Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors.
Identifieur interne : 000293 ( Ncbi/Checkpoint ); précédent : 000292; suivant : 000294Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors.
Auteurs : N. Echeverry [Suisse] ; G. Ziltener [Suisse] ; D. Barbone [États-Unis] ; W. Weder [Suisse] ; R A Stahel [Suisse] ; V C Broaddus [États-Unis] ; E. Felley-Bosco [Suisse]Source :
- Cell death & disease [ 2041-4889 ] ; 2015.
Descripteurs français
- KwdFr :
- Autophagie (), Composés hétérocycliques bicycliques (pharmacologie), Humains, Imidazoles (pharmacologie), Inhibiteurs de protéines kinases (pharmacologie), Mésothéliome (anatomopathologie), Mésothéliome (métabolisme), Mésothéliome (traitement médicamenteux), Phosphatidylinositol 3-kinases (métabolisme), Phosphorylation, Prolifération cellulaire (), Pyrimidines (pharmacologie), Quinoléines (pharmacologie), Synergie des médicaments, Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Sérine-thréonine kinases TOR (métabolisme), Transduction du signal, Tumeurs de la plèvre (anatomopathologie), Tumeurs de la plèvre (métabolisme), Tumeurs de la plèvre (traitement médicamenteux), Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (métabolisme), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- anatomopathologie : Mésothéliome, Tumeurs de la plèvre, Tumeurs du poumon.
- antagonistes et inhibiteurs : Sérine-thréonine kinases TOR.
- métabolisme : Mésothéliome, Phosphatidylinositol 3-kinases, Sérine-thréonine kinases TOR, Tumeurs de la plèvre, Tumeurs du poumon.
- pharmacologie : Composés hétérocycliques bicycliques, Imidazoles, Inhibiteurs de protéines kinases, Pyrimidines, Quinoléines.
- traitement médicamenteux : Mésothéliome, Tumeurs de la plèvre, Tumeurs du poumon.
- Autophagie, Humains, Phosphorylation, Prolifération cellulaire, Synergie des médicaments, Transduction du signal.
English descriptors
- KwdEn :
- Autophagy (drug effects), Bridged Bicyclo Compounds, Heterocyclic (pharmacology), Cell Proliferation (drug effects), Drug Synergism, Humans, Imidazoles (pharmacology), Lung Neoplasms (drug therapy), Lung Neoplasms (metabolism), Lung Neoplasms (pathology), Mesothelioma (drug therapy), Mesothelioma (metabolism), Mesothelioma (pathology), Phosphatidylinositol 3-Kinases (metabolism), Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Pleural Neoplasms (drug therapy), Pleural Neoplasms (metabolism), Pleural Neoplasms (pathology), Protein Kinase Inhibitors (pharmacology), Pyrimidines (pharmacology), Quinolines (pharmacology), Signal Transduction, TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , antagonists & inhibitors : TOR Serine-Threonine Kinases.
- chemical , metabolism : TOR Serine-Threonine Kinases.
- chemical , pharmacology : Bridged Bicyclo Compounds, Heterocyclic, Imidazoles, Protein Kinase Inhibitors, Pyrimidines, Quinolines.
- drug effects : Autophagy, Cell Proliferation.
- drug therapy : Lung Neoplasms, Mesothelioma, Pleural Neoplasms.
- metabolism : Lung Neoplasms, Mesothelioma, Phosphatidylinositol 3-Kinases, Pleural Neoplasms.
- pathology : Lung Neoplasms, Mesothelioma, Pleural Neoplasms.
- Drug Synergism, Humans, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Signal Transduction.
Abstract
Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention.
DOI: 10.1038/cddis.2015.124
PubMed: 25950487
Affiliations:
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Autophagy (drug effects)</term>
<term>Bridged Bicyclo Compounds, Heterocyclic (pharmacology)</term>
<term>Cell Proliferation (drug effects)</term>
<term>Drug Synergism</term>
<term>Humans</term>
<term>Imidazoles (pharmacology)</term>
<term>Lung Neoplasms (drug therapy)</term>
<term>Lung Neoplasms (metabolism)</term>
<term>Lung Neoplasms (pathology)</term>
<term>Mesothelioma (drug therapy)</term>
<term>Mesothelioma (metabolism)</term>
<term>Mesothelioma (pathology)</term>
<term>Phosphatidylinositol 3-Kinases (metabolism)</term>
<term>Phosphoinositide-3 Kinase Inhibitors</term>
<term>Phosphorylation</term>
<term>Pleural Neoplasms (drug therapy)</term>
<term>Pleural Neoplasms (metabolism)</term>
<term>Pleural Neoplasms (pathology)</term>
<term>Protein Kinase Inhibitors (pharmacology)</term>
<term>Pyrimidines (pharmacology)</term>
<term>Quinolines (pharmacology)</term>
<term>Signal Transduction</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>Autophagie ()</term>
<term>Composés hétérocycliques bicycliques (pharmacologie)</term>
<term>Humains</term>
<term>Imidazoles (pharmacologie)</term>
<term>Inhibiteurs de protéines kinases (pharmacologie)</term>
<term>Mésothéliome (anatomopathologie)</term>
<term>Mésothéliome (métabolisme)</term>
<term>Mésothéliome (traitement médicamenteux)</term>
<term>Phosphatidylinositol 3-kinases (métabolisme)</term>
<term>Phosphorylation</term>
<term>Prolifération cellulaire ()</term>
<term>Pyrimidines (pharmacologie)</term>
<term>Quinoléines (pharmacologie)</term>
<term>Synergie des médicaments</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Transduction du signal</term>
<term>Tumeurs de la plèvre (anatomopathologie)</term>
<term>Tumeurs de la plèvre (métabolisme)</term>
<term>Tumeurs de la plèvre (traitement médicamenteux)</term>
<term>Tumeurs du poumon (anatomopathologie)</term>
<term>Tumeurs du poumon (métabolisme)</term>
<term>Tumeurs du poumon (traitement médicamenteux)</term>
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<term>Imidazoles</term>
<term>Protein Kinase Inhibitors</term>
<term>Pyrimidines</term>
<term>Quinolines</term>
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<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Mésothéliome</term>
<term>Tumeurs de la plèvre</term>
<term>Tumeurs du poumon</term>
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<term>Phosphatidylinositol 3-kinases</term>
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<term>Tumeurs de la plèvre</term>
<term>Tumeurs du poumon</term>
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<term>Mesothelioma</term>
<term>Pleural Neoplasms</term>
</keywords>
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<term>Inhibiteurs de protéines kinases</term>
<term>Pyrimidines</term>
<term>Quinoléines</term>
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<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Mésothéliome</term>
<term>Tumeurs de la plèvre</term>
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<term>Humans</term>
<term>Phosphoinositide-3 Kinase Inhibitors</term>
<term>Phosphorylation</term>
<term>Signal Transduction</term>
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<term>Humains</term>
<term>Phosphorylation</term>
<term>Prolifération cellulaire</term>
<term>Synergie des médicaments</term>
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<front><div type="abstract" xml:lang="en">Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention. </div>
</front>
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