Gemcitabine resistance mediated by ribonucleotide reductase M2 in lung squamous cell carcinoma is reversed by GW8510 through autophagy induction.
Identifieur interne : 000C34 ( Main/Exploration ); précédent : 000C33; suivant : 000C35Gemcitabine resistance mediated by ribonucleotide reductase M2 in lung squamous cell carcinoma is reversed by GW8510 through autophagy induction.
Auteurs : Ping Chen [République populaire de Chine] ; Jian-Nong Wu [République populaire de Chine] ; Yang Shu [République populaire de Chine] ; He-Guo Jiang [République populaire de Chine] ; Xiao-Hui Zhao [République populaire de Chine] ; Hai Qian [République populaire de Chine] ; Kang Chen [République populaire de Chine] ; Ting Lan [République populaire de Chine] ; Chen-Guo Chen [République populaire de Chine] ; Jian Li [Oman]Source :
- Clinical science (London, England : 1979) [ 1470-8736 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux, Antinéoplasiques antimétabolites (pharmacologie), Autophagie (), Carcinome épidermoïde (anatomopathologie), Carcinome épidermoïde (enzymologie), Carcinome épidermoïde (traitement médicamenteux), Cellules cancéreuses en culture, Désoxycytidine (analogues et dérivés), Désoxycytidine (pharmacologie), Humains, Hétérogreffes, Indoles (pharmacologie), Mâle, Ribonucleoside diphosphate reductase (antagonistes et inhibiteurs), Ribonucleoside diphosphate reductase (physiologie), Régulation de l'expression des gènes tumoraux (), Régulation négative (), Résistance aux médicaments antinéoplasiques (), Résistance aux médicaments antinéoplasiques (physiologie), Souris de lignée NOD, Tests d'activité antitumorale sur modèle de xénogreffe, Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (enzymologie), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- analogues et dérivés : Désoxycytidine.
- anatomopathologie : Carcinome épidermoïde, Tumeurs du poumon.
- antagonistes et inhibiteurs : Ribonucleoside diphosphate reductase.
- enzymologie : Carcinome épidermoïde, Tumeurs du poumon.
- pharmacologie : Antinéoplasiques antimétabolites, Désoxycytidine, Indoles.
- physiologie : Ribonucleoside diphosphate reductase, Résistance aux médicaments antinéoplasiques.
- traitement médicamenteux : Carcinome épidermoïde, Tumeurs du poumon.
- Animaux, Autophagie, Cellules cancéreuses en culture, Humains, Hétérogreffes, Mâle, Régulation de l'expression des gènes tumoraux, Régulation négative, Résistance aux médicaments antinéoplasiques, Souris de lignée NOD, Tests d'activité antitumorale sur modèle de xénogreffe.
English descriptors
- KwdEn :
- Animals, Antimetabolites, Antineoplastic (pharmacology), Autophagy (drug effects), Carcinoma, Squamous Cell (drug therapy), Carcinoma, Squamous Cell (enzymology), Carcinoma, Squamous Cell (pathology), Deoxycytidine (analogs & derivatives), Deoxycytidine (pharmacology), Down-Regulation (drug effects), Drug Resistance, Neoplasm (drug effects), Drug Resistance, Neoplasm (physiology), Gene Expression Regulation, Neoplastic (drug effects), Heterografts, Humans, Indoles (pharmacology), Lung Neoplasms (drug therapy), Lung Neoplasms (enzymology), Lung Neoplasms (pathology), Male, Mice, Inbred NOD, Ribonucleoside Diphosphate Reductase (antagonists & inhibitors), Ribonucleoside Diphosphate Reductase (physiology), Tumor Cells, Cultured, Xenograft Model Antitumor Assays.
- MESH :
- chemical , analogs & derivatives : Deoxycytidine.
- chemical , antagonists & inhibitors : Ribonucleoside Diphosphate Reductase.
- chemical , pharmacology : Antimetabolites, Antineoplastic, Deoxycytidine, Indoles.
- drug effects : Autophagy, Down-Regulation, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic.
- drug therapy : Carcinoma, Squamous Cell, Lung Neoplasms.
- enzymology : Carcinoma, Squamous Cell, Lung Neoplasms.
- pathology : Carcinoma, Squamous Cell, Lung Neoplasms.
- physiology : Drug Resistance, Neoplasm, Ribonucleoside Diphosphate Reductase.
- Animals, Heterografts, Humans, Male, Mice, Inbred NOD, Tumor Cells, Cultured, Xenograft Model Antitumor Assays.
Abstract
Although chemotherapeutic regimen containing gemcitabine is the first-line therapy for advanced lung squamous cell carcinoma (LSCC), gemcitabine resistance remains an important clinical problem. Some studies suggest that overexpressions of ribonucleotide reductase (RNR) subunit M2 (RRM2) may be involved in gemcitabine resistance. We used a novel RRM2 inhibitor, GW8510, as a gemcitabine sensitization agent to investigate the therapeutic utility in reversing gemcitabine resistance in LSCC. Results showed that the expressions of RRM2 were increased in gemcitabine intrinsic resistant LSCC cells upon gemcitabine treatment. GW8510 not only suppressed LSCC cell survival, but also sensitized gemcitabine-resistant cells to gemcitabine through autophagy induction mediated by RRM2 down-regulation along with decrease in dNTP levels. The combination of GW8510 and gemcitabine produced a synergistic effect on killing LSCC cells. The synergism of the two agents was impeded by addition of autophagy inhibitors chloroquine (CQ) or bafilomycin A1 (Baf A1), or knockdown of the autophagy gene, Bcl-2-interacting protein 1 (BECN1). Moreover, GW8510-caused LSCC cell sensitization to gemcitabine through autophagy induction was parallel with impairment of DNA double-strand break (DSB) repair and marked increase in cell apoptosis, revealing a cross-talk between autophagy and DNA damage repair, and an interplay between autophagy and apoptosis. Finally, gemcitabine sensitization mediated by autophagy induction through GW8510-caused RRM2 down-regulation was demonstrated in vivo in gemcitabine-resistant LSCC tumor xenograft, further indicating that the sensitization is dependent on autophagy activation. In conclusion, GW8510 can reverse gemcitabine resistance in LSCC cells through RRM2 downregulation-mediated autophagy induction, and GW850 may be a promising therapeutic agent against LSCC as it combined with gemcitabine.
DOI: 10.1042/CS20180010
PubMed: 29853661
Affiliations:
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Chine</country><wicri:regionArea>Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang</wicri:regionArea><wicri:noRegion>Zhenjiang</wicri:noRegion></affiliation></author><author><name sortKey="Qian, Hai" sort="Qian, Hai" uniqKey="Qian H" first="Hai" last="Qian">Hai Qian</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical Science, Jiangsu University, Zhenjiang, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Medical Science, Jiangsu University, Zhenjiang</wicri:regionArea><wicri:noRegion>Zhenjiang</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Kang" sort="Chen, Kang" uniqKey="Chen K" first="Kang" last="Chen">Kang Chen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang</wicri:regionArea><wicri:noRegion>Zhenjiang</wicri:noRegion></affiliation></author><author><name sortKey="Lan, Ting" sort="Lan, Ting" uniqKey="Lan T" first="Ting" last="Lan">Ting Lan</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical Science, Jiangsu University, Zhenjiang, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Medical Science, Jiangsu University, Zhenjiang</wicri:regionArea><wicri:noRegion>Zhenjiang</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Chen Guo" sort="Chen, Chen Guo" uniqKey="Chen C" first="Chen-Guo" last="Chen">Chen-Guo Chen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang</wicri:regionArea><wicri:noRegion>Zhenjiang</wicri:noRegion></affiliation></author><author><name sortKey="Li, Jian" sort="Li, Jian" uniqKey="Li J" first="Jian" last="Li">Jian Li</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China lijian541226@163.com.</nlm:affiliation><country wicri:rule="url">Oman</country><wicri:regionArea>Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang</wicri:regionArea><wicri:noRegion>Zhenjiang</wicri:noRegion></affiliation></author></analytic><series><title level="j">Clinical science (London, England : 1979)</title><idno type="eISSN">1470-8736</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antimetabolites, Antineoplastic (pharmacology)</term><term>Autophagy (drug effects)</term><term>Carcinoma, Squamous Cell (drug therapy)</term><term>Carcinoma, Squamous Cell (enzymology)</term><term>Carcinoma, Squamous Cell (pathology)</term><term>Deoxycytidine (analogs & derivatives)</term><term>Deoxycytidine (pharmacology)</term><term>Down-Regulation (drug effects)</term><term>Drug Resistance, Neoplasm (drug effects)</term><term>Drug Resistance, Neoplasm (physiology)</term><term>Gene Expression Regulation, Neoplastic (drug effects)</term><term>Heterografts</term><term>Humans</term><term>Indoles (pharmacology)</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (enzymology)</term><term>Lung Neoplasms (pathology)</term><term>Male</term><term>Mice, Inbred NOD</term><term>Ribonucleoside Diphosphate Reductase (antagonists & inhibitors)</term><term>Ribonucleoside Diphosphate Reductase (physiology)</term><term>Tumor Cells, Cultured</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antinéoplasiques antimétabolites (pharmacologie)</term><term>Autophagie ()</term><term>Carcinome épidermoïde (anatomopathologie)</term><term>Carcinome épidermoïde (enzymologie)</term><term>Carcinome épidermoïde (traitement médicamenteux)</term><term>Cellules cancéreuses en culture</term><term>Désoxycytidine (analogues et dérivés)</term><term>Désoxycytidine (pharmacologie)</term><term>Humains</term><term>Hétérogreffes</term><term>Indoles (pharmacologie)</term><term>Mâle</term><term>Ribonucleoside diphosphate reductase (antagonistes et inhibiteurs)</term><term>Ribonucleoside diphosphate reductase (physiologie)</term><term>Régulation de l'expression