{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:49:45Z","timestamp":1787003385183,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T00:00:00Z","timestamp":1573516800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T00:00:00Z","timestamp":1573516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor survival rates. The current standard treatment includes chemotherapy with temozolomide (TMZ), but acquisition of resistance is a persistent clinical problem limiting the successful treatment of GBM. The purpose of our study was to investigate therapeutic effects of nitroxoline (NTX) against TMZ-resistant GBM\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    in TMZ-resistant GBM-bearing mouse model, which was correlated with diffusion-weighted imaging (DWI). For\n                    <jats:italic>in vitro<\/jats:italic>\n                    study, we used TMZ-resistant GBM cell lines and evaluated therapeutic effects of NTX by clonogenic and migration assays. Quantitative RT-PCR was used to investigate the expression level of TMZ-resistant genes after NTX treatment. For\n                    <jats:italic>in vivo<\/jats:italic>\n                    study, we performed 9.4\u2009T MR imaging to obtain T2WI for tumor volume measurement and DWI for assessment of apparent diffusion coefficient (ADC) changes by NTX in TMZ-resistant GBM mice (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098). Moreover, we performed regression analysis for the relationship between ADC and histological findings, which reflects the changes in cellularity and apurinic\/apyrimidinic endonuclease-1 (APE-1) expression. We observed the recovery of TMZ-induced morphological changes, a reduced number of colonies and a decreased rate of migration capacity in TMZ-resistant cells after NTX treatment. The expression of APE-1 was significantly decreased in TMZ-resistant cells after NTX treatment compared with those without treatment. In an\n                    <jats:italic>in vivo<\/jats:italic>\n                    study, NTX reduced tumor growth in TMZ-resistant GBM mice (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0122). Moreover, ADC was increased in the NTX-treated TMZ-resistant GBM mice compared to the control group (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0079), which was prior to a tumor volume decrease. The cellularity and APE-1 expression by histology were negatively correlated with the ADC value, which in turn resulted in longer survival in NTX group. The decreased expression of APE-1 by NTX leads to therapeutic effects and is inversely correlated with ADC in TMZ-resistant GBM. Therefore, NTX is suggested as potential therapeutic candidate against TMZ-resistant GBM.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-53147-9","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T06:03:18Z","timestamp":1573538598000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Decreased APE-1 by Nitroxoline Enhances Therapeutic Effect in a Temozolomide-resistant Glioblastoma: Correlation with Diffusion Weighted Imaging"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-5813","authenticated-orcid":false,"given":"Hye Rim","family":"Cho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3140-8960","authenticated-orcid":false,"given":"Nisha","family":"Kumari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8761-0837","authenticated-orcid":false,"given":"Nishant","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6697-5829","authenticated-orcid":false,"given":"Hien Thi","family":"Vu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeonjin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0412-2270","authenticated-orcid":false,"given":"Seung Hong","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,12]]},"reference":[{"key":"53147_CR1","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1056\/NEJMoa043330","volume":"352","author":"R Stupp","year":"2005","unstructured":"Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352, 987\u2013996, https:\/\/doi.org\/10.1056\/NEJMoa043330 (2005).","journal-title":"N Engl J Med"},{"key":"53147_CR2","first-page":"5171","volume":"29","author":"G Minniti","year":"2009","unstructured":"Minniti, G., Muni, R., Lanzetta, G., Marchetti, P. & Enrici, R. M. Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. Anticancer Res 29, 5171\u20135184 (2009).","journal-title":"Anticancer Res"},{"key":"53147_CR3","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1056\/NEJMoa043331","volume":"352","author":"ME Hegi","year":"2005","unstructured":"Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352, 997\u20131003, https:\/\/doi.org\/10.1056\/NEJMoa043331 (2005).","journal-title":"N Engl J Med"},{"key":"53147_CR4","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.gendis.2016.04.007","volume":"3","author":"SY Lee","year":"2016","unstructured":"Lee, S. Y. Temozolomide resistance in glioblastoma multiforme. Genes Dis 3, 198\u2013210, https:\/\/doi.org\/10.1016\/j.gendis.2016.04.007 (2016).","journal-title":"Genes Dis"},{"key":"53147_CR5","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1172\/Jci59334","volume":"122","author":"S Agnihotri","year":"2012","unstructured":"Agnihotri, S. et al. Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients. J Clin Invest 122, 253\u2013266, https:\/\/doi.org\/10.1172\/Jci59334 (2012).","journal-title":"J Clin Invest"},{"key":"53147_CR6","doi-asserted-by":"publisher","first-page":"2308","DOI":"10.1158\/0008-5472.CAN-10-3213","volume":"71","author":"EM Goellner","year":"2011","unstructured":"Goellner, E. M. et al. Overcoming temozolomide resistance in glioblastoma via dual inhibition of NAD+ biosynthesis and base excision repair. Cancer Res 71, 2308\u20132317, https:\/\/doi.org\/10.1158\/0008-5472.CAN-10-3213 (2011).","journal-title":"Cancer Res"},{"key":"53147_CR7","doi-asserted-by":"publisher","first-page":"5687","DOI":"10.1002\/smll.201500540","volume":"11","author":"A Bertucci","year":"2015","unstructured":"Bertucci, A. et al. Combined Delivery of Temozolomide and Anti-miR221 PNA Using Mesoporous Silica Nanoparticles Induces Apoptosis in Resistant Glioma Cells. Small 11, 5687\u20135695, https:\/\/doi.org\/10.1002\/smll.201500540 (2015).","journal-title":"Small"},{"key":"53147_CR8","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/j.tips.2013.06.005","volume":"34","author":"SC Gupta","year":"2013","unstructured":"Gupta, S. C., Sung, B., Prasad, S., Webb, L. J. & Aggarwal, B. B. Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci 34, 508\u2013517, https:\/\/doi.org\/10.1016\/j.tips.2013.06.005 (2013).","journal-title":"Trends Pharmacol Sci"},{"key":"53147_CR9","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.canlet.2011.06.032","volume":"312","author":"HC Jiang","year":"2011","unstructured":"Jiang, H. C. et al. Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline). Cancer Lett 312, 11\u201317, https:\/\/doi.org\/10.1016\/j.canlet.2011.06.032 (2011).","journal-title":"Cancer Lett"},{"key":"53147_CR10","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1002\/cmdc.201100098","volume":"6","author":"B Mirkovic","year":"2011","unstructured":"Mirkovic, B. et al. Novel Mechanism of Cathepsin B Inhibition by Antibiotic Nitroxoline and Related Compounds. Chemmedchem 6, 1351\u20131356, https:\/\/doi.org\/10.1002\/cmdc.201100098 (2011).","journal-title":"Chemmedchem"},{"key":"53147_CR11","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1093\/neuonc\/nou139","volume":"17","author":"J Lazovic","year":"2015","unstructured":"Lazovic, J. et al. Nitroxoline induces apoptosis and slows glioma growth in vivo. Neuro-Oncology 17, 53\u201362, https:\/\/doi.org\/10.1093\/neuonc\/nou139 (2015).","journal-title":"Neuro-Oncology"},{"key":"53147_CR12","doi-asserted-by":"publisher","unstructured":"Tourell, M. C. et al. The distribution of the apparent diffusion coefficient as an indicator of the response to chemotherapeutics in ovarian tumour xenografts. Scientific Reports 7, https:\/\/doi.org\/10.1038\/srep42905 (2017).","DOI":"10.1038\/srep42905"},{"key":"53147_CR13","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1148\/rg.316115515","volume":"31","author":"AA Malayeri","year":"2011","unstructured":"Malayeri, A. A. et al. Principles and Applications of Diffusion-weighted Imaging in Cancer Detection, Staging, and Treatment Follow-up. Radiographics 31, 1773\u20131791, https:\/\/doi.org\/10.1148\/rg.316115515 (2011).","journal-title":"Radiographics"},{"key":"53147_CR14","doi-asserted-by":"publisher","unstructured":"Le Bihan, D. & Iima, M. Diffusion Magnetic Resonance Imaging: What Water Tells Us about Biological Tissues. Plos Biol 13, https:\/\/doi.org\/10.1371\/journal.pbio.1002203 (2015).","DOI":"10.1371\/journal.pbio.1002203"},{"key":"53147_CR15","doi-asserted-by":"crossref","unstructured":"Sugahara, T. et al. Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas. Jmri-Journal of Magnetic Resonance Imaging 9, 53\u201360, doi:10.1002\/(Sici)1522-2586(199901)9:1<53::Aid-Jmri7>3.0.Co;2-2 (1999).","DOI":"10.1002\/(SICI)1522-2586(199901)9:1<53::AID-JMRI7>3.0.CO;2-2"},{"key":"53147_CR16","doi-asserted-by":"publisher","first-page":"102","DOI":"10.2174\/1874467211205010102","volume":"5","author":"J Zhang","year":"2012","unstructured":"Zhang, J., Stevens, M. F. & Bradshaw, T. D. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol 5, 102\u2013114 (2012).","journal-title":"Curr Mol Pharmacol"},{"key":"53147_CR17","doi-asserted-by":"publisher","first-page":"314","DOI":"10.3389\/fonc.2018.00314","volume":"8","author":"AL Hudson","year":"2018","unstructured":"Hudson, A. L. et al. Glioblastoma Recurrence Correlates With Increased APE1 and Polarization Toward an Immuno-Suppressive Microenvironment. Front Oncol 8, 314, https:\/\/doi.org\/10.3389\/fonc.2018.00314 (2018).","journal-title":"Front Oncol"},{"key":"53147_CR18","doi-asserted-by":"publisher","unstructured":"Lai, S. W. et al. Differential Characterization of Temozolomide-Resistant Human Glioma Cells. Int J Mol Sci 19, https:\/\/doi.org\/10.3390\/ijms19010127 (2018).","DOI":"10.3390\/ijms19010127"},{"key":"53147_CR19","doi-asserted-by":"publisher","first-page":"3127","DOI":"10.1158\/0008-5472.CAN-14-3616","volume":"75","author":"JL McFaline-Figueroa","year":"2015","unstructured":"McFaline-Figueroa, J. L. et al. Minor Changes in Expression of the Mismatch Repair Protein MSH2 Exert a Major Impact on Glioblastoma Response to Temozolomide. Cancer Res 75, 3127\u20133138, https:\/\/doi.org\/10.1158\/0008-5472.CAN-14-3616 (2015).","journal-title":"Cancer Res"},{"key":"53147_CR20","doi-asserted-by":"publisher","unstructured":"Munoz, J. L. et al. Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis 5, https:\/\/doi.org\/10.1038\/cddis.2014.111 (2014).","DOI":"10.1038\/cddis.2014.111"},{"key":"53147_CR21","first-page":"3008","volume":"8","author":"JR Silber","year":"2002","unstructured":"Silber, J. R. et al. The apurinic\/apyrimidinic endonuclease activity of Ape1\/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress. Clin Cancer Res 8, 3008\u20133018 (2002).","journal-title":"Clin Cancer Res"},{"key":"53147_CR22","doi-asserted-by":"publisher","first-page":"3589","DOI":"10.1007\/s00018-010-0486-4","volume":"67","author":"G Tell","year":"2010","unstructured":"Tell, G., Fantini, D. & Quadrifoglio, F. Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment. Cell Mol Life Sci 67, 3589\u20133608, https:\/\/doi.org\/10.1007\/s00018-010-0486-4 (2010).","journal-title":"Cell Mol Life Sci"},{"key":"53147_CR23","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.molcel.2004.12.029","volume":"17","author":"H Fung","year":"2005","unstructured":"Fung, H. & Demple, B. A vital role for Ape1\/Ref1 protein in repairing spontaneous DNA damage in human cells. Mol Cell 17, 463\u2013470, https:\/\/doi.org\/10.1016\/j.molcel.2004.12.029 (2005).","journal-title":"Mol Cell"},{"key":"53147_CR24","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.ceb.2007.11.010","volume":"20","author":"JW Hammond","year":"2008","unstructured":"Hammond, J. W., Cai, D. W. & Verhey, K. J. Tubulin modifications and their cellular functions. Curr Opin Cell Biol 20, 71\u201376, https:\/\/doi.org\/10.1016\/j.ceb.2007.11.010 (2008).","journal-title":"Curr Opin Cell Biol"},{"key":"53147_CR25","doi-asserted-by":"publisher","first-page":"887","DOI":"10.3892\/or.2011.1145","volume":"25","author":"WI Henry","year":"2011","unstructured":"Henry, W. I., Dubois, J. & Quick, Q. A. The