Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells.
Identifieur interne : 000E89 ( Main/Exploration ); précédent : 000E88; suivant : 000E90Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells.
Auteurs : Weilong Yao [États-Unis] ; Ping Yue [États-Unis] ; Guojing Zhang [États-Unis] ; Taofeek K. Owonikoko [États-Unis] ; Fadlo R. Khuri [États-Unis] ; Shi-Yong Sun [États-Unis]Source :
- Cancer letters [ 1872-7980 ] ; 2015.
Descripteurs français
- KwdFr :
- Autophagie (), Benzimidazoles (pharmacologie), Carcinome pulmonaire non à petites cellules (anatomopathologie), Carcinome pulmonaire non à petites cellules (enzymologie), Humains, Lignée cellulaire tumorale, MAP Kinase Kinase Kinases (antagonistes et inhibiteurs), Phosphatidylinositol 3-kinases (métabolisme), Protéines proto-oncogènes c-akt (métabolisme), Transduction du signal (), Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (enzymologie).
- MESH :
- anatomopathologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- antagonistes et inhibiteurs : MAP Kinase Kinase Kinases.
- enzymologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- métabolisme : Phosphatidylinositol 3-kinases, Protéines proto-oncogènes c-akt.
- pharmacologie : Benzimidazoles.
- Autophagie, Humains, Lignée cellulaire tumorale, Transduction du signal.
English descriptors
- KwdEn :
- Autophagy (drug effects), Benzimidazoles (pharmacology), Carcinoma, Non-Small-Cell Lung (enzymology), Carcinoma, Non-Small-Cell Lung (pathology), Cell Line, Tumor, Humans, Lung Neoplasms (enzymology), Lung Neoplasms (pathology), MAP Kinase Kinase Kinases (antagonists & inhibitors), Phosphatidylinositol 3-Kinases (metabolism), Proto-Oncogene Proteins c-akt (metabolism), Signal Transduction (drug effects).
- MESH :
- chemical , antagonists & inhibitors : MAP Kinase Kinase Kinases.
- chemical , metabolism : Proto-Oncogene Proteins c-akt.
- chemical , pharmacology : Benzimidazoles.
- drug effects : Autophagy, Signal Transduction.
- enzymology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- metabolism : Phosphatidylinositol 3-Kinases.
- pathology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- Cell Line, Tumor, Humans.
Abstract
Human non-small cell lung cancer (NSCLC) displays activated MEK/ERK signaling due to a high frequency of K-Ras mutation and is thus a potential candidate for MEK-targeted therapy. The current study focuses on demonstrating the activity of MEK162 (binimetinib), a MEK inhibitor under clinical testing, against NSCLC and exploring possible mechanism-driven strategies to enhance its therapeutic efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied potencies through induction of G1 cell cycle arrest and apoptosis. Moreover, it induces autophagy and accordingly the combination of MEK162 with the autophagy inhibitor, chloroquine, synergistically inhibits the growth of NSCLC cells and enhances apoptosis. MEK162 activates Akt signaling while effectively inhibiting MEK/ERK signaling. Accordingly, the combination of MEK162 and BKM120 (buparlisib), a pan-PI3K inhibitor, abrogates induced Akt activation and significantly augments therapeutic efficacy against the growth of NSCLC cells both in vitro and in vivo. Hence our findings warrant further evaluation of these rational combinations in the clinic.
DOI: 10.1016/j.canlet.2015.04.028
PubMed: 25937299
Affiliations:
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Khuri</name><affiliation wicri:level="2"><nlm:affiliation>Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author><author><name sortKey="Sun, Shi Yong" sort="Sun, Shi Yong" uniqKey="Sun S" first="Shi-Yong" last="Sun">Shi-Yong Sun</name><affiliation wicri:level="2"><nlm:affiliation>Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. 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The current study focuses on demonstrating the activity of MEK162 (binimetinib), a MEK inhibitor under clinical testing, against NSCLC and exploring possible mechanism-driven strategies to enhance its therapeutic efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied potencies through induction of G1 cell cycle arrest and apoptosis. Moreover, it induces autophagy and accordingly the combination of MEK162 with the autophagy inhibitor, chloroquine, synergistically inhibits the growth of NSCLC cells and enhances apoptosis. MEK162 activates Akt signaling while effectively inhibiting MEK/ERK signaling. Accordingly, the combination of MEK162 and BKM120 (buparlisib), a pan-PI3K inhibitor, abrogates induced Akt activation and significantly augments therapeutic efficacy against the growth of NSCLC cells both in vitro and in vivo. Hence our findings warrant further evaluation of these rational combinations in the clinic. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Géorgie (États-Unis)</li></region></list><tree><country name="États-Unis"><region name="Géorgie (États-Unis)"><name sortKey="Yao, Weilong" sort="Yao, Weilong" uniqKey="Yao W" first="Weilong" last="Yao">Weilong Yao</name></region><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="Sun, Shi Yong" sort="Sun, Shi Yong" uniqKey="Sun S" first="Shi-Yong" last="Sun">Shi-Yong Sun</name><name sortKey="Yue, Ping" sort="Yue, Ping" uniqKey="Yue P" first="Ping" last="Yue">Ping Yue</name><name sortKey="Zhang, Guojing" sort="Zhang, Guojing" uniqKey="Zhang G" first="Guojing" last="Zhang">Guojing Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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