{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:16:57Z","timestamp":1788344217655,"version":"build-2803163510"},"reference-count":67,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,2,2]],"date-time":"2019-02-02T00:00:00Z","timestamp":1549065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["iNOVA4Health - UID\/Multi\/04462\/2013"],"award-info":[{"award-number":["iNOVA4Health - UID\/Multi\/04462\/2013"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% \u00b1 5.27% compared to 63.55% \u00b1 17.49% for 2D), upregulation of CD44, PROM1, SOX9, and SNAI1 genes (1.83 \u00b1 0.34, 2.54 \u00b1 0.51, 2.03 \u00b1 0.15, and 6.12 \u00b1 1.59 times) and high self-renewal capability (352 \u00b1 55 colonies compared to 253 \u00b1 42 for 2D). Incubation with OPE (1 mg\/mL) significantly inhibited cell proliferation and modulated cancer stemness and self-renewal ability: colony formation, ALDH1 activity, and the expression of cancer stemness biomarkers PROM1 and LGR5 were significantly reduced (0.66 \u00b1 0.15 and 0.51 \u00b1 0.14 times, respectively). Among all PMFs, tangeretin was the most efficient in targeting the CSC population by decreasing colony formation and the expression of PROM1 and LGR5. Scutellarein tetramethylether was shown to modulate markers of mesenchymal\/metastatic transition (increasing CDH1 and reducing ZEB1 and SNAI1) and nobiletin was capable of downregulating PROM1 and SNAI1 expression. Importantly, all PMFs and OPE were shown to synergistically interact with 5-fluorouracil, improving the antiproliferative response of this drug.<\/jats:p>","DOI":"10.3390\/nu11020326","type":"journal-article","created":{"date-parts":[[2019,2,5]],"date-time":"2019-02-05T11:31:07Z","timestamp":1549366267000},"page":"326","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Polymethoxylated Flavones Target Cancer Stemness and Improve the Antiproliferative Effect of 5-Fluorouracil in a 3D Cell Model of Colorectal Cancer"],"prefix":"10.3390","volume":"11","author":[{"given":"Carolina V.","family":"Pereira","sequence":"first","affiliation":[{"name":"iBET, Instituto de Biologia Experimental e Tecnol\u00f3gica, Apartado 12, 2780-901 Oeiras, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Duarte","sequence":"additional","affiliation":[{"name":"Unidade de Investiga\u00e7\u00e3o em Patobiologia Molecular (UIPM), Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia","family":"Silva","sequence":"additional","affiliation":[{"name":"Unidade de Investiga\u00e7\u00e3o em Patobiologia Molecular (UIPM), Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreia","family":"Bento da Silva","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal"},{"name":"Faculdade de Farm\u00e1cia da Universidade de Lisboa, Av das For\u00e7as Armadas, 1649-019 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina M. M.","family":"Duarte","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7464-0217","authenticated-orcid":false,"given":"Alejandro","family":"Cifuentes","sequence":"additional","affiliation":[{"name":"Laboratory of Foodomics, Institute of Food Science Research (CIAL, CSIC), Calle Nicol\u00e1s Cabrera 9, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6728-4325","authenticated-orcid":false,"given":"Virginia","family":"Garc\u00eda-Ca\u00f1as","sequence":"additional","affiliation":[{"name":"Molecular Nutrition and Metabolism, Institute of Food Science Research (CIAL, CSIC) Calle Nicol\u00e1s Cabrera 9, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R.","family":"Bronze","sequence":"additional","affiliation":[{"name":"iBET, Instituto de Biologia Experimental e Tecnol\u00f3gica, Apartado 12, 2780-901 Oeiras, Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal"},{"name":"Faculdade de Farm\u00e1cia da Universidade de Lisboa, Av das For\u00e7as Armadas, 1649-019 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Albuquerque","sequence":"additional","affiliation":[{"name":"Unidade de Investiga\u00e7\u00e3o em Patobiologia Molecular (UIPM), Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Teresa","family":"Serra","sequence":"additional","affiliation":[{"name":"iBET, Instituto de Biologia Experimental e Tecnol\u00f3gica, Apartado 12, 2780-901 Oeiras, Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1136\/gutjnl-2015-310912","article-title":"Global patterns and trends in colorectal cancer incidence and mortality","volume":"66","author":"Arnold","year":"2017","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/35102167","article-title":"Stem cells, cancer, and cancer stem cells","volume":"414","author":"Reya","year":"2001","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/nrc2499","article-title":"Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions","volume":"8","author":"Visvader","year":"2008","journal-title":"Nat. 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