{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:09:24Z","timestamp":1777900164120,"version":"3.51.4"},"reference-count":48,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Most high\u2010risk neuroblastoma patients who relapse succumb to disease despite the existing therapy. We recently reported increased event\u2010free and overall survival in neuroblastoma patients receiving difluoromethylornithine (DFMO) during maintenance therapy. The effect of DFMO on cellular processes associated with neuroblastoma tumorigenesis needs further elucidation. Previous studies have shown cytotoxicity with IC50 values &gt;5\u201315\u2009mM, these doses are physiologically unattainable in patients, prompting further mechanistic studies at therapeutic doses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We characterized the effect of DFMO on cell viability, cell cycle, apoptosis, neurosphere formation, and protein expression in\u00a0vitro using five established neuroblastoma cell lines (BE2C, CHLA\u201090, SHSY5Y, SMS\u2010KCNR, and NGP) at clinically relevant doses of 0, 50, 100, 500, 1000, and 2500\u2009\u03bcM. Limiting Dilution studies of tumor formation in murine models were performed. Statistical analysis was done using GraphPad and the level of significance set at <jats:italic>p<\/jats:italic>\u2009=\u20090.05.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There was not a significant loss of cell viability or gain of apoptotic activity in the in\u00a0vitro assays (<jats:italic>p<\/jats:italic>\u2009&gt;\u20090.05). DFMO treatment initiated G1 to S phase cell cycle arrest. There was a dose\u2010dependent decrease in frequency and size of neurospheres and a dose\u2010dependent increase in beta\u2010galactosidase activity in all cell lines. Tumor formation was decreased in xenografts both with DFMO\u2010pretreated cells and in mice treated with DFMO.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>DFMO treatment is cytostatic at physiologically relevant doses and inhibits tumor initiation and progression in mice. This study suggests that DFMO, inhibits neuroblastoma by targeting cellular processes integral to neuroblastoma tumorigenesis at clinically relevant doses.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.7207","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T09:26:59Z","timestamp":1714469219000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<scp>DFMO<\/scp> inhibition of neuroblastoma tumorigenesis"],"prefix":"10.1002","volume":"13","author":[{"given":"Divya","family":"Gandra","sequence":"first","affiliation":[{"name":"Department of Pediatrics Penn State Health Children's Hospital  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David H.","family":"Mulama","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Levine Children's Hospital  Charlotte North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-8356","authenticated-orcid":false,"given":"David M.","family":"Foureau","sequence":"additional","affiliation":[{"name":"Department of Medicine Levine Cancer Institute  Charlotte North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly Q.","family":"McKinney","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Levine Children's Hospital  Charlotte North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Levine Children's Hospital  Charlotte North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaitlyn","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Levine Children's Hospital  Charlotte North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Haw","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Levine Children's Hospital  Charlotte North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhinav","family":"Nagulapally","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Penn State Health Children's Hospital  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5599-4757","authenticated-orcid":false,"given":"Giselle L.","family":"Saulnier\u00a0Sholler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Penn State Health Children's Hospital  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,4,30]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6725a2"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492"},{"key":"e_1_2_11_4_1","unstructured":"Neuroblastoma Survival Rates | American Cancer Society [Internet]. Accessed December 7 2021.https:\/\/www.cancer.org\/cancer\/neuroblastoma\/detection\u2010diagnosis\u2010staging\/survival\u2010rates.html"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1148\/rg.2018170132"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-018-2796-z"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-016-3195-3"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1014"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a014415"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2011.08.001"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1999.276.3.C684"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1454"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2018.12.012"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM118.003336"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2436"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-3305-3-15"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31510-6"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2768"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33044"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00442"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26088"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00300234"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21654"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31669"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0127246"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-32659-w"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-2126(99)00161-7"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.00322"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3112"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2007.08.012"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.019"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13003"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqac058"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-022-00450-9"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5425"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.7.3309"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12082134"},{"key":"e_1_2_11_38_1","article-title":"Alpha\u2010difluoromethylornithine, an irreversible inhibitor of polyamine biosynthesis, as a therapeutic strategy against hyperproliferative and infectious diseases","volume":"6","author":"LoGiudice N","year":"2018","journal-title":"Med Sci (Basel)"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9145-7_9"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1964"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/apm.12207"},{"key":"e_1_2_11_42_1","first-page":"186","article-title":"Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy","volume":"28","author":"Yang S","year":"2012","journal-title":"Oncol Rep"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005799"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208808"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.489"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6866"},{"key":"e_1_2_11_47_1","first-page":"7754","article-title":"Polyamine depletion in human melanoma cells leads to G1 arrest associated with induction of p21WAF1\/CIP1\/SDI1, changes in the expression of p21\u2010regulated genes, and a senescence\u2010like phenotype","volume":"61","author":"Kramer DL","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01057761"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11050707"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.7207","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T14:57:17Z","timestamp":1728572237000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.7207"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,30]]},"references-count":48,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1002\/cam4.7207"],"URL":"https:\/\/doi.org\/10.1002\/cam4.7207","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,30]]},"assertion":[{"value":"2023-04-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e7207"}}