{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T20:30:26Z","timestamp":1775075426229,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,4]],"date-time":"2020-02-04T00:00:00Z","timestamp":1580774400000},"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":["UID\/DTP\/04567\/2019"],"award-info":[{"award-number":["UID\/DTP\/04567\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The renal cell carcinoma (RCC) is the most common type of kidney cancer. Identifying novel and more effective therapies, while minimizing toxicity, continues to be fundamental in curtailing RCC. Rutin, a bioflavonoid widely found in nature, has shown promising anticancer properties, but with limited applicability due to its poor water solubility and pharmacokinetics. Thus, the potential anticancer effects of rutin toward a human renal cancer cell line (786-O), while considering its safety in Vero kidney cells, was assessed, as well as the applicability of ionic liquids (ILs) to improve drug delivery. Rutin (up to 50 \u00b5M) did not show relevant cytotoxic effects in Vero cells. However, in 786-O cells, a significant decrease in cell viability was already observed at 50 \u00b5M. Moreover, exposure to rutin caused a significant increase in the sub-G1 population of 786-O cells, reinforcing the possible anticancer activity of this biomolecule. Two choline-amino acid ILs, at non-toxic concentrations, enhanced rutin\u2019s solubility\/loading while allowing the maintenance of rutin\u2019s anticancer effects. Globally, our findings suggest that rutin may have a beneficial impact against RCC and that its combination with ILs ensures that this poorly soluble drug is successfully incorporated into ILs\u2013nanoparticles hybrid systems, allowing controlled drug delivery.<\/jats:p>","DOI":"10.3390\/biom10020233","type":"journal-article","created":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T02:59:18Z","timestamp":1580957958000},"page":"233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["Anticancer Activity of Rutin and Its Combination with Ionic Liquids on Renal Cells"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5964-2062","authenticated-orcid":false,"given":"Rita","family":"Caparica","sequence":"first","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences &amp; Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"},{"name":"Department of Biomedical Sciences, University of Alcal\u00e1, Ctra. Madrid-Barcelona Km. 33.600, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3129-6495","authenticated-orcid":false,"given":"Ana","family":"J\u00falio","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences &amp; Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"},{"name":"Department of Biomedical Sciences, University of Alcal\u00e1, Ctra. Madrid-Barcelona Km. 33.600, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9876-9015","authenticated-orcid":false,"given":"Maria Eduarda Machado","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"CQE, and Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Campo Grande 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9197-3024","authenticated-orcid":false,"given":"Andr\u00e9 Rolim","family":"Baby","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Pharmaceutical Sciences, University of S\u00e3o Paulo, 580 Prof. Lineu Prestes Av., Bl. 15, S\u00e3o Paulo, SP 05508-900, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1115-9282","authenticated-orcid":false,"given":"Pedro","family":"Fonte","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences &amp; Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"},{"name":"iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"},{"name":"Center for Marine Sciences (CCMar), University of Algarve and Department of Chemistry and Pharmacy, 8005-139 Faro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5604-6142","authenticated-orcid":false,"given":"Jo\u00e3o Guilherme","family":"Costa","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences &amp; Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5150-9910","authenticated-orcid":false,"given":"T\u00e2nia","family":"Santos de Almeida","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences &amp; Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"},{"name":"CQE, and Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Campo Grande 1749-016 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.12688\/f1000research.13179.1","article-title":"Renal cell carcinoma\u202f: A review of biology and pathophysiology","volume":"7","author":"Nabi","year":"2018","journal-title":"F1000Research"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yeh, I.