R406 elicits anti-Warburg effect via Syk-dependent and -independent mechanisms to trigger apoptosis in glioma stem cells
Given that glioma stem cells (GSCs) play a critical role in the initiation and chemoresistance in glioblastoma multiforme (GBM), targeting GSCs is an attractive strategy to treat GBM. Utilizing an anti-cancer compound library, we identified R406, the active metabolite of a FDA-approved Syk inhibitor...
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| Veröffentlicht in: | Cell death & disease 2019-05, Vol.10 (5), p.358, Article 358 |
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| creator | Sun, Shuxin Xue, Dongdong Chen, Zhijie Ou-yang, Ying Zhang, Ji Mai, Jialuo Gu, Jiayv Lu, Wanjun Liu, Xincheng Liu, Wenfeng Sheng, Longxiang Lu, Bingzheng Lin, Yuan Xing, Fan Chen, Zhongping Mou, Yonggao Yan, Guangmei Zhu, Wenbo Sai, Ke |
| description | Given that glioma stem cells (GSCs) play a critical role in the initiation and chemoresistance in glioblastoma multiforme (GBM), targeting GSCs is an attractive strategy to treat GBM. Utilizing an anti-cancer compound library, we identified R406, the active metabolite of a FDA-approved Syk inhibitor for immune thrombocytopenia (ITP), with remarkable cytotoxicity against GSCs but not normal neural stem cells. R406 significantly inhibited neurosphere formation and triggered apoptosis in GSCs. R406 induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and subsequently production of excess ROS in GSCs. R406 also diminished tumor growth and efficiently sensitized gliomas to temozolomide in GSC-initiating xenograft mouse models. Mechanistically, the anti-GSC effect of R406 was due to the disruption of Syk/PI3K signaling in Syk-positive GSCs and PI3K/Akt pathway in Syk-negative GSCs respectively. Overall, these findings not only identify R406 as a promising GSC-targeting agent but also reveal the important role of Syk and PI3K pathways in the regulation of energy metabolism in GSCs. |
| doi_str_mv | 10.1038/s41419-019-1587-0 |
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Utilizing an anti-cancer compound library, we identified R406, the active metabolite of a FDA-approved Syk inhibitor for immune thrombocytopenia (ITP), with remarkable cytotoxicity against GSCs but not normal neural stem cells. R406 significantly inhibited neurosphere formation and triggered apoptosis in GSCs. R406 induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and subsequently production of excess ROS in GSCs. R406 also diminished tumor growth and efficiently sensitized gliomas to temozolomide in GSC-initiating xenograft mouse models. Mechanistically, the anti-GSC effect of R406 was due to the disruption of Syk/PI3K signaling in Syk-positive GSCs and PI3K/Akt pathway in Syk-negative GSCs respectively. Overall, these findings not only identify R406 as a promising GSC-targeting agent but also reveal the important role of Syk and PI3K pathways in the regulation of energy metabolism in GSCs.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-019-1587-0</identifier><identifier>PMID: 31043589</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; 13 ; 13/100 ; 38/89 ; 631/154/555 ; 631/67/1922 ; 64/60 ; 82 ; 96/2 ; 96/34 ; AKT protein ; Animal models ; Animals ; Antibodies ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Biochemistry ; Biomedical and Life Sciences ; Brain Neoplasms - drug therapy ; Brain Neoplasms - genetics ; Brain Neoplasms - mortality ; Brain Neoplasms - pathology ; Cell Adhesion - drug effects ; Cell Biology ; Cell Culture ; Chemoresistance ; Cytotoxicity ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Energy metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Glioblastoma ; Glioblastoma - drug therapy ; Glioblastoma - genetics ; Glioblastoma - mortality ; Glioblastoma - pathology ; Glioma ; Glioma cells ; Glycolysis ; Glycolysis - drug effects ; Glycolysis - genetics ; Humans ; Idiopathic thrombocytopenic purpura ; Immunology ; Life Sciences ; Mice, Nude ; Neoplastic Stem Cells ; Neural stem cells ; Oxazines - pharmacology ; Oxidative phosphorylation ; Oxidative Phosphorylation - drug effects ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Pyridines - pharmacology ; Reactive oxygen species ; Signal Transduction ; Stem cell transplantation ; Stem cells ; Survival Analysis ; Syk Kinase - antagonists & inhibitors ; Syk Kinase - genetics ; Syk Kinase - metabolism ; Syk protein ; Temozolomide ; Temozolomide - pharmacology ; Thrombocytopenia ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Cell death & disease, 2019-05, Vol.10 (5), p.358, Article 358</ispartof><rights>The Author(s) 2019</rights><rights>The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-f6933605acfb37b86ffaefece4b8962aa144372a69dcb17d6cab5170b4522f873</citedby><cites>FETCH-LOGICAL-c470t-f6933605acfb37b86ffaefece4b8962aa144372a69dcb17d6cab5170b4522f873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494878/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494878/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31043589$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Shuxin</creatorcontrib><creatorcontrib>Xue, Dongdong</creatorcontrib><creatorcontrib>Chen, Zhijie</creatorcontrib><creatorcontrib>Ou-yang, Ying</creatorcontrib><creatorcontrib>Zhang, Ji</creatorcontrib><creatorcontrib>Mai, Jialuo</creatorcontrib><creatorcontrib>Gu, Jiayv</creatorcontrib><creatorcontrib>Lu, Wanjun</creatorcontrib><creatorcontrib>Liu, Xincheng</creatorcontrib><creatorcontrib>Liu, Wenfeng</creatorcontrib><creatorcontrib>Sheng, Longxiang</creatorcontrib><creatorcontrib>Lu, Bingzheng</creatorcontrib><creatorcontrib>Lin, Yuan</creatorcontrib><creatorcontrib>Xing, Fan</creatorcontrib><creatorcontrib>Chen, Zhongping</creatorcontrib><creatorcontrib>Mou, Yonggao</creatorcontrib><creatorcontrib>Yan, Guangmei</creatorcontrib><creatorcontrib>Zhu, Wenbo</creatorcontrib><creatorcontrib>Sai, Ke</creatorcontrib><title>R406 elicits anti-Warburg effect via Syk-dependent and -independent mechanisms to trigger apoptosis in glioma stem cells</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Given that glioma stem cells (GSCs) play a critical role in the initiation and chemoresistance in glioblastoma multiforme (GBM), targeting GSCs is an attractive strategy to treat GBM. Utilizing an anti-cancer compound library, we identified R406, the active metabolite of a FDA-approved Syk inhibitor for immune thrombocytopenia (ITP), with remarkable cytotoxicity against GSCs but not normal neural stem cells. R406 significantly inhibited neurosphere formation and triggered apoptosis in GSCs. R406 induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and subsequently production of excess ROS in GSCs. R406 also diminished tumor growth and efficiently sensitized gliomas to temozolomide in GSC-initiating xenograft mouse models. Mechanistically, the anti-GSC effect of R406 was due to the disruption of Syk/PI3K signaling in Syk-positive GSCs and PI3K/Akt pathway in Syk-negative GSCs respectively. Overall, these findings not only identify R406 as a promising GSC-targeting agent but also reveal the important role of Syk and PI3K pathways in the regulation of energy metabolism in GSCs.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>13</subject><subject>13/100</subject><subject>38/89</subject><subject>631/154/555</subject><subject>631/67/1922</subject><subject>64/60</subject><subject>82</subject><subject>96/2</subject><subject>96/34</subject><subject>AKT protein</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - mortality</subject><subject>Brain Neoplasms - pathology</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Chemoresistance</subject><subject>Cytotoxicity</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Energy metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glioblastoma</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - mortality</subject><subject>Glioblastoma - pathology</subject><subject>Glioma</subject><subject>Glioma cells</subject><subject>Glycolysis</subject><subject>Glycolysis - drug effects</subject><subject>Glycolysis - genetics</subject><subject>Humans</subject><subject>Idiopathic thrombocytopenic purpura</subject><subject>Immunology</subject><subject>Life Sciences</subject><subject>Mice, Nude</subject><subject>Neoplastic Stem Cells</subject><subject>Neural stem cells</subject><subject>Oxazines - pharmacology</subject><subject>Oxidative phosphorylation</subject><subject>Oxidative Phosphorylation - drug effects</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Pyridines - pharmacology</subject><subject>Reactive oxygen species</subject><subject>Signal Transduction</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Survival Analysis</subject><subject>Syk Kinase - antagonists & inhibitors</subject><subject>Syk Kinase - genetics</subject><subject>Syk Kinase - metabolism</subject><subject>Syk