Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism
Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can indu...
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| Veröffentlicht in: | Molecular cancer therapeutics 2017-11, Vol.16 (11), p.2502-2515 |
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| creator | Wiedmer, Tabea Blank, Annika Pantasis, Sophia Normand, Lea Bill, Ruben Krebs, Philippe Tschan, Mario P Marinoni, Ilaria Perren, Aurel |
| description | Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis
, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials.
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| doi_str_mv | 10.1158/1535-7163.MCT-17-0136 |
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, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials.
.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-17-0136</identifier><identifier>PMID: 28729403</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>Angiogenesis Inhibitors - administration & dosage ; Angiogenesis Inhibitors - chemistry ; Animals ; Antiangiogenics ; Apoptosis ; Apoptosis - drug effects ; Autophagy ; Autophagy - drug effects ; Biotechnology ; Cancer ; Cell death ; Cell Line, Tumor ; Cell Membrane Permeability - drug effects ; Cell Proliferation - drug effects ; Chloroquine ; Clinical trials ; Drug Resistance, Neoplasm - drug effects ; Drug Synergism ; Drugs ; Effectiveness ; Enzyme inhibitors ; Gene Knockdown Techniques ; Humans ; Indoles - administration & dosage ; Indoles - chemistry ; Inhibition ; Inhibitors ; Lysosomal-Associated Membrane Protein 2 - genetics ; Lysosomes ; Lysosomes - chemistry ; Medical research ; Membrane proteins ; Mice ; Neovascularization, Pathologic - drug therapy ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - pathology ; Neuroendocrine tumors ; Neuroendocrine Tumors - drug therapy ; Neuroendocrine Tumors - genetics ; Neuroendocrine Tumors - pathology ; Pancreas ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Patients ; Phagocytosis ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - chemistry ; Protein-tyrosine kinase ; Proteins ; Pyrroles - administration & dosage ; Pyrroles - chemistry ; Rodents ; Tumors ; Tyrosine</subject><ispartof>Molecular cancer therapeutics, 2017-11, Vol.16 (11), p.2502-2515</ispartof><rights>2017 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc Nov 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-1e2530bf71801648c8037f4e923737f02466a2621355da4818897300e5f651ed3</citedby><cites>FETCH-LOGICAL-c436t-1e2530bf71801648c8037f4e923737f02466a2621355da4818897300e5f651ed3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3354,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28729403$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wiedmer, Tabea</creatorcontrib><creatorcontrib>Blank, Annika</creatorcontrib><creatorcontrib>Pantasis, Sophia</creatorcontrib><creatorcontrib>Normand, Lea</creatorcontrib><creatorcontrib>Bill, Ruben</creatorcontrib><creatorcontrib>Krebs, Philippe</creatorcontrib><creatorcontrib>Tschan, Mario P</creatorcontrib><creatorcontrib>Marinoni, Ilaria</creatorcontrib><creatorcontrib>Perren, Aurel</creatorcontrib><title>Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis
, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials.
.</description><subject>Angiogenesis Inhibitors - administration & dosage</subject><subject>Angiogenesis Inhibitors - chemistry</subject><subject>Animals</subject><subject>Antiangiogenics</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Chloroquine</subject><subject>Clinical trials</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Synergism</subject><subject>Drugs</subject><subject>Effectiveness</subject><subject>Enzyme inhibitors</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Indoles - administration & dosage</subject><subject>Indoles - chemistry</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>Lysosomal-Associated Membrane Protein 2 - genetics</subject><subject>Lysosomes</subject><subject>Lysosomes - chemistry</subject><subject>Medical research</subject><subject>Membrane proteins</subject><subject>Mice</subject><subject>Neovascularization, Pathologic - drug therapy</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Neuroendocrine tumors</subject><subject>Neuroendocrine Tumors - drug therapy</subject><subject>Neuroendocrine Tumors - genetics</subject><subject>Neuroendocrine Tumors - pathology</subject><subject>Pancreas</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Patients</subject><subject>Phagocytosis</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein-tyrosine kinase</subject><subject>Proteins</subject><subject>Pyrroles - administration & dosage</subject><subject>Pyrroles - chemistry</subject><subject>Rodents</subject><subject>Tumors</subject><subject>Tyrosine</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUFPGzEQha2KCijlJ7SyxKWXBY-99nqPKKIQKbRIpGfL8c42Rlk72LtU-fc4DeXQ0zyNvhnNvEfIF2CXAFJfgRSyakCJy_vZsoKmYiDUB3Ja-rrSEuqjv_rAnJBPOT8xBrrlcExOuG54WzNxSv5cT2Pcru3vHZ2HtV_50cdA58M2xRfM9HEKpRP8it70vXfW7agP9MEGl9CO3tEfOKWIoYsu-YB0OQ0xZfriLbV0scsxxwGrDrcFwTDSe3RrG3wePpOPvd1kPH-rZ-TX95vl7K5a_Lydz64XlauFGitALgVb9Q1oBqrWTjPR9DW2XDRFMF4rZbniIKTsbK1B67YRjKHslQTsxBn5dthbHnqeMI9m8NnhZmMDxikbaDmXTArBCnrxH_oUpxTKdYXSoniqVFsoeaBcijkn7M02-cGmnQFm9smYvetm77opyRhozD6ZMvf1bfu0GrB7n_oXhXgFz7SJIA</recordid><startdate>201711</startdate><enddate>201711</enddate><creator>Wiedmer, Tabea</creator><creator>Blank, Annika</creator><creator>Pantasis, Sophia</creator><creator>Normand, Lea</creator><creator>Bill, Ruben</creator><creator>Krebs, Philippe</creator><creator>Tschan, Mario P</creator><creator>Marinoni, Ilaria</creator><creator>Perren, Aurel</creator><general>American Association for Cancer Research Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201711</creationdate><title>Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism</title><author>Wiedmer, Tabea ; Blank, Annika ; Pantasis, Sophia ; Normand, Lea ; Bill, Ruben ; Krebs, Philippe ; Tschan, Mario P ; Marinoni, Ilaria ; Perren, Aurel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-1e2530bf71801648c8037f4e923737f02466a2621355da4818897300e5f651ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Angiogenesis Inhibitors - administration & dosage</topic><topic>Angiogenesis Inhibitors - chemistry</topic><topic>Animals</topic><topic>Antiangiogenics</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Biotechnology</topic><topic>Cancer</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Cell Membrane Permeability - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Chloroquine</topic><topic>Clinical trials</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Synergism</topic><topic>Drugs</topic><topic>Effectiveness</topic><topic>Enzyme inhibitors</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Indoles - administration & dosage</topic><topic>Indoles - chemistry</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>Lysosomal-Associated Membrane Protein 2 - genetics</topic><topic>Lysosomes</topic><topic>Lysosomes - chemistry</topic><topic>Medical research</topic><topic>Membrane proteins</topic><topic>Mice</topic><topic>Neovascularization, Pathologic - drug therapy</topic><topic>Neovascularization, Pathologic - genetics</topic><topic>Neovascularization, Pathologic - pathology</topic><topic>Neuroendocrine tumors</topic><topic>Neuroendocrine Tumors - drug therapy</topic><topic>Neuroendocrine Tumors - genetics</topic><topic>Neuroendocrine Tumors - pathology</topic><topic>Pancreas</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Patients</topic><topic>Phagocytosis</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein-tyrosine kinase</topic><topic>Proteins</topic><topic>Pyrroles - administration & dosage</topic><topic>Pyrroles - chemistry</topic><topic>Rodents</topic><topic>Tumors</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wiedmer, Tabea</creatorcontrib><creatorcontrib>Blank, Annika</creatorcontrib><creatorcontrib>Pantasis, Sophia</creatorcontrib><creatorcontrib>Normand, Lea</creatorcontrib><creatorcontrib>Bill, Ruben</creatorcontrib><creatorcontrib>Krebs, Philippe</creatorcontrib><creatorcontrib>Tschan, Mario P</creatorcontrib><creatorcontrib>Marinoni, Ilaria</creatorcontrib><creatorcontrib>Perren, Aurel</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wiedmer, Tabea</au><au>Blank, Annika</au><au>Pantasis, Sophia</au><au>Normand, Lea</au><au>Bill, Ruben</au><au>Krebs, Philippe</au><au>Tschan, Mario P</au><au>Marinoni, Ilaria</au><au>Perren, Aurel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2017-11</date><risdate>2017</risdate><volume>16</volume><issue>11</issue><spage>2502</spage><epage>2515</epage><pages>2502-2515</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis
, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials.
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| subjects | Angiogenesis Inhibitors - administration & dosage Angiogenesis Inhibitors - chemistry Animals Antiangiogenics Apoptosis Apoptosis - drug effects Autophagy Autophagy - drug effects Biotechnology Cancer Cell death Cell Line, Tumor Cell Membrane Permeability - drug effects Cell Proliferation - drug effects Chloroquine Clinical trials Drug Resistance, Neoplasm - drug effects Drug Synergism Drugs Effectiveness Enzyme inhibitors Gene Knockdown Techniques Humans Indoles - administration & dosage Indoles - chemistry Inhibition Inhibitors Lysosomal-Associated Membrane Protein 2 - genetics Lysosomes Lysosomes - chemistry Medical research Membrane proteins Mice Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - genetics Neovascularization, Pathologic - pathology Neuroendocrine tumors Neuroendocrine Tumors - drug therapy Neuroendocrine Tumors - genetics Neuroendocrine Tumors - pathology Pancreas Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Patients Phagocytosis Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemistry Protein-tyrosine kinase Proteins Pyrroles - administration & dosage Pyrroles - chemistry Rodents Tumors Tyrosine |
| title | Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism |
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