microtubule inhibiting agent epothilone B antagonizes glioma cell motility associated with reorganization of the actin-binding protein alpha-actinin 4. Oncol Rep 25, 887\u2013893, https:\/\/doi.org\/10.3892\/or.2011.1145 (2011).","journal-title":"Oncol Rep"},{"key":"53147_CR26","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.1200\/JCO.2005.03.089","volume":"23","author":"F Lefranc","year":"2005","unstructured":"Lefranc, F., Brotchi, J. & Kiss, R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 23, 2411\u20132422, https:\/\/doi.org\/10.1200\/JCO.2005.03.089 (2005).","journal-title":"J Clin Oncol"},{"key":"53147_CR27","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1634\/theoncologist.12-12-1395","volume":"12","author":"F Lefranc","year":"2007","unstructured":"Lefranc, F., Facchini, V. & Kiss, R. Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 12, 1395\u20131403, https:\/\/doi.org\/10.1634\/theoncologist.12-12-1395 (2007).","journal-title":"Oncologist"},{"key":"53147_CR28","doi-asserted-by":"publisher","first-page":"39759","DOI":"10.1074\/jbc.M110.147504","volume":"285","author":"CR Oliva","year":"2010","unstructured":"Oliva, C. R. et al. Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain. Journal of Biological Chemistry 285, 39759\u201339767, https:\/\/doi.org\/10.1074\/jbc.M110.147504 (2010).","journal-title":"Journal of Biological Chemistry"},{"key":"53147_CR29","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1158\/1535-7163.Mct-08-0854","volume":"8","author":"MJ Clarke","year":"2009","unstructured":"Clarke, M. J. et al. Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines. Molecular Cancer Therapeutics 8, 407\u2013414, https:\/\/doi.org\/10.1158\/1535-7163.Mct-08-0854 (2009).","journal-title":"Molecular Cancer Therapeutics"},{"key":"53147_CR30","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1148\/radiol.13121362","volume":"268","author":"K Koral","year":"2013","unstructured":"Koral, K. et al. Common Pediatric Cerebellar Tumors: Correlation between Cell Densities and Apparent Diffusion Coefficient Metrics. Radiology 268, 532\u2013537, https:\/\/doi.org\/10.1148\/radiol.13121362 (2013).","journal-title":"Radiology"},{"key":"53147_CR31","doi-asserted-by":"publisher","first-page":"624","DOI":"10.2214\/Ajr.12.8679","volume":"200","author":"M Zulfiqar","year":"2013","unstructured":"Zulfiqar, M., Yousem, D. M. & Lai, H. ADC Values and Prognosis of Malignant Astrocytomas: Does Lower ADC Predict a Worse Prognosis Independent of Grade of Tumor?-A Meta-Analysis. Am J Roentgenol 200, 624\u2013629, https:\/\/doi.org\/10.2214\/Ajr.12.8679 (2013).","journal-title":"Am J Roentgenol"},{"key":"53147_CR32","doi-asserted-by":"publisher","first-page":"882","DOI":"10.3174\/ajnr.A2385","volume":"32","author":"WB Pope","year":"2011","unstructured":"Pope, W. B. et al. Apparent diffusion coefficient histogram analysis stratifies progression-free survival in newly diagnosed bevacizumab-treated glioblastoma. AJNR Am J Neuroradiol 32, 882\u2013889, https:\/\/doi.org\/10.3174\/ajnr.A2385 (2011).","journal-title":"AJNR Am J Neuroradiol"},{"key":"53147_CR33","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1007\/s11060-012-0847-y","volume":"108","author":"WB Pope","year":"2012","unstructured":"Pope, W. B. et al. Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi-center study. J Neuro-Oncol 108, 491\u2013498, https:\/\/doi.org\/10.1007\/s11060-012-0847-y (2012).","journal-title":"J Neuro-Oncol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-53147-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-53147-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-53147-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T10:56:39Z","timestamp":1671274599000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-53147-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,12]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["53147"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-53147-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,12]]},"assertion":[{"value":"8 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16613"}}