protein</subject><subject>Temozolomide</subject><subject>Temozolomide - pharmacology</subject><subject>Thrombocytopenia</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1UU1LHTEUDUWpou8HdFMCXafmazKZTaGIrcKDQlVchkwmGWNnkjHJk_rvzeNZPxYNXBJyzz3ncA8Anwj-SjCTJ5kTTjqEa5FGtgh_AIcUc4K4lN3em_cBWOV8h-thDNNGfAQHjGDOGtkdgr-_ORbQTt74kqEOxaMbnfpNGqF1zpoCH7yGl49_0GAXGwYbSkUNEPnw-jFbc6uDz3OGJcKS_DjaBPUSlxKzz9AHOE4-zhrmYmdo7DTlY7Dv9JTt6vk-Atc_zq5Oz9H618-L0-9rZHiLC3KiY0zgRhvXs7aXwjltqy_Le9kJqjXhnLVUi24wPWkHYXTfkBb3vKHUyZYdgW873mXTz3Yw1W_Sk1qSn3V6VFF79b4T_K0a44MSvOOylZXgyzNBivcbm4u6i5sUqmdFKZFUSMK3MmSHMinmnKx7USBYbfNSu7xUzUtt81K4znx-a-1l4l86FUB3gFxboe70Vfr_rE8lJaLN</recordid><startdate>20190501</startdate><enddate>20190501</enddate><creator>Sun, Shuxin</creator><creator>Xue, Dongdong</creator><creator>Chen, Zhijie</creator><creator>Ou-yang, Ying</creator><creator>Zhang, Ji</creator><creator>Mai, Jialuo</creator><creator>Gu, Jiayv</creator><creator>Lu, Wanjun</creator><creator>Liu, Xincheng</creator><creator>Liu, Wenfeng</creator><creator>Sheng, Longxiang</creator><creator>Lu, Bingzheng</creator><creator>Lin, Yuan</creator><creator>Xing, Fan</creator><creator>Chen, Zhongping</creator><creator>Mou, Yonggao</creator><creator>Yan, Guangmei</creator><creator>Zhu, Wenbo</creator><creator>Sai, Ke</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><scope>C6C</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20190501</creationdate><title>R406 elicits anti-Warburg effect via Syk-dependent and -independent mechanisms to trigger apoptosis in glioma stem cells</title><author>Sun, Shuxin ; Xue, Dongdong ; Chen, Zhijie ; Ou-yang, Ying ; Zhang, Ji ; Mai, Jialuo ; Gu, Jiayv ; Lu, Wanjun ; Liu, Xincheng ; Liu, Wenfeng ; Sheng, Longxiang ; Lu, Bingzheng ; Lin, Yuan ; Xing, Fan ; Chen, Zhongping ; Mou, Yonggao ; Yan, Guangmei ; Zhu, Wenbo ; Sai, Ke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-f6933605acfb37b86ffaefece4b8962aa144372a69dcb17d6cab5170b4522f873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>13</topic><topic>13/100</topic><topic>38/89</topic><topic>631/154/555</topic><topic>631/67/1922</topic><topic>64/60</topic><topic>82</topic><topic>96/2</topic><topic>96/34</topic><topic>AKT protein</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - genetics</topic><topic>Brain Neoplasms - mortality</topic><topic>Brain Neoplasms - pathology</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Chemoresistance</topic><topic>Cytotoxicity</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Energy metabolism</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Glioblastoma</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - genetics</topic><topic>Glioblastoma - mortality</topic><topic>Glioblastoma - pathology</topic><topic>Glioma</topic><topic>Glioma cells</topic><topic>Glycolysis</topic><topic>Glycolysis - drug effects</topic><topic>Glycolysis - genetics</topic><topic>Humans</topic><topic>Idiopathic thrombocytopenic purpura</topic><topic>Immunology</topic><topic>Life Sciences</topic><topic>Mice, Nude</topic><topic>Neoplastic Stem Cells</topic><topic>Neural stem cells</topic><topic>Oxazines - pharmacology</topic><topic>Oxidative phosphorylation</topic><topic>Oxidative Phosphorylation - drug effects</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Pyridines - pharmacology</topic><topic>Reactive oxygen species</topic><topic>Signal Transduction</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Survival Analysis</topic><topic>Syk Kinase - antagonists & inhibitors</topic><topic>Syk Kinase - genetics</topic><topic>Syk Kinase - metabolism</topic><topic>Syk protein</topic><topic>Temozolomide</topic><topic>Temozolomide - pharmacology</topic><topic>Thrombocytopenia</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Shuxin</creatorcontrib><creatorcontrib>Xue, Dongdong</creatorcontrib><creatorcontrib>Chen, Zhijie</creatorcontrib><creatorcontrib>Ou-yang, Ying</creatorcontrib><creatorcontrib>Zhang, Ji</creatorcontrib><creatorcontrib>Mai, Jialuo</creatorcontrib><creatorcontrib>Gu, Jiayv</creatorcontrib><creatorcontrib>Lu, Wanjun</creatorcontrib><creatorcontrib>Liu, Xincheng</creatorcontrib><creatorcontrib>Liu, Wenfeng</creatorcontrib><creatorcontrib>Sheng, Longxiang</creatorcontrib><creatorcontrib>Lu, Bingzheng</creatorcontrib><creatorcontrib>Lin, Yuan</creatorcontrib><creatorcontrib>Xing, Fan</creatorcontrib><creatorcontrib>Chen, Zhongping</creatorcontrib><creatorcontrib>Mou, Yonggao</creatorcontrib><creatorcontrib>Yan, Guangmei</creatorcontrib><creatorcontrib>Zhu, Wenbo</creatorcontrib><creatorcontrib>Sai, Ke</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Shuxin</au><au>Xue, Dongdong</au><au>Chen, Zhijie</au><au>Ou-yang, Ying</au><au>Zhang, Ji</au><au>Mai, Jialuo</au><au>Gu, Jiayv</au><au>Lu, Wanjun</au><au>Liu, Xincheng</au><au>Liu, Wenfeng</au><au>Sheng, Longxiang</au><au>Lu, Bingzheng</au><au>Lin, Yuan</au><au>Xing, Fan</au><au>Chen, Zhongping</au><au>Mou, Yonggao</au><au>Yan, Guangmei</au><au>Zhu, Wenbo</au><au>Sai, Ke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>R406 