des gènes tumoraux ()</term><term>Régulation négative ()</term><term>Résistance aux médicaments antinéoplasiques ()</term><term>Résistance aux médicaments antinéoplasiques (physiologie)</term><term>Souris de lignée NOD</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term><term>Tumeurs du poumon (anatomopathologie)</term><term>Tumeurs du poumon (enzymologie)</term><term>Tumeurs du poumon (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Deoxycytidine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Ribonucleoside Diphosphate Reductase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antimetabolites, Antineoplastic</term><term>Deoxycytidine</term><term>Indoles</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Désoxycytidine</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome épidermoïde</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Ribonucleoside diphosphate reductase</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>Down-Regulation</term><term>Drug Resistance, Neoplasm</term><term>Gene Expression Regulation, Neoplastic</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Squamous Cell</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Carcinome épidermoïde</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Carcinoma, Squamous Cell</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Carcinoma, Squamous Cell</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques antimétabolites</term><term>Désoxycytidine</term><term>Indoles</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Ribonucleoside diphosphate reductase</term><term>Résistance aux médicaments antinéoplasiques</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Drug Resistance, Neoplasm</term><term>Ribonucleoside Diphosphate Reductase</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome épidermoïde</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Heterografts</term><term>Humans</term><term>Male</term><term>Mice, Inbred NOD</term><term>Tumor Cells, Cultured</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Autophagie</term><term>Cellules cancéreuses en culture</term><term>Humains</term><term>Hétérogreffes</term><term>Mâle</term><term>Régulation de l'expression des gènes tumoraux</term><term>Régulation négative</term><term>Résistance aux médicaments antinéoplasiques</term><term>Souris de lignée NOD</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Although chemotherapeutic regimen containing gemcitabine is the first-line therapy for advanced lung squamous cell carcinoma (LSCC), gemcitabine resistance remains an important clinical problem. Some studies suggest that overexpressions of ribonucleotide reductase (RNR) subunit M2 (RRM2) may be involved in gemcitabine resistance. We used a novel RRM2 inhibitor, GW8510, as a gemcitabine sensitization agent to investigate the therapeutic utility in reversing gemcitabine resistance in LSCC. Results showed that the expressions of RRM2 were increased in gemcitabine intrinsic resistant LSCC cells upon gemcitabine treatment. GW8510 not only suppressed LSCC cell survival, but also sensitized gemcitabine-resistant cells to gemcitabine through autophagy induction mediated by RRM2 down-regulation along with decrease in dNTP levels. The combination of GW8510 and gemcitabine produced a synergistic effect on killing LSCC cells. The synergism of the two agents was impeded by addition of autophagy inhibitors chloroquine (CQ) or bafilomycin A1 (Baf A1), or knockdown of the autophagy gene, Bcl-2-interacting protein 1 (<i>BECN1</i>). Moreover, GW8510-caused LSCC cell sensitization to gemcitabine through autophagy induction was parallel with impairment of DNA double-strand break (DSB) repair and marked increase in cell apoptosis, revealing a cross-talk between autophagy and DNA damage repair, and an interplay between autophagy and apoptosis. Finally, gemcitabine sensitization mediated by autophagy induction through GW8510-caused RRM2 down-regulation was demonstrated <i>in vivo</i> in gemcitabine-resistant LSCC tumor xenograft, further indicating that the sensitization is dependent on autophagy activation. In conclusion, GW8510 can reverse gemcitabine resistance in LSCC cells through RRM2 downregulation-mediated autophagy induction, and GW850 may be a promising therapeutic agent against LSCC as it combined with gemcitabine.</div></front></TEI><affiliations><list><country><li>Oman</li><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Chen, Ping" sort="Chen, Ping" uniqKey="Chen P" first="Ping" last="Chen">Ping Chen</name></noRegion><name sortKey="Chen, Chen Guo" sort="Chen, Chen Guo" uniqKey="Chen C" first="Chen-Guo" last="Chen">Chen-Guo Chen</name><name sortKey="Chen, Kang" sort="Chen, Kang" uniqKey="Chen K" first="Kang" last="Chen">Kang Chen</name><name sortKey="Jiang, He Guo" sort="Jiang, He Guo" uniqKey="Jiang H" first="He-Guo" last="Jiang">He-Guo Jiang</name><name sortKey="Lan, Ting" sort="Lan, Ting" uniqKey="Lan T" first="Ting" last="Lan">Ting Lan</name><name sortKey="Qian, Hai" sort="Qian, Hai" uniqKey="Qian H" first="Hai" last="Qian">Hai Qian</name><name sortKey="Shu, Yang" sort="Shu, Yang" uniqKey="Shu Y" first="Yang" last="Shu">Yang Shu</name><name sortKey="Wu, Jian Nong" sort="Wu, Jian Nong" uniqKey="Wu J" first="Jian-Nong" last="Wu">Jian-Nong Wu</name><name sortKey="Zhao, Xiao Hui" sort="Zhao, Xiao Hui" uniqKey="Zhao X" first="Xiao-Hui" last="Zhao">Xiao-Hui Zhao</name></country><country name="Oman"><noRegion><name sortKey="Li, Jian" sort="Li, Jian" uniqKey="Li J" first="Jian" last="Li">Jian Li</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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