{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T17:37:44Z","timestamp":1788629864419,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,7,6]],"date-time":"2024-07-06T00:00:00Z","timestamp":1720224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PLEC2021-007523\/AEI\/10.13039\/501100011033","award":["PI19\/00372"],"award-info":[{"award-number":["PI19\/00372"]}]},{"name":"European Union\u2014NextGenerationEU","award":["PI19\/00372"],"award-info":[{"award-number":["PI19\/00372"]}]},{"name":"Instituto de Salud Carlos III","award":["PI19\/00372"],"award-info":[{"award-number":["PI19\/00372"]}]},{"name":"European Union ERDF\/ESF","award":["PI19\/00372"],"award-info":[{"award-number":["PI19\/00372"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is highly aggressive. Despite an initial positive response to chemotherapy, most patients experience rapid disease progression leading to relapse and metastasis. This is attributed to the presence of breast cancer stem cells (BCSCs) within the tumor, which are characterized by self-renewal, pluripotency, and resistance mechanisms. Targeting BCSCs has become critical as conventional therapies fail to eradicate them due to a lack of specific targets. Curcumin, a polyphenol derived from turmeric (Curcuma longa), exhibits anticancer effects against breast cancer cells and BCSCs. The use of curcumin derivatives has been suggested as an approach to overcome the bioavailability and solubility problems of curcumin in humans, thereby increasing its anticancer effects. The aim of this study was to evaluate the cellular and molecular effects of six synthetic compounds derived from the natural polyphenol epigallocatechin gallate (EGCG) (TL1, TL2) and curcumin derivatives (TL3, TL4, TL5, and TL6) on a TNBC mesenchymal stem-like cell line. The activity of the compounds against BCSCs was also determined by a mammosphere inhibition assay and studying different BCSC markers by Western blotting. Finally, a drug combination assay was performed with the most promising compounds to evaluate their potential synergistic effects with the chemotherapeutic agents doxorubicin, cisplatin, and paclitaxel. The results showed that compounds exhibited specific cytotoxicity against the TNBC cell line and BCSCs. Interestingly, the combination of the curcumin derivative TL3 with doxorubicin and cisplatin displayed a synergistic effect in TNBC cells.<\/jats:p>","DOI":"10.3390\/ijms25137446","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T12:21:03Z","timestamp":1720441263000},"page":"7446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Inhibition of Cancer Stem-like Cells by Curcumin and Other Polyphenol Derivatives in MDA-MB-231 TNBC Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4532-9866","authenticated-orcid":false,"given":"Maria","family":"Ros","sequence":"first","affiliation":[{"name":"New Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, Faculty of Medicine, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9869-7488","authenticated-orcid":false,"given":"Gerard","family":"Riesco-Llach","sequence":"additional","affiliation":[{"name":"Laboratori d\u2019Innovaci\u00f3 en Processos i Productes de S\u00edntesi Org\u00e0nica (LIPPSO), Department of Chemistry, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1017-7216","authenticated-orcid":false,"given":"Emma","family":"Polonio-Alcal\u00e1","sequence":"additional","affiliation":[{"name":"New Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, Faculty of Medicine, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7443-8388","authenticated-orcid":false,"given":"Pere Miquel","family":"Morla-Barcelo","sequence":"additional","affiliation":[{"name":"Grupo Multidisciplinar de Oncolog\u00eda Traslacional, Institut Universitari d\u2019Investigaci\u00f3 en Ci\u00e8ncies de la Salut (IUNICS), Universitat de les Illes Balears, 07122 Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Ruiz-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, University of Gothenburg, 405 30 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9792-6106","authenticated-orcid":false,"given":"Lidia","family":"Feliu","sequence":"additional","affiliation":[{"name":"Laboratori d\u2019Innovaci\u00f3 en Processos i Productes de S\u00edntesi Org\u00e0nica (LIPPSO), Department of Chemistry, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4988-4970","authenticated-orcid":false,"given":"Marta","family":"Planas","sequence":"additional","affiliation":[{"name":"Laboratori d\u2019Innovaci\u00f3 en Processos i Productes de S\u00edntesi Org\u00e0nica (LIPPSO), Department of Chemistry, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2715-7043","authenticated-orcid":false,"given":"Teresa","family":"Puig","sequence":"additional","affiliation":[{"name":"New Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, Faculty of Medicine, University of Girona, 17003 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer Statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41572-019-0111-2","article-title":"Breast Cancer","volume":"5","author":"Harbeck","year":"2019","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Vagia, E., Mahalingam, D., and Cristofanilli, M. (2020). The Landscape of Targeted Therapies in TNBC. Cancers, 12.","DOI":"10.3390\/cancers12040916"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nedeljkovi\u0107, M., and Damjanovi\u0107, A. (2019). Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer-How We Can Rise to the Challenge. Cells, 8.","DOI":"10.3390\/cells8090957"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"813","DOI":"10.2217\/bmm-2017-0398","article-title":"Cancer Stem Cells in Triple-Negative Breast Cancer: A Potential Target and Prognostic Marker","volume":"12","author":"Chen","year":"2018","journal-title":"Biomark. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Park, C. (2019). Nam Targeting Cancer Stem Cells in Triple-Negative Breast Cancer. Cancers., 11.","DOI":"10.3390\/cancers11070965"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/978-1-0716-1948-3_16","article-title":"ER+ Breast Cancer Mammosphere Formation and Analysis","volume":"2422","author":"Singleton","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wei, Y., Li, Y., Chen, Y., Liu, P., Huang, S., Zhang, Y., Sun, Y., Wu, Z., Hu, M., and Wu, Q. (2022). ALDH1: A Potential Therapeutic Target for Cancer Stem Cells in Solid Tumors. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1026278"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5681","DOI":"10.21873\/anticanres.11151","article-title":"Targeting Cellular Signaling Pathways in Breast Cancer Stem Cells and Its Implication for Cancer Treatment","volume":"36","author":"Pires","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105320","DOI":"10.1016\/j.phrs.2020.105320","article-title":"Breast Cancer Stem Cells, Heterogeneity, Targeting Therapies and Therapeutic Implications","volume":"163","author":"Zeng","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s13287-021-02321-w","article-title":"Signaling Pathways Governing Breast Cancer Stem Cells Behavior","volume":"12","author":"Song","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Talib, W.H., Alsalahat, I., Daoud, S., Abutayeh, R.F., and Mahmod, A.I. (2020). Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation. Molecules, 25.","DOI":"10.3390\/molecules25225319"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7608","DOI":"10.1158\/1078-0432.CCR-09-0856","article-title":"Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity","volume":"15","author":"Puig","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13027-020-0270-5","article-title":"Current Shreds of Evidence on the Anticancer Role of EGCG in Triple Negative Breast Cancer: An Update of the Current State of Knowledge","volume":"15","author":"Bimonte","year":"2020","journal-title":"Infect Agent. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/j.1749-6632.2010.05777.x","article-title":"Novel Anti-Fatty Acid Synthase Compounds with Anti-Cancer Activity in HER2+ Breast Cancer","volume":"1210","author":"Oliveras","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5013","DOI":"10.1021\/jm2016045","article-title":"New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity","volume":"55","author":"Turrado","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Crous-Mas\u00f3, J., Palomeras, S., Relat, J., Cam\u00f3, C., Mart\u00ednez-Garza, \u00da., Planas, M., Feliu, L., and Puig, T. (2018). (\u2212)-Epigallocatechin 3-Gallate Synthetic Analogues Inhibit Fatty Acid Synthase and Show Anticancer Activity in Triple Negative Breast Cancer. Molecules, 23.","DOI":"10.3390\/molecules23051160"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gir\u00f3-Perafita, A., Rabionet, M., Planas, M., Feliu, L., Ciurana, J., Ruiz-Mart\u00ednez, S., and Puig, T. (2019). EGCG-Derivative G28 Shows High Efficacy Inhibiting the Mammosphere-Forming Capacity of Sensitive and Resistant TNBC Models. Molecules, 24.","DOI":"10.3390\/molecules24061027"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1038\/s41418-023-01178-1","article-title":"Curcumin Activates a ROS\/KEAP1\/NRF2\/MiR-34a\/b\/c Cascade to Suppress Colorectal Cancer Metastasis","volume":"30","author":"Liu","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Giordano, A., and Tommonaro, G. (2019). Tommonaro Curcumin and Cancer. Nutrients, 11.","DOI":"10.3390\/nu11102376"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.fshw.2018.06.001","article-title":"Anticancer Effect of Curcumin on Breast Cancer and Stem Cells","volume":"7","author":"Liu","year":"2018","journal-title":"Food Sci. Hum. Wellness"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6","DOI":"10.7243\/2052-6199-1-6","article-title":"Curcumin and Its Derivatives in Breast Cancer: Current Developments and Potential for the Treatment of Drug-Resistant Cancers","volume":"1","author":"Cridge","year":"2013","journal-title":"Oncol. Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.semcancer.2016.09.001","article-title":"Targeting Cancer Stem Cells and Signaling Pathways by Phytochemicals: Novel Approach for Breast Cancer Therapy","volume":"40\u201341","author":"Dandawate","year":"2016","journal-title":"Semin. Cancer Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.msec.2018.10.071","article-title":"Folic Acid Conjugated Curcumin Loaded Biopolymeric Gum Acacia Microsphere for Triple Negative Breast Cancer Therapy in Invitro and Invivo Model","volume":"95","author":"Pal","year":"2019","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mbese, Z., Khwaza, V., and Aderibigbe, B.A. (2019). Curcumin and Its Derivatives as Potential Therapeutic Agents in Prostate, Colon and Breast Cancers. Molecules, 24.","DOI":"10.3390\/molecules24234386"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s12935-015-0241-x","article-title":"Targeting Colorectal Cancer Stem Cells Using Curcumin and Curcumin Analogues: Insights into the Mechanism of the Therapeutic Efficacy","volume":"15","author":"Ramasamy","year":"2015","journal-title":"Cancer Cell Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"36185","DOI":"10.1039\/C7RA06580A","article-title":"The: In Vivo Anti-Tumor Effect of Curcumin Derivative (2 E,6 E)-2,6-Bis(4-Hydroxy-3-Methoxybenzylidene)Cyclohexanone (BHMC) on 4T1 Breast Cancer Cells","volume":"7","author":"Razak","year":"2017","journal-title":"RSC Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1111\/j.1349-7006.2009.01220.x","article-title":"New Curcumin Analogues Exhibit Enhanced Growth-Suppressive Activity and Inhibit AKT and Signal Transducer and Activator of Transcription 3 Phosphorylation in Breast and Prostate Cancer Cells","volume":"100","author":"Lin","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/S0223-5234(97)83288-6","article-title":"1,5-Diphenyl-1,4-Pentadiene-3-Ones and Cyclic Analogues as Antioxidative Agents. Synthesis and Structure-Activity Relationship","volume":"32","author":"Sardjiman","year":"1997","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6275","DOI":"10.1016\/j.bmc.2010.07.026","article-title":"New Antitumoral Agents I: In Vitro Anticancer Activity and in Vivo Acute Toxicity of Synthetic 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)-1,4-Pentadien-3-One and Derivatives","volume":"18","author":"Rando","year":"2010","journal-title":"Bioorganic Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1080\/21691401.2017.1423495","article-title":"PH-Sensitive Polymeric Nanoparticles of MPEG-PLGA-PGlu with Hybrid Core for Simultaneous Encapsulation of Curcumin and Doxorubicin to Kill the Heterogeneous Tumour Cells in Breast Cancer","volume":"46","author":"Yuan","year":"2018","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"152740","DOI":"10.1016\/j.phymed.2018.11.001","article-title":"Anti-Metastasis Activity of Curcumin against Breast Cancer via the Inhibition of Stem Cell-like Properties and EMT","volume":"58","author":"Hu","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/ptr.7305","article-title":"Curcumin and Its Derivatives in Cancer Therapy: Potentiating Antitumor Activity of Cisplatin and Reducing Side Effects","volume":"36","author":"Abadi","year":"2022","journal-title":"Phyther. Res."},{"key":"ref_34","first-page":"829","article-title":"Comparison of Mammosphere Formation from Breast Cancer Cell Lines and Primary Breast Tumors","volume":"6","author":"Wang","year":"2014","journal-title":"J. Thorac. Dis."},{"key":"ref_35","first-page":"321","article-title":"Regulation of Cancer Stem Cells in Triple Negative Breast Cancer","volume":"4","author":"Fultang","year":"2021","journal-title":"Cancer Drug Resist."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1097\/CAD.0000000000000584","article-title":"Sonic Hedgehog and Wnt\/\u03b2-Catenin Pathways Mediate Curcumin Inhibition of Breast Cancer Stem Cells","volume":"29","author":"Li","year":"2018","journal-title":"Anticancer Drugs"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1038\/bjc.2013.642","article-title":"Silencing NOTCH Signaling Causes Growth Arrest in Both Breast Cancer Stem Cells and Breast Cancer Cells","volume":"109","author":"Suman","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_38","first-page":"2741","article-title":"Effect of Curcumin on the Cell Surface Markers CD44 and CD24 in Breast Cancer","volume":"39","author":"Calaf","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"He, L., Wick, N., Germans, S.K., and Peng, Y. (2021). The Role of Breast Cancer Stem Cells in Chemoresistance and Metastasis in Triple-Negative Breast Cancer. Cancers, 13.","DOI":"10.3390\/cancers13246209"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Landeros, N., Castillo, I., and P\u00e9rez-Castro, R. (2023). Preclinical and Clinical Trials of New Treatment Strategies Targeting Cancer Stem Cells in Subtypes of Breast Cancer. Cells, 12.","DOI":"10.3390\/cells12050720"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.cmet.2017.11.001","article-title":"JAK\/STAT3-Regulated Fatty Acid \u03b2-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance","volume":"27","author":"Wang","year":"2018","journal-title":"Cell Metab."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Zhou, Q., Ye, M., Lu, Y., Zhang, H., Chen, Q., Huang, S., and Su, S. (2015). Curcumin Improves the Tumoricidal Effect of Mitomycin C by Suppressing ABCG2 Expression in Stem Cell-like Breast Cancer Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136694"},{"key":"ref_43","first-page":"5162","article-title":"Curcumin Reverses Doxorubicin Resistance via Inhibition the Efflux Function of ABCB4 in Doxorubicin-resistant Breast Cancer Cells","volume":"19","author":"Wen","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_44","first-page":"2381","article-title":"Curcumin and Paclitaxel Induce Cell Death in Breast Cancer Cell Lines","volume":"40","author":"Calaf","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2017.07.022","article-title":"Pharmacokinetic Interactions of Curcuminoids with Conventional Drugs: A Review","volume":"209","author":"Bahramsoltani","year":"2017","journal-title":"J. Ethnopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Polonio-Alcal\u00e1, E., Palomeras, S., Torres-Oteros, D., Relat, J., Planas, M., Feliu, L., Ciurana, J., Ruiz-Mart\u00ednez, S., and Puig, T. (2020). Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models. Cancers, 12.","DOI":"10.3390\/cancers12051283"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/13\/7446\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:11:15Z","timestamp":1760109075000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/13\/7446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,6]]},"references-count":47,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25137446"],"URL":"https:\/\/doi.org\/10.3390\/ijms25137446","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,6]]}}}