Augmentation of NVP-BEZ235's anticancer activity against human lung cancer cells by blockage of autophagy.
Identifieur interne : 001479 ( Main/Exploration ); précédent : 001478; suivant : 001480Augmentation of NVP-BEZ235's anticancer activity against human lung cancer cells by blockage of autophagy.
Auteurs : Cheng-Xiong Xu [États-Unis] ; Liqun Zhao ; Ping Yue ; Guofu Fang ; Hui Tao ; Taofeek K. Owonikoko ; Suresh S. Ramalingam ; Fadlo R. Khuri ; Shi-Yong SunSource :
- Cancer biology & therapy [ 1555-8576 ] ; 2011.
Descripteurs français
- KwdFr :
- Animaux, Apoptose (), Autophagie (), Carcinome pulmonaire non à petites cellules (anatomopathologie), Carcinome pulmonaire non à petites cellules (traitement médicamenteux), Charge tumorale (), Chloroquine (pharmacologie), Chloroquine (usage thérapeutique), Femelle, Humains, Imidazoles (pharmacologie), Imidazoles (usage thérapeutique), Lignée cellulaire tumorale, Prolifération cellulaire (), Protéines proto-oncogènes c-akt (antagonistes et inhibiteurs), Protéines proto-oncogènes c-akt (métabolisme), Quinoléines (pharmacologie), Quinoléines (usage thérapeutique), Souris, Souris nude, Synergie des médicaments, Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Sérine-thréonine kinases TOR (métabolisme), Tests d'activité antitumorale sur modèle de xénogreffe, Transduction du signal, Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- anatomopathologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- antagonistes et inhibiteurs : Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- métabolisme : Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- pharmacologie : Chloroquine, Imidazoles, Quinoléines.
- traitement médicamenteux : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- usage thérapeutique : Chloroquine, Imidazoles, Quinoléines.
- Animaux, Apoptose, Autophagie, Charge tumorale, Femelle, Humains, Lignée cellulaire tumorale, Prolifération cellulaire, Souris, Souris nude, Synergie des médicaments, Tests d'activité antitumorale sur modèle de xénogreffe, Transduction du signal.
English descriptors
- KwdEn :
- Animals, Apoptosis (drug effects), Autophagy (drug effects), Carcinoma, Non-Small-Cell Lung (drug therapy), Carcinoma, Non-Small-Cell Lung (pathology), Cell Line, Tumor, Cell Proliferation (drug effects), Chloroquine (pharmacology), Chloroquine (therapeutic use), Drug Synergism, Female, Humans, Imidazoles (pharmacology), Imidazoles (therapeutic use), Lung Neoplasms (drug therapy), Lung Neoplasms (pathology), Mice, Mice, Nude, Proto-Oncogene Proteins c-akt (antagonists & inhibitors), Proto-Oncogene Proteins c-akt (metabolism), Quinolines (pharmacology), Quinolines (therapeutic use), Signal Transduction, TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism), Tumor Burden (drug effects), Xenograft Model Antitumor Assays.
- MESH :
- chemical , antagonists & inhibitors : Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , metabolism : Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Chloroquine, Imidazoles, Quinolines.
- drug effects : Apoptosis, Autophagy, Cell Proliferation, Tumor Burden.
- drug therapy : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- pathology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- chemical , therapeutic use : Chloroquine, Imidazoles, Quinolines.
- Animals, Cell Line, Tumor, Drug Synergism, Female, Humans, Mice, Mice, Nude, Signal Transduction, Xenograft Model Antitumor Assays.
Abstract
Autophagy is a cellular lysosomal degradation pathway essential for regulation of cell survival and death to maintain homeostasis. This process is negatively regulated by mammalian target of rapamycin (mTOR) signaling and often counteracts efficacy of certain cancer therapeutic agents. NVP-BEZ235 (BEZ235) is a novel, orally bioavailable dual PI3K/mTOR inhibitor that has exhibited promising activity against non-small cell lung cancer (NSCLC) in preclinical models. The current study focuses on evaluating the role of BEZ235 in regulating autophagy. BEZ235 was effective in inhibiting the growth of NSCLC cells including induction of apoptosis. It also potently induced the expression of type-II LC3, indicating induction of autophagy. When BEZ235 was used in combination with the lysosomal or autophagic inhibitor chloroquine (CQ), enhanced inhibitory effects on monolayer growth and colony formation of NSCLC cells was observed. In addition, enhanced induction of apoptosis was also detected in cells exposed to the combination of BEZ235 and CQ. Moreover, the combination of BEZ235 and CQ was more effective than each single agent alone in inhibiting the growth of NSCLC xenografts in nude mice. Thus, induction of autophagy by BEZ235 appears to be a survival mechanism that may counteract its anticancer effects. Based on these, we suggest a strategy to enhance BEZ235's anticancer efficacy by blockade of autophagy.
