{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T02:41:56Z","timestamp":1782873716337,"version":"3.54.5"},"reference-count":37,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PAPIIT-UNAM","award":["205920"],"award-info":[{"award-number":["205920"]}]},{"name":"PAPIIT-UNAM","award":["203919"],"award-info":[{"award-number":["203919"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuroblastoma (Nb), the most common extracranial tumor in children, exhibited remarkable phenotypic diversity and heterogeneous clinical behavior. Tumors with MYCN overexpression have a worse prognosis. MYCN promotes tumor progression by inducing cell proliferation, de-differentiation, and dysregulated mitochondrial metabolism. Cyclophosphamide (CFF) at minimum effective oral doses (metronomic therapy) exerts beneficial actions on chemoresistant cancers. Molecular iodine (I2) in coadministration with all-trans retinoic acid synergizes apoptosis and cell differentiation in Nb cells. This work analyzes the impact of I2 and CFF on the viability (culture) and tumor progression (xenografts) of Nb chemoresistant SK-N-BE(2) cells. Results showed that both molecules induce dose-response antiproliferative effects, and I2 increases the sensibility of Nb cells to CFF, triggering PPAR\u03b3 expression and acting as a mitocan in mitochondrial metabolism. In vivo oral I2\/metronomic CFF treatments showed significant inhibition in xenograft growth, decreasing proliferation (Survivin) and activating apoptosis signaling (P53, Bax\/Bcl-2). In addition, I2 decreased the expression of master markers of malignancy (MYCN, TrkB), vasculature remodeling, and increased differentiation signaling (PPAR\u03b3 and TrkA). Furthermore, I2 supplementation prevented loss of body weight and hemorrhagic cystitis secondary to CFF in nude mice. These results allow us to propose the I2 supplement in metronomic CFF treatments to increase the effectiveness of chemotherapy and reduce side effects.<\/jats:p>","DOI":"10.3390\/ijms22168936","type":"journal-article","created":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T08:44:45Z","timestamp":1629449085000},"page":"8936","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Molecular Iodine\/Cyclophosphamide Synergism on Chemoresistant Neuroblastoma Models"],"prefix":"10.3390","volume":"22","author":[{"given":"Winniberg","family":"\u00c1lvarez-Le\u00f3n","sequence":"first","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Juriquilla, Quer\u00e9taro 76230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7509-3617","authenticated-orcid":false,"given":"Irasema","family":"Mendieta","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Juriquilla, Quer\u00e9taro 76230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2605-4632","authenticated-orcid":false,"given":"Evangelina","family":"Delgado-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Juriquilla, Quer\u00e9taro 76230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Anguiano","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Juriquilla, Quer\u00e9taro 76230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-8304","authenticated-orcid":false,"given":"Carmen","family":"Aceves","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Juriquilla, Quer\u00e9taro 76230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"MYCN Function in Neuroblastoma Development","volume":"10","author":"Otte","year":"2020","journal-title":"Front. 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