title: The ellagic acid derivative 4,4'-di-O-methylellagic acid efficiently inhibits colon cancer cell growth through a mechanism involving WNT16.
abstract: Ellagic acid (EA) and some derivatives have been reported to inhibit cancer cell proliferation, induce cell cycle arrest, and modulate some important cellular processes related to cancer. This study aimed to identify possible structure-activity relationships of EA and some in vivo derivatives in their antiproliferative effect on both human colon cancer and normal cells, and to compare this activity with that of other polyphenols. Our results showed that 4,4'-di-O-methylellagic acid (4,4'-DiOMEA) was the most effective compound in the inhibition of colon cancer cell proliferation. 4,4'-DiOMEA was 13-fold more effective than other compounds of the same family. In addition, 4,4'-DiOMEA was very active against colon cancer cells resistant to the chemotherapeutic agent 5-fluoracil, whereas no effect was observed in nonmalignant colon cells. Moreover, no correlation between antiproliferative and antioxidant activities was found, further supporting that structure differences might result in dissimilar molecular targets involved in their differential effects. Finally, microarray analysis revealed that 4,4'-DiOMEA modulated Wnt signaling, which might be involved in the potential antitumor action of this compound. Our results suggest that structural-activity differences between EA and 4,4'-DiOMEA might constitute the basis for a new strategy in anticancer drug discovery based on these chemical modifications.
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.) ana.ramirez@imdea.org aramirez@iib.uam.es.
authors.forename: Ana
authors.identifier: http://orcid.org/0000-0003-1439-7494
authors.initials: A
authors.lastname: Ramírez de Molina
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Teodoro
authors.initials: T
authors.lastname: Vargas
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Susana
authors.initials: S
authors.lastname: Molina
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Jenifer
authors.initials: J
authors.lastname: Sánchez
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Jorge
authors.initials: J
authors.lastname: Martínez-Romero
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Margarita
authors.initials: M
authors.lastname: González-Vallinas
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Martín-Hernández
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Ruth
authors.initials: R
authors.lastname: Sánchez-Martínez
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Marta
authors.initials: M
authors.lastname: Gómez de Cedrón
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Alberto
authors.initials: A
authors.lastname: Dávalos
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Luca
authors.initials: L
authors.lastname: Calani
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Daniele
authors.initials: D
authors.lastname: Del Rio
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Sarrías
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Espín
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Tomás-Barberán
authors.affiliation: Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas (CEI UAM+CSIC), Madrid, Spain (A.R.d.M., T.V., S.M., J.S., J.M.-R., M.G.-V., R.M.-H., R.S.-M., M.G.d.C., A.D., G.R.); LS9 Interlab Group, Laboratory of Phytochemicals in Physiology, Department of Food Science, University of Parma, Parma, Italy (L.C., D.D.R.); and Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Campus de Espinardo, Murcia, Spain (A.G.-S., J.C.E., F.A.T.-B.).
authors.forename: Guillermo
authors.initials: G
authors.lastname: Reglero
mesh_terms: D016588:Anticarcinogenic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004610:Ellagic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C551431:4,4'-O-methylellagic acid; D016588:Anticarcinogenic Agents; C417262:WNT16 protein, human; D051153:Wnt Proteins; D004610:Ellagic Acid; D005472:Fluorouracil