DOI: 10.4161/cbt.12.6.16397
PubMed: 21738008
Affiliations:
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Khuri</name></author><author><name sortKey="Sun, Shi Yong" sort="Sun, Shi Yong" uniqKey="Sun S" first="Shi-Yong" last="Sun">Shi-Yong Sun</name></author></analytic><series><title level="j">Cancer biology & therapy</title><idno type="eISSN">1555-8576</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Apoptosis (drug effects)</term><term>Autophagy (drug effects)</term><term>Carcinoma, Non-Small-Cell Lung (drug therapy)</term><term>Carcinoma, Non-Small-Cell Lung (pathology)</term><term>Cell Line, Tumor</term><term>Cell Proliferation (drug effects)</term><term>Chloroquine (pharmacology)</term><term>Chloroquine (therapeutic use)</term><term>Drug Synergism</term><term>Female</term><term>Humans</term><term>Imidazoles (pharmacology)</term><term>Imidazoles (therapeutic use)</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (pathology)</term><term>Mice</term><term>Mice, Nude</term><term>Proto-Oncogene Proteins c-akt (antagonists & inhibitors)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Quinolines (pharmacology)</term><term>Quinolines (therapeutic use)</term><term>Signal Transduction</term><term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Tumor Burden (drug effects)</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Apoptose ()</term><term>Autophagie ()</term><term>Carcinome pulmonaire non à petites cellules (anatomopathologie)</term><term>Carcinome pulmonaire non à petites cellules (traitement médicamenteux)</term><term>Charge tumorale ()</term><term>Chloroquine (pharmacologie)</term><term>Chloroquine (usage thérapeutique)</term><term>Femelle</term><term>Humains</term><term>Imidazoles (pharmacologie)</term><term>Imidazoles (usage thérapeutique)</term><term>Lignée cellulaire tumorale</term><term>Prolifération cellulaire ()</term><term>Protéines proto-oncogènes c-akt (antagonistes et inhibiteurs)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Quinoléines (pharmacologie)</term><term>Quinoléines (usage thérapeutique)</term><term>Souris</term><term>Souris nude</term><term>Synergie des médicaments</term><term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term><term>Transduction du signal</term><term>Tumeurs du poumon (anatomopathologie)</term><term>Tumeurs du poumon (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Chloroquine</term><term>Imidazoles</term><term>Quinolines</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines proto-oncogènes c-akt</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Autophagy</term><term>Cell Proliferation</term><term>Tumor Burden</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéines proto-oncogènes c-akt</term><term>Sérine-thréonine kinases TOR</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>Chloroquine</term><term>Imidazoles</term><term>Quinoléines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Chloroquine</term><term>Imidazoles</term><term>Quinolines</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Chloroquine</term><term>Imidazoles</term><term>Quinoléines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Drug Synergism</term><term>Female</term><term>Humans</term><term>Mice</term><term>Mice, Nude</term><term>Signal Transduction</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Apoptose</term><term>Autophagie</term><term>Charge tumorale</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Prolifération cellulaire</term><term>Souris</term><term>Souris nude</term><term>Synergie des médicaments</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term><term>Transduction du signal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Autophagy is a cellular lysosomal degradation pathway essential for regulation of cell survival and death to maintain homeostasis. This process is negatively regulated by mammalian target of rapamycin (mTOR) signaling and often counteracts efficacy of certain cancer therapeutic agents. NVP-BEZ235 (BEZ235) is a novel, orally bioavailable dual PI3K/mTOR inhibitor that has exhibited promising activity against non-small cell lung cancer (NSCLC) in preclinical models. The current study focuses on evaluating the role of BEZ235 in regulating autophagy. BEZ235 was effective in inhibiting the growth of NSCLC cells including induction of apoptosis. It also potently induced the expression of type-II LC3, indicating induction of autophagy. When BEZ235 was used in combination with the lysosomal or autophagic inhibitor chloroquine (CQ), enhanced inhibitory effects on monolayer growth and colony formation of NSCLC cells was observed. In addition, enhanced induction of apoptosis was also detected in cells exposed to the combination of BEZ235 and CQ. Moreover, the combination of BEZ235 and CQ was more effective than each single agent alone in inhibiting the growth of NSCLC xenografts in nude mice. Thus, induction of autophagy by BEZ235 appears to be a survival mechanism that may counteract its anticancer effects. Based on these, we suggest a strategy to enhance BEZ235's anticancer efficacy by blockade of autophagy.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Géorgie (États-Unis)</li></region></list><tree><noCountry><name sortKey="Fang, Guofu" sort="Fang, Guofu" uniqKey="Fang G" first="Guofu" last="Fang">Guofu Fang</name><name sortKey="Khuri, Fadlo R" sort="Khuri, Fadlo R" uniqKey="Khuri F" first="Fadlo R" last="Khuri">Fadlo R. Khuri</name><name sortKey="Owonikoko, Taofeek K" sort="Owonikoko, Taofeek K" uniqKey="Owonikoko T" first="Taofeek K" last="Owonikoko">Taofeek K. Owonikoko</name><name sortKey="Ramalingam, Suresh S" sort="Ramalingam, Suresh S" uniqKey="Ramalingam S" first="Suresh S" last="Ramalingam">Suresh S. Ramalingam</name><name sortKey="Sun, Shi Yong" sort="Sun, Shi Yong" uniqKey="Sun S" first="Shi-Yong" last="Sun">Shi-Yong Sun</name><name sortKey="Tao, Hui" sort="Tao, Hui" uniqKey="Tao H" first="Hui" last="Tao">Hui Tao</name><name sortKey="Yue, Ping" sort="Yue, Ping" uniqKey="Yue P" first="Ping" last="Yue">Ping Yue</name><name sortKey="Zhao, Liqun" sort="Zhao, Liqun" uniqKey="Zhao L" first="Liqun" last="Zhao">Liqun Zhao</name></noCountry><country name="États-Unis"><region name="Géorgie (États-Unis)"><name sortKey="Xu, Cheng Xiong" sort="Xu, Cheng Xiong" uniqKey="Xu C" first="Cheng-Xiong" last="Xu">Cheng-Xiong Xu</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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