Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer.
Identifieur interne : 000C14 ( Main/Exploration ); précédent : 000C13; suivant : 000C15Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer.
Auteurs : Xi Wu [République populaire de Chine] ; Xue Xue [République populaire de Chine] ; Lihui Wang [République populaire de Chine] ; Wenjing Wang [République populaire de Chine] ; Jian Han [République populaire de Chine] ; Xiaoxue Sun [République populaire de Chine] ; Haotian Zhang [République populaire de Chine] ; Yueyang Liu [République populaire de Chine] ; Xiaohang Che [République populaire de Chine] ; Jingyu Yang [République populaire de Chine] ; Chunfu Wu [République populaire de Chine]Source :
- European journal of pharmacology [ 1879-0712 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux, Antinéoplasiques (), Antinéoplasiques (pharmacologie), Apoptose (), Autophagie (), Carcinome pulmonaire non à petites cellules (anatomopathologie), Cuivre (), Disulfirame (), Disulfirame (pharmacologie), Humains, Lignée cellulaire tumorale, Mâle, Prolifération cellulaire (), Souris, Souris de lignée BALB C, Tests d'activité antitumorale sur modèle de xénogreffe, Tumeurs du poumon (anatomopathologie).
- MESH :
- anatomopathologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- pharmacologie : Antinéoplasiques, Disulfirame.
- Animaux, Antinéoplasiques, Apoptose, Autophagie, Cuivre, Disulfirame, Humains, Lignée cellulaire tumorale, Mâle, Prolifération cellulaire, Souris, Souris de lignée BALB C, Tests d'activité antitumorale sur modèle de xénogreffe.
English descriptors
- KwdEn :
- Animals, Antineoplastic Agents (chemistry), Antineoplastic Agents (pharmacology), Apoptosis (drug effects), Autophagy (drug effects), Carcinoma, Non-Small-Cell Lung (pathology), Cell Line, Tumor, Cell Proliferation (drug effects), Copper (chemistry), Disulfiram (chemistry), Disulfiram (pharmacology), Humans, Lung Neoplasms (pathology), Male, Mice, Mice, Inbred BALB C, Xenograft Model Antitumor Assays.
- MESH :
- chemical , chemistry : Antineoplastic Agents, Copper, Disulfiram.
- chemical , pharmacology : Antineoplastic Agents, Disulfiram.
- drug effects : Apoptosis, Autophagy, Cell Proliferation.
- pathology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- Animals, Cell Line, Tumor, Humans, Male, Mice, Mice, Inbred BALB C, Xenograft Model Antitumor Assays.
Abstract
Autophagy, a cellular survival mechanism, is thought to allow the recycling of cellular breakdown products when cancer cells are subjected to chemotherapy, thus decreasing drug-induced apoptosis. Disulfiram (DSF), a drug widely used to control alcoholism, possesses anticancer activity by inducing apoptosis in vitro and in vivo in a copper (Cu)-dependent manner. Our previous studies proved that DSF/Cu exerts increased anti-tumor effects on non-small cell lung cancer (NSCLC) xenograft models, and inhibits NSCLC recurrence driven by ALDH-positive cancer stem cells. The present study is designed to investigate whether DSF/Cu can induce autophagy in NSCLC cells and to determine the relationship between autophagy and apoptosis. First, we observed that DSF/Cu induced significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells, accompanied by the formation of vacuoles in the cytoplasm. Next, we investigated the levels of autophagic markers, including LC3II (microtubule-associated protein 1 light chain 3), ATG5 and p62 with or without chloroquine by Western blot. In addition, we observed co-localization of LC3 and the lysosomal protein LAMP2 (lysosome-associated membrane protein 2) after treatment with DSF/Cu. The results showed that DSF/Cu induced autophagy. Finally, we demonstrated that DSF/Cu-induced apoptosis was greatly enhanced when autophagy was suppressed with Atg5 siRNA or 3-MA in NSCLC cells. This synergistic effect of DSF/Cu and 3-MA was further confirmed in the NSCLC xenograft model. Taken together, our results show that DSF/Cu stimulates autophagy in NSCLC cells, which is an impediment to DSF/Cu-induced apoptosis.