elicits anti-Warburg effect via Syk-dependent and -independent mechanisms to trigger apoptosis in glioma stem cells</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2019-05-01</date><risdate>2019</risdate><volume>10</volume><issue>5</issue><spage>358</spage><pages>358-</pages><artnum>358</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Given that glioma stem cells (GSCs) play a critical role in the initiation and chemoresistance in glioblastoma multiforme (GBM), targeting GSCs is an attractive strategy to treat GBM. Utilizing an anti-cancer compound library, we identified R406, the active metabolite of a FDA-approved Syk inhibitor for immune thrombocytopenia (ITP), with remarkable cytotoxicity against GSCs but not normal neural stem cells. R406 significantly inhibited neurosphere formation and triggered apoptosis in GSCs. R406 induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and subsequently production of excess ROS in GSCs. R406 also diminished tumor growth and efficiently sensitized gliomas to temozolomide in GSC-initiating xenograft mouse models. Mechanistically, the anti-GSC effect of R406 was due to the disruption of Syk/PI3K signaling in Syk-positive GSCs and PI3K/Akt pathway in Syk-negative GSCs respectively. Overall, these findings not only identify R406 as a promising GSC-targeting agent but also reveal the important role of Syk and PI3K pathways in the regulation of energy metabolism in GSCs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31043589</pmid><doi>10.1038/s41419-019-1587-0</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6494878 |
| source | MEDLINE; Nature Free; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Springer Nature OA Free Journals |
| subjects | 1-Phosphatidylinositol 3-kinase 13 13/100 38/89 631/154/555 631/67/1922 64/60 82 96/2 96/34 AKT protein Animal models Animals Antibodies Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Biochemistry Biomedical and Life Sciences Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain Neoplasms - mortality Brain Neoplasms - pathology Cell Adhesion - drug effects Cell Biology Cell Culture Chemoresistance Cytotoxicity Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Energy metabolism Female Gene Expression Regulation, Neoplastic Glioblastoma Glioblastoma - drug therapy Glioblastoma - genetics Glioblastoma - mortality Glioblastoma - pathology Glioma Glioma cells Glycolysis Glycolysis - drug effects Glycolysis - genetics Humans Idiopathic thrombocytopenic purpura Immunology Life Sciences Mice, Nude Neoplastic Stem Cells Neural stem cells Oxazines - pharmacology Oxidative phosphorylation Oxidative Phosphorylation - drug effects Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Pyridines - pharmacology Reactive oxygen species Signal Transduction Stem cell transplantation Stem cells Survival Analysis Syk Kinase - antagonists & inhibitors Syk Kinase - genetics Syk Kinase - metabolism Syk protein Temozolomide Temozolomide - pharmacology Thrombocytopenia Xenograft Model Antitumor Assays Xenografts |
| title | R406 elicits anti-Warburg effect via Syk-dependent and -independent mechanisms to trigger apoptosis in glioma stem cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T00%3A31%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=R406%20elicits%20anti-Warburg%20effect%20via%20Syk-dependent%20and%20-independent%20mechanisms%20to%20trigger%20apoptosis%20in%20glioma%20stem%20cells&rft.jtitle=Cell%20death%20&%20disease&rft.au=Sun,%20Shuxin&rft.date=2019-05-01&rft.volume=10&rft.issue=5&rft.spage=358&rft.pages=358-&rft.artnum=358&rft.issn=2041-4889&rft.eissn=2041-4889&rft_id=info:doi/10.1038/s41419-019-1587-0&rft_dat=%3Cproquest_pubme%3E2218268147%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2218268147&rft_id=info:pmid/31043589&rfr_iscdi=true |