ChloroquineV1, Ncbi, Merge, bibRecord, 000395

Blocking autophagy improves the anti-tumor activity of afatinib in lung adenocarcinoma with activating EGFR mutations in vitro and in vivo.

Identifieur interne : 000395 ( Ncbi/Merge ); précédent : 000394; suivant : 000396

Blocking autophagy improves the anti-tumor activity of afatinib in lung adenocarcinoma with activating EGFR mutations in vitro and in vivo.

Auteurs : Xiangxiang Hu [République populaire de Chine] ; Si Shi [République populaire de Chine] ; Huan Wang [République populaire de Chine] ; Xiaochen Yu [République populaire de Chine] ; Qian Wang [République populaire de Chine] ; Shanshan Jiang [République populaire de Chine] ; Dianwen Ju [République populaire de Chine] ; Li Ye [République populaire de Chine] ; Meiqing Feng [République populaire de Chine]

Source :

Scientific reports [ 2045-2322 ] ; 2017.

RBID : pubmed:28676644

Descripteurs français

KwdFr :
- Animaux, Apoptose (), Apoptose (génétique), Autophagie (), Autophagie (génétique), Caspase-3 (métabolisme), Espèces réactives de l'oxygène (métabolisme), Humains, Inhibiteurs de protéines kinases (pharmacologie), Lignée cellulaire tumorale, Modèles animaux de maladie humaine, Protéines proto-oncogènes c-akt (métabolisme), Récepteurs ErbB (antagonistes et inhibiteurs), Récepteurs ErbB (génétique), Souris, Sérine-thréonine kinases TOR (métabolisme), Tests d'activité antitumorale sur modèle de xénogreffe, Transduction du signal ().
MESH :
- antagonistes et inhibiteurs : Récepteurs ErbB.
- génétique : Apoptose, Autophagie, Récepteurs ErbB.
- métabolisme : Caspase-3, Espèces réactives de l'oxygène, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- pharmacologie : Inhibiteurs de protéines kinases.
- Animaux, Apoptose, Autophagie, Humains, Lignée cellulaire tumorale, Modèles animaux de maladie humaine, Souris, Tests d'activité antitumorale sur modèle de xénogreffe, Transduction du signal.

English descriptors

KwdEn :
- Adenocarcinoma of Lung (genetics), Adenocarcinoma of Lung (metabolism), Adenocarcinoma of Lung (pathology), Afatinib (pharmacology), Animals, Apoptosis (drug effects), Apoptosis (genetics), Autophagy (drug effects), Autophagy (genetics), Caspase 3 (metabolism), Cell Line, Tumor, Disease Models, Animal, ErbB Receptors (antagonists & inhibitors), ErbB Receptors (genetics), Humans, Mice, Protein Kinase Inhibitors (pharmacology), Proto-Oncogene Proteins c-akt (metabolism), Reactive Oxygen Species (metabolism), Signal Transduction (drug effects), TOR Serine-Threonine Kinases (metabolism), Xenograft Model Antitumor Assays.
MESH :
- chemical , antagonists & inhibitors : ErbB Receptors.
- chemical , genetics : ErbB Receptors.
- chemical , metabolism : Caspase 3, Proto-Oncogene Proteins c-akt, Reactive Oxygen Species, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Afatinib, Protein Kinase Inhibitors.
- drug effects : Apoptosis, Autophagy, Signal Transduction.
- genetics : Adenocarcinoma of Lung, Apoptosis, Autophagy.
- metabolism : Adenocarcinoma of Lung.
- pathology : Adenocarcinoma of Lung.
- Animals, Cell Line, Tumor, Disease Models, Animal, Humans, Mice, Xenograft Model Antitumor Assays.

Abstract

Afatinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, afatinib's clinical application is still hampered by acquired resistance. Recently, autophagy is considered as an important mechanism of resistance to TKI. Herein, we investigated the autophagy induction as well as its influence on anti-lung adenocarcinoma activity of afatinib in two activating EGFR-mutants H1975 and H1650 cells. First, Growth inhibition and caspase-dependent apoptosis were observed in afatinib-treated H1975 and H1650 cells. Then we confirmed afatinib-induced autophagy in H1975 and H1650 cells. Importantly, autophagy inhibition using chloroquine (CQ) and 3-MA enhanced the cytotoxicity of afatinib, elucidating the cytoprotective role of autophagy in lung adenocarcinoma therapy with afatinib. Further study suggested that Akt/mTOR and Erk signaling pathways were involved in afatinib-induced autophagy, and reactive oxygen species (ROS) acted as an intracellular transducer regulating both autophagy and apoptosis in afatinib-treated H1975 and H1650 cells. Moreover, the in vivo experiment in xenograft model using H1975 cell line confirmed the enhanced anti-lung adenocarcinoma efficacy of afatinib when combined with autophagy inhibitor CQ. Thus, blocking autophagy may be a promising strategy to overcome resistance and increase sensitivity to afatinib in lung adenocarcinoma harboring activating EGFR mutations.