DOI: 10.1016/j.ejphar.2018.02.039
PubMed: 29547841
Affiliations:
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Le document en format XML
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<term>Antineoplastic Agents (pharmacology)</term>
<term>Apoptosis (drug effects)</term>
<term>Autophagy (drug effects)</term>
<term>Carcinoma, Non-Small-Cell Lung (pathology)</term>
<term>Cell Line, Tumor</term>
<term>Cell Proliferation (drug effects)</term>
<term>Copper (chemistry)</term>
<term>Disulfiram (chemistry)</term>
<term>Disulfiram (pharmacology)</term>
<term>Humans</term>
<term>Lung Neoplasms (pathology)</term>
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<term>Mice</term>
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<term>Xenograft Model Antitumor Assays</term>
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<term>Antinéoplasiques ()</term>
<term>Antinéoplasiques (pharmacologie)</term>
<term>Apoptose ()</term>
<term>Autophagie ()</term>
<term>Carcinome pulmonaire non à petites cellules (anatomopathologie)</term>
<term>Cuivre ()</term>
<term>Disulfirame ()</term>
<term>Disulfirame (pharmacologie)</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Mâle</term>
<term>Prolifération cellulaire ()</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe</term>
<term>Tumeurs du poumon (anatomopathologie)</term>
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<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Copper</term>
<term>Disulfiram</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Disulfiram</term>
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<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term>
<term>Autophagy</term>
<term>Cell Proliferation</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term>
<term>Lung Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Disulfirame</term>
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<term>Cell Line, Tumor</term>
<term>Humans</term>
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<term>Antinéoplasiques</term>
<term>Apoptose</term>
<term>Autophagie</term>
<term>Cuivre</term>
<term>Disulfirame</term>
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<term>Lignée cellulaire tumorale</term>
<term>Mâle</term>
<term>Prolifération cellulaire</term>
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<front><div type="abstract" xml:lang="en">Autophagy, a cellular survival mechanism, is thought to allow the recycling of cellular breakdown products when cancer cells are subjected to chemotherapy, thus decreasing drug-induced apoptosis. Disulfiram (DSF), a drug widely used to control alcoholism, possesses anticancer activity by inducing apoptosis in vitro and in vivo in a copper (Cu)-dependent manner. Our previous studies proved that DSF/Cu exerts increased anti-tumor effects on non-small cell lung cancer (NSCLC) xenograft models, and inhibits NSCLC recurrence driven by ALDH-positive cancer stem cells. The present study is designed to investigate whether DSF/Cu can induce autophagy in NSCLC cells and to determine the relationship between autophagy and apoptosis. First, we observed that DSF/Cu induced significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells, accompanied by the formation of vacuoles in the cytoplasm. Next, we investigated the levels of autophagic markers, including LC3II (microtubule-associated protein 1 light chain 3), ATG5 and p62 with or without chloroquine by Western blot. In addition, we observed co-localization of LC3 and the lysosomal protein LAMP2 (lysosome-associated membrane protein 2) after treatment with DSF/Cu. The results showed that DSF/Cu induced autophagy. Finally, we demonstrated that DSF/Cu-induced apoptosis was greatly enhanced when autophagy was suppressed with Atg5 siRNA or 3-MA in NSCLC cells. This synergistic effect of DSF/Cu and 3-MA was further confirmed in the NSCLC xenograft model. Taken together, our results show that DSF/Cu stimulates autophagy in NSCLC cells, which is an impediment to DSF/Cu-induced apoptosis.</div>
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<name sortKey="Xue, Xue" sort="Xue, Xue" uniqKey="Xue X" first="Xue" last="Xue">Xue Xue</name>
<name sortKey="Yang, Jingyu" sort="Yang, Jingyu" uniqKey="Yang J" first="Jingyu" last="Yang">Jingyu Yang</name>
<name sortKey="Zhang, Haotian" sort="Zhang, Haotian" uniqKey="Zhang H" first="Haotian" last="Zhang">Haotian Zhang</name>
</country>
</tree>
</affiliations>
</record>
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