-J., Chen, S.-C., Yen, M.-C., Wu, Y.-H., Hung, C.-H., and Kuo, P.-L. (2019). 6-Shogaol Suppresses 2-Amino-1-Methyl-6- Phenylimidazo [4,5-b] Pyridine (PhIP)-Induced Human 786-O Renal Cell Carcinoma Osteoclastogenic Activity and Metastatic Potential. Nutrients, 11.","DOI":"10.3390\/nu11102306"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ou, Y., Li, J., Wang, J., Chang, C., Wu, C., Chen, W., Kuan, Y., Liao, S., Lu, H., and Chen, C. (2019). Fibronectin Promotes Cell Growth and Migration in Human Renal Cell Carcinoma Cells. Mol. Sci., 20.","DOI":"10.3390\/ijms20112792"},{"key":"ref_4","first-page":"348","article-title":"Expression and epigenetic regulatory mechanism of BNIP3 in clear cell renal cell carcinoma","volume":"54","author":"Shao","year":"2019","journal-title":"Int. J. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lin, C.Y., Chen, P.-N., Hsu, L.-S., Kuo, D.Y.K., Chu, S.-C., and Hsieh, Y.-S.H. (2014). Inhibition of the invasion and migration of renal carcinoma 786-o-si3 cells in vitro and in vivo by Koelreuteria formosana extract. Mol. Med. Rep., 3334\u20133342.","DOI":"10.3892\/mmr.2014.2587"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Costa, J.G., Saraiva, N., Batinic-Haberle, I., Castro, M., Oliveira, N.G., and Fernandes, A.S. (2019). The SOD Mimic MnTnHex-2-PyP 5 + Reduces the Viability and Migration of 786-O Human Renal Cancer Cells. Antioxidants, 8.","DOI":"10.3390\/antiox8100490"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.etp.2010.03.005","article-title":"Investigation of cytotoxic, apoptosis-inducing, genotoxic and protective effects of the flavonoid rutin in HTC hepatic cells","volume":"63","year":"2011","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nafees, S., Mehdi, S.H., Zafaryab, M., Zeya, B., Sarwar, T., and Rizvi, M.A. (2018). Synergistic Interaction of Rutin and Silibinin on Human Colon Cancer Cell Line. Arch. Med. Res.","DOI":"10.1016\/j.arcmed.2018.09.008"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1002\/ptr.5878","article-title":"Rutin, a Quercetin Glycoside, Restores Chemosensitivity in Human Breast Cancer Cells","volume":"31","author":"Iriti","year":"2017","journal-title":"Phyther. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Garc\u00eda, D., P\u00e9rez-Hern\u00e1ndez, M., Korrodi-Greg\u00f3rio, L., Quesada, R., Ramos, R., Baixeras, N., P\u00e9rez-Tom\u00e1s, R., and Soto-Cerrato, V. (2019). The Natural-Based Antitumor Compound T21 Decreases Survivin Levels through Potent STAT3 Inhibition in Lung Cancer Models. Biomolecules, 9.","DOI":"10.3390\/biom9080361"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sudhakaran, M., Sardesai, S., and Doseff, A.I. (2019). Flavonoids\u202f: New Frontier for Immuno-Regulation and Breast Cancer Control. antioxidants, 8.","DOI":"10.3390\/antiox8040103"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sharifi-rad, J., Ozleyen, A., Tumer, T.B., Adetunji, C.O., Omari, N.E., Balahbib, A., Taheri, Y., Bouyahya, A., Martorell, M., and Martins, N. (2019). Natural Products and Synthetic Analogs as a Source of Antitumor Drugs. Biomolecules, 9.","DOI":"10.3390\/biom9110679"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nikfarjam, B.A., Adineh, M., Hajiali, F., and Nassiri-asl, M. (2017). Treatment with Rutin-A Therapeutic Strategy for Neutrophil-Mediated Inflammatory and Autoimmune Diseases. J. Pharmacopuncture, 52\u201356.","DOI":"10.3831\/KPI.2017.20.003"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Enogieru, A.B., Haylett, W., Hiss, D.C., Bardien, S., and Ekpo, O.E. (2018). Rutin as a Potent Antioxidant\u202f: Implications for Neurodegenerative Disorders. Oxid. Med. Cell. Longev.","DOI":"10.1155\/2018\/6241017"},{"key":"ref_15","unstructured":"Bispo, A., Coelho, P.L.C., Oliveira, M.d.N., Oliