Autophagy blockade enhances HDAC inhibitors' pro-apoptotic effects: potential implications for the treatment of a therapeutic-resistant malignancy.
Identifieur interne : 001478 ( Main/Exploration ); précédent : 001477; suivant : 001479Autophagy blockade enhances HDAC inhibitors' pro-apoptotic effects: potential implications for the treatment of a therapeutic-resistant malignancy.
Auteurs : Gonzalo Lopez [États-Unis] ; Keila Torres ; Dina LevSource :
- Autophagy [ 1554-8635 ] ; 2011.
Descripteurs français
- KwdFr :
- Animaux, Antinéoplasiques (pharmacologie), Apoptose, Autophagie, Chloroquine (pharmacologie), Humains, Inhibiteurs de désacétylase d'histone (métabolisme), Inhibiteurs de désacétylase d'histone (pharmacologie), Modèles biologiques, Métastase tumorale, Régulation de l'expression des gènes tumoraux, Souris, Transplantation tumorale, Tumeurs des gaines nerveuses (métabolisme), Tumeurs des gaines nerveuses (traitement médicamenteux), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- métabolisme : Inhibiteurs de désacétylase d'histone, Tumeurs des gaines nerveuses.
- pharmacologie : Antinéoplasiques, Chloroquine, Inhibiteurs de désacétylase d'histone.
- traitement médicamenteux : Tumeurs des gaines nerveuses, Tumeurs du poumon.
- Animaux, Apoptose, Autophagie, Humains, Modèles biologiques, Métastase tumorale, Régulation de l'expression des gènes tumoraux, Souris, Transplantation tumorale.
English descriptors
- KwdEn :
- Animals, Antineoplastic Agents (pharmacology), Apoptosis, Autophagy, Chloroquine (pharmacology), Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors (metabolism), Histone Deacetylase Inhibitors (pharmacology), Humans, Lung Neoplasms (drug therapy), Mice, Models, Biological, Neoplasm Metastasis, Neoplasm Transplantation, Nerve Sheath Neoplasms (drug therapy), Nerve Sheath Neoplasms (metabolism).
- MESH :
- chemical , metabolism : Histone Deacetylase Inhibitors.
- chemical , pharmacology : Antineoplastic Agents, Chloroquine, Histone Deacetylase Inhibitors.
- drug therapy : Lung Neoplasms, Nerve Sheath Neoplasms.
- metabolism : Nerve Sheath Neoplasms.
- Animals, Apoptosis, Autophagy, Gene Expression Regulation, Neoplastic, Humans, Mice, Models, Biological, Neoplasm Metastasis, Neoplasm Transplantation.
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, highly metastatic, poor prognosis tumors for which effective therapeutic strategies are currently lacking. We summarize recent work focusing on preclinical evaluation of histone deacetylase inhibitors (HDACis) for the treatment of MPNST. HDACis are a novel drug class with anti-cancer therapeutic promise. Using human MPNST cell lines and xenograft models we found that a MPNST subset is highly sensitive to HDACis, whereas a fraction is relatively resistant. HDACis were found to induce autophagy in all MPNST cells in vitro and in vivo; in "sensitive" MPNST cells autophagy occurs in concert with apoptosis, whereas unopposed autophagy develops in "resistant" cells. Genetic and chemical autophagy blockade significantly enhances HDACi-induced apoptotic cell death in both resistant and sensitive cells. Combined chloroquine and HDACi treatment abrogates growth of human MPNST xenografts and lung metastases. The potential role of autophagy in cancer therapeutic response remains controversial; however, our study supports HDACi-induced autophagy as a MPNST survival mechanism. These data also imply that the consequences of drug-induced autophagy may be compound-type, tumor-type, or even molecular context-dependent, suggesting a complex crosstalk between autophagy and apoptosis. Clinical trials evaluating HDACis with autophagy blockade for therapy of MPNST therefore merit consideration.
DOI: 10.4161/auto.7.4.14680
PubMed: 21224727
Affiliations:
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Le document en format XML
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<term>Antineoplastic Agents (pharmacology)</term>
<term>Apoptosis</term>
<term>Autophagy</term>
<term>Chloroquine (pharmacology)</term>
<term>Gene Expression Regulation, Neoplastic</term>
<term>Histone Deacetylase Inhibitors (metabolism)</term>
<term>Histone Deacetylase Inhibitors (pharmacology)</term>
<term>Humans</term>
<term>Lung Neoplasms (drug therapy)</term>
<term>Mice</term>
<term>Models, Biological</term>
<term>Neoplasm Metastasis</term>
<term>Neoplasm Transplantation</term>
<term>Nerve Sheath Neoplasms (drug therapy)</term>
<term>Nerve Sheath Neoplasms (metabolism)</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antinéoplasiques (pharmacologie)</term>
<term>Apoptose</term>
<term>Autophagie</term>
<term>Chloroquine (pharmacologie)</term>
<term>Humains</term>
<term>Inhibiteurs de désacétylase d'histone (métabolisme)</term>
<term>Inhibiteurs de désacétylase d'histone (pharmacologie)</term>
<term>Modèles biologiques</term>
<term>Métastase tumorale</term>
<term>Régulation de l'expression des gènes tumoraux</term>
<term>Souris</term>
<term>Transplantation tumorale</term>
<term>Tumeurs des gaines nerveuses (métabolisme)</term>
<term>Tumeurs des gaines nerveuses (traitement médicamenteux)</term>
<term>Tumeurs du poumon (traitement médicamenteux)</term>
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<term>Chloroquine</term>
<term>Histone Deacetylase Inhibitors</term>
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<term>Inhibiteurs de désacétylase d'histone</term>
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<term>Tumeurs du poumon</term>
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<term>Apoptosis</term>
<term>Autophagy</term>
<term>Gene Expression Regulation, Neoplastic</term>
<term>Humans</term>
<term>Mice</term>
<term>Models, Biological</term>
<term>Neoplasm Metastasis</term>
<term>Neoplasm Transplantation</term>
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<term>Apoptose</term>
<term>Autophagie</term>
<term>Humains</term>
<term>Modèles biologiques</term>
<term>Métastase tumorale</term>
<term>Régulation de l'expression des gènes tumoraux</term>
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<front><div type="abstract" xml:lang="en">Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, highly metastatic, poor prognosis tumors for which effective therapeutic strategies are currently lacking. We summarize recent work focusing on preclinical evaluation of histone deacetylase inhibitors (HDACis) for the treatment of MPNST. HDACis are a novel drug class with anti-cancer therapeutic promise. Using human MPNST cell lines and xenograft models we found that a MPNST subset is highly sensitive to HDACis, whereas a fraction is relatively resistant. HDACis were found to induce autophagy in all MPNST cells in vitro and in vivo; in "sensitive" MPNST cells autophagy occurs in concert with apoptosis, whereas unopposed autophagy develops in "resistant" cells. Genetic and chemical autophagy blockade significantly enhances HDACi-induced apoptotic cell death in both resistant and sensitive cells. Combined chloroquine and HDACi treatment abrogates growth of human MPNST xenografts and lung metastases. The potential role of autophagy in cancer therapeutic response remains controversial; however, our study supports HDACi-induced autophagy as a MPNST survival mechanism. These data also imply that the consequences of drug-induced autophagy may be compound-type, tumor-type, or even molecular context-dependent, suggesting a complex crosstalk between autophagy and apoptosis. Clinical trials evaluating HDACis with autophagy blockade for therapy of MPNST therefore merit consideration.</div>
</front>
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