Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells.
Identifieur interne : 000D02 ( Main/Merge ); précédent : 000D01; suivant : 000D03Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells.
Auteurs : Zheng-Hai Tang [République populaire de Chine] ; Wen-Xiang Cao [République populaire de Chine] ; Min-Xia Su [République populaire de Chine] ; Xiuping Chen [République populaire de Chine] ; Jin-Jian Lu [République populaire de Chine]Source :
- Toxicology and applied pharmacology [ 1096-0333 ] ; 2017.
Descripteurs français
- KwdFr :
- Acrylamides, Antinéoplasiques (pharmacologie), Antinéoplasiques (usage thérapeutique), Apoptose (), Apoptose (physiologie), Autophagie (), Autophagie (physiologie), Carcinome pulmonaire non à petites cellules (métabolisme), Carcinome pulmonaire non à petites cellules (traitement médicamenteux), Cellules A549, Cellules HCT116, Dérivés de l'aniline, Espèces réactives de l'oxygène (métabolisme), Humains, Pipérazines (pharmacologie), Pipérazines (usage thérapeutique), Relation dose-effet des médicaments, Survie cellulaire (), Survie cellulaire (physiologie), Tumeurs du poumon (métabolisme), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- métabolisme : Carcinome pulmonaire non à petites cellules, Espèces réactives de l'oxygène, Tumeurs du poumon.
- pharmacologie : Antinéoplasiques, Pipérazines.
- physiologie : Apoptose, Autophagie, Survie cellulaire.
- traitement médicamenteux : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- usage thérapeutique : Antinéoplasiques, Pipérazines.
- Acrylamides, Apoptose, Autophagie, Cellules A549, Cellules HCT116, Dérivés de l'aniline, Humains, Relation dose-effet des médicaments, Survie cellulaire.
English descriptors
- KwdEn :
- A549 Cells, Acrylamides, Aniline Compounds, Antineoplastic Agents (pharmacology), Antineoplastic Agents (therapeutic use), Apoptosis (drug effects), Apoptosis (physiology), Autophagy (drug effects), Autophagy (physiology), Carcinoma, Non-Small-Cell Lung (drug therapy), Carcinoma, Non-Small-Cell Lung (metabolism), Cell Survival (drug effects), Cell Survival (physiology), Dose-Response Relationship, Drug, HCT116 Cells, Humans, Lung Neoplasms (drug therapy), Lung Neoplasms (metabolism), Piperazines (pharmacology), Piperazines (therapeutic use), Reactive Oxygen Species (metabolism).
- MESH :
- chemical , metabolism : Reactive Oxygen Species.
- chemical , pharmacology : Antineoplastic Agents, Piperazines.
- chemical , therapeutic use : Antineoplastic Agents, Piperazines.
- chemical : Acrylamides, Aniline Compounds.
- drug effects : Apoptosis, Autophagy, Cell Survival.
- drug therapy : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- metabolism : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- physiology : Apoptosis, Autophagy, Cell Survival.
- A549 Cells, Dose-Response Relationship, Drug, HCT116 Cells, Humans.
Abstract
Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-l-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells.
DOI: 10.1016/j.taap.2017.02.017
PubMed: 28237877
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pubmed:28237877Le document en format XML
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<front><div type="abstract" xml:lang="en">Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-l-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells.</div>
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