DOI: 10.1038/s41598-017-04258-8
PubMed: 28676644

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<term>Adenocarcinoma of Lung (pathology)</term>
<term>Afatinib (pharmacology)</term>
<term>Animals</term>
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<term>Autophagy (drug effects)</term>
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<term>Cell Line, Tumor</term>
<term>Disease Models, Animal</term>
<term>ErbB Receptors (antagonists & inhibitors)</term>
<term>ErbB Receptors (genetics)</term>
<term>Humans</term>
<term>Mice</term>
<term>Protein Kinase Inhibitors (pharmacology)</term>
<term>Proto-Oncogene Proteins c-akt (metabolism)</term>
<term>Reactive Oxygen Species (metabolism)</term>
<term>Signal Transduction (drug effects)</term>
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<term>Xenograft Model Antitumor Assays</term>
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<term>Apoptose ()</term>
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<term>Autophagie (génétique)</term>
<term>Caspase-3 (métabolisme)</term>
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<front><div type="abstract" xml:lang="en">Afatinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, afatinib's clinical application is still hampered by acquired resistance. Recently, autophagy is considered as an important mechanism of resistance to TKI. Herein, we investigated the autophagy induction as well as its influence on anti-lung adenocarcinoma activity of afatinib in two activating EGFR-mutants H1975 and H1650 cells. First, Growth inhibition and caspase-dependent apoptosis were observed in afatinib-treated H1975 and H1650 cells. Then we confirmed afatinib-induced autophagy in H1975 and H1650 cells. Importantly, autophagy inhibition using chloroquine (CQ) and 3-MA enhanced the cytotoxicity of afatinib, elucidating the cytoprotective role of autophagy in lung adenocarcinoma therapy with afatinib. Further study suggested that Akt/mTOR and Erk signaling pathways were involved in afatinib-induced autophagy, and reactive oxygen species (ROS) acted as an intracellular transducer regulating both autophagy and apoptosis in afatinib-treated H1975 and H1650 cells. Moreover, the in vivo experiment in xenograft model using H1975 cell line confirmed the enhanced anti-lung adenocarcinoma efficacy of afatinib when combined with autophagy inhibitor CQ. Thus, blocking autophagy may be a promising strategy to overcome resistance and increase sensitivity to afatinib in lung adenocarcinoma harboring activating EGFR mutations.</div>
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<Abstract><AbstractText>Afatinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, afatinib's clinical application is still hampered by acquired resistance. Recently, autophagy is considered as an important mechanism of resistance to TKI. Herein, we investigated the autophagy induction as well as its influence on anti-lung adenocarcinoma activity of afatinib in two activating EGFR-mutants H1975 and H1650 cells. First, Growth inhibition and caspase-dependent apoptosis were observed in afatinib-treated H1975 and H1650 cells. Then we confirmed afatinib-induced autophagy in H1975 and H1650 cells. Importantly, autophagy inhibition using chloroquine (CQ) and 3-MA enhanced the cytotoxicity of afatinib, elucidating the cytoprotective role of autophagy in lung adenocarcinoma therapy with afatinib. Further study suggested that Akt/mTOR and Erk signaling pathways were involved in afatinib-induced autophagy, and reactive oxygen species (ROS) acted as an intracellular transducer regulating both autophagy and apoptosis in afatinib-treated H1975 and H1650 cells. Moreover, the in vivo experiment in xenograft model using H1975 cell line confirmed the enhanced anti-lung adenocarcinoma efficacy of afatinib when combined with autophagy inhibitor CQ. Thus, blocking autophagy may be a promising strategy to overcome resistance and increase sensitivity to afatinib in lung adenocarcinoma harboring activating EGFR mutations.</AbstractText>
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<ForeName>Si</ForeName>
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   |texte=   Blocking autophagy improves the anti-tumor activity of afatinib in lung adenocarcinoma with activating EGFR mutations in vitro and in vivo.
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Blocking autophagy improves the anti-tumor activity of afatinib in lung adenocarcinoma with activating EGFR mutations in vitro and in vivo.

Blocking autophagy improves the anti-tumor activity of afatinib in lung adenocarcinoma with activating EGFR mutations in vitro and in vivo.

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