{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:13:55Z","timestamp":1787015635818,"version":"build-2736575974"},"reference-count":34,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,1,8]],"date-time":"2018-01-08T00:00:00Z","timestamp":1515369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["RI2175\/1\u20101"],"award-info":[{"award-number":["RI2175\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Although bevacizumab initially shows high response rates in gliomas and other tumours, therapy resistance usually develops later. Because anti\u2010angiogenic agents are supposed to induce hypoxia, we asked whether rendering glioma cells independent of oxidative phosphorylation modulates their sensitivity against hypoxia and bevacizumab. LNT\u2010229 glioma cells without functional mitochondria (rho\n                      <jats:sup>0<\/jats:sup>\n                      ) and control (rho\n                      <jats:sup>+<\/jats:sup>\n                      ) cells were generated. LNT\u2010229 rho\n                      <jats:sup>0<\/jats:sup>\n                      \u2010cells displayed reduced expression of oxidative phosphorylation\u2010related genes and diminished oxygen consumption. Conversely, glycolysis was up\u2010regulated in these cells, as shown by increased lactate production and stronger expression of glucose transporter\u20101 and lactate dehydrogenase\u2010A. However, hypoxia\u2010induced cell death\n                      <jats:italic>in\u00a0vitro<\/jats:italic>\n                      was nearly completely abolished in the LNT\u2010229 rho\n                      <jats:sup>0<\/jats:sup>\n                      \u2010cells, these cells were more sensitive towards glucose restriction and the treatment with the glycolysis inhibitor 2\u2010deoxy\u2010D\u2010glucose. In an orthotopic mouse xenograft experiment, bevacizumab induced hypoxia as reflected by elevated Hypoxia\u2010inducible factor 1\u2010alpha staining in both, rho\n                      <jats:sup>+<\/jats:sup>\n                      \u2010 and rho\n                      <jats:sup>0<\/jats:sup>\n                      \u2010tumours. However, it prolonged survival only in the mice bearing rho\n                      <jats:sup>+<\/jats:sup>\n                      \u2010tumours (74\u00a0days vs. 105\u00a0days,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.024 log\u2010rank test) and had no effect on survival in mice carrying LNT\u2010229 rho\n                      <jats:sup>0<\/jats:sup>\n                      \u2010tumours (75\u00a0days vs. 70\u00a0days,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.52 log\u2010rank test). Interestingly, inhibition of glycolysis\n                      <jats:italic>in\u00a0vivo<\/jats:italic>\n                      with 2\u2010deoxy\u2010D\u2010glucose re\u2010established sensitivity of rho\n                      <jats:sup>0<\/jats:sup>\n                      \u2010tumours against bevacizumab (98\u00a0days vs. 80\u00a0days,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.0001). In summary, ablation of oxidative phosphorylation in glioma cells leads to a more glycolytic and hypoxia\u2010resistant phenotype and is sufficient to induce bevacizumab\u2010refractory tumours. These results add to increasing evidence that a switch towards glycolysis is one mechanism how tumour cells may evade anti\u2010angiogenic treatments and suggest anti\u2010glycolytic strategies as promising approaches to overcome bevacizumab resistance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14264-fig-0006-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  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