{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:47:38Z","timestamp":1788583658525,"version":"build-2803163510"},"reference-count":81,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2016,7,1]],"date-time":"2016-07-01T00:00:00Z","timestamp":1467331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:<\/jats:italic>\n                    <\/jats:bold>\n                    Tumor hypoxia is a major biological factor causing poor patient outcome. Evidence is increasing that improved protection against reactive oxygen species (ROS) participates in therapy resistance of chronically hypoxic cancer cells. We aimed at characterizing the relevance of improved ROS defense for radiation resistance of cancer cells with tolerance to cycling anoxia\/re-oxygenation stress (\u201canoxia-tolerant\u201d) and at designing rational treatment strategies for overcoming the resulting therapy resistance by targeting the underlying mechanisms identified in an\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    model.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:<\/jats:italic>\n                    <\/jats:bold>\n                    We demonstrate that chronic exposure of NCH-H460 lung adenocarcinoma, DU145 prostate cancer, and T98G glioblastoma cells to cycling anoxia\/re-oxygenation stress induced upregulation of the aspartate-aminotransferase glutamic-oxaloacetic transaminase (\n                    <jats:italic toggle=\"yes\">GOT1<\/jats:italic>\n                    ), particularly in RAS-driven anoxia-tolerant NCI-H460 cells. Altered glutamine utilization of the anoxia-tolerant cancer cells contributed to the observed decrease in cellular ROS levels, the increase in cellular glutathione levels, and improved cell survival on ROS-inducing treatments, including exposure to ionizing radiation. Importantly, targeting glutamine-dependent antioxidant capacity or glutathione metabolism allowed us to hit anoxia-tolerant cancer cells and to overcome their increased resistance to radiation-induced cell death. Targeting glutathione metabolism by Piperlongumine also improved the radiation response of anoxia-tolerant NCI-H460 cells\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    .\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation:<\/jats:italic>\n                    <\/jats:bold>\n                    Improved antioxidant capacity downstream of up-regulated\n                    <jats:italic toggle=\"yes\">GOT1<\/jats:italic>\n                    -expression is a characteristic of anoxia-tolerant cancer cells and is predictive for a specific vulnerability to inhibition of glutamine utilization or glutathione metabolism, respectively.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    <\/jats:bold>\n                    Unraveling the molecular alterations underlying improved ROS defense of anoxia-tolerant cancer cells allows the design of rational strategies for overcoming radiation resistance caused by tumor cell heterogeneity in hypoxic tumors.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                    25, 89\u2013107.\n                  <\/jats:p>","DOI":"10.1089\/ars.2015.6589","type":"journal-article","created":{"date-parts":[[2016,3,28]],"date-time":"2016-03-28T23:30:03Z","timestamp":1459207803000},"page":"89-107","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":58,"title":["Targeted Inhibition of Glutamine-Dependent Glutathione Metabolism Overcomes Death Resistance Induced by Chronic Cycling Hypoxia"],"prefix":"10.1177","volume":"25","author":[{"given":"Johann","family":"Matschke","sequence":"first","affiliation":[{"name":"University Hospital Essen","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Riffkin","sequence":"additional","affiliation":[{"name":"University Hospital Essen","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Klein","sequence":"additional","affiliation":[{"name":"University Hospital Essen","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Handrick","sequence":"additional","affiliation":[{"name":"University of Applied Sciences","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutz","family":"L\u00fcdemann","sequence":"additional","affiliation":[{"name":"University Hospital Essen","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Metzen","sequence":"additional","affiliation":[{"name":"University Hospital Essen","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomer","family":"Shlomi","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Biology &amp; Lokey Center for Life Science and Engineering, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Stuschke","sequence":"additional","affiliation":[{"name":"University Hospital Essen","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Jendrossek","sequence":"additional","affiliation":[{"name":"University Hospital Essen","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2016,7,10]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400959"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1080\/07853890410018231"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3007"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2006.07.007"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2015.09.007"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2344"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1367"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01535-06"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-017-9211-0_18"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605573"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13014-015-0457-x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40170-015-0137-1"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206530109"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nos195"},{"key":"e_1_3_3_16_2","first-page":"3387","article-title":"Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene","volume":"62","author":"Comerford KM","year":"2002","unstructured":"Comerford KM, , Wallace TJ, , Karhausen J, , Louis NA, , Montalto MC, , and Colgan SP. 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