{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T03:55:51Z","timestamp":1777434951397,"version":"3.51.4"},"reference-count":58,"publisher":"SAGE Publications","issue":"10","license":[{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"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":[[2018,10]]},"abstract":"<jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>The purpose of this study was to investigate differential nicotinamide adenine dinucleotide phosphate, reduced (NADPH) production between radiation-sensitive and -resistant head and neck squamous cell carcinoma (HNSCC) cell lines and whether these differences are predictive of sensitivity to the chemotherapeutic \u03b2-lapachone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We have developed a novel human genome-scale metabolic modeling platform that combines transcriptomic, kinetic, thermodynamic, and metabolite concentration data. Upon incorporation of this information into cell line-specific models, we observed that the radiation-resistant HNSCC model redistributed flux through several major NADPH-producing reactions. Upon RNA interference of canonical NADPH-producing genes, the metabolic network can further reroute flux through alternate NADPH biosynthesis pathways in a cell line-specific manner. Model predictions of perturbations in cellular NADPH production after gene knockdown match well with experimentally verified effects of \u03b2-lapachone treatment on NADPH\/NADP\n                      <jats:sup>+<\/jats:sup>\n                      ratio and cell viability. This computational approach accurately predicts HNSCC-specific oxidoreductase genes that differentially affect cell viability between radiation-responsive and radiation-resistant cancer cells upon \u03b2-lapachone treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:<\/jats:title>\n                    <jats:p>Quantitative genome-scale metabolic models that incorporate multiple levels of biological data are applied to provide accurate predictions of responses to a NADPH-dependent redox cycling chemotherapeutic drug under a variety of perturbations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      Our modeling approach suggests differences in metabolism and \u03b2-lapachone redox cycling that underlie phenotypic differences in radiation-sensitive and -resistant cancer cells. This approach can be extended to investigate the synergistic action of NAD(P)H: quinone oxidoreductase 1 bioactivatable drugs and radiation therapy.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                      29, 937\u2013952.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/ars.2017.7048","type":"journal-article","created":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T09:51:01Z","timestamp":1501581061000},"page":"937-952","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":28,"title":["Genome-Scale Modeling of NADPH-Driven \u03b2-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.1177","volume":"29","author":[{"given":"Joshua E.","family":"Lewis","sequence":"first","affiliation":[{"name":"Georgia Institute of Technology and Emory University","place":["Georgia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Costantini","sequence":"additional","affiliation":[{"name":"Georgia Institute of Technology","place":["Georgia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jade","family":"Mims","sequence":"additional","affiliation":[{"name":"Wake Forest School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaofei","family":"Chen","sequence":"additional","affiliation":[{"name":"Wake Forest School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina M.","family":"Furdui","sequence":"additional","affiliation":[{"name":"Wake Forest School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Boothman","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa L.","family":"Kemp","sequence":"additional","affiliation":[{"name":"Georgia Institute of Technology and Emory University","place":["Georgia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2018,10,1]]},"reference":[{"key":"e_1_3_3_2_2","unstructured":"The Human Protein Atlas. http:\/\/proteinatlas.org\/2017 (accessed June30 2017)."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5690"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000082"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702176104"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0962"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00299"},{"key":"e_1_3_3_8_2","first-page":"5361","article-title":"Potentiation of halogenated pyrimidine radiosensitizers in human carcinoma cells by beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione), a novel DNA repair inhibitor","volume":"47","author":"Boothman DA","year":"1987","unstructured":"Boothman DA, , Greer S, , and Pardee AB. 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