodihydroquinazolinone mdivi-1 as a member of a novel class of small molecules that are able to induce Bax- and Bak-independent mitochondrial outer membrane permeabilization when combined with cisplatin, thereby efficiently triggering apoptosis in platinum resistant tumor cells. In the present structure activity relationship (SAR) study of a computationally selected library of mdivi-1 related small molecules, we established a pharmacophore model that can lead to the enhancement of platinum drug efficacy and Bax/Bak-independent mitochondrial apoptosis. Specifically, we found that a thiourea function is necessary but not sufficient for the synergism of this class of thioxodihydroquinazolinones with cisplatin. We were also able to identify more potent mdivi-1 analogs through this SAR study, which will guide future designs with the goal to develop novel combination regimens for the treatment of platinum and multidrug resistant tumors.</p></div></front></TEI><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li><li>Pékin</li></settlement><orgName><li>Université de Pittsburgh</li></orgName></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Qian, Wei" sort="Qian, Wei" uniqKey="Qian W" first="Wei" last="Qian">Wei Qian</name></region><name sortKey="Roginskaya, Vera" sort="Roginskaya, Vera" uniqKey="Roginskaya V" first="Vera" last="Roginskaya">Vera Roginskaya</name><name sortKey="Salamoun, Joseph" sort="Salamoun, Joseph" uniqKey="Salamoun J" first="Joseph" last="Salamoun">Joseph Salamoun</name><name sortKey="Van Houten, Bennett" sort="Van Houten, Bennett" uniqKey="Van Houten B" first="Bennett" last="Van Houten">Bennett Van Houten</name><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Wang, Jingnan" sort="Wang, Jingnan" uniqKey="Wang J" first="Jingnan" last="Wang">Jingnan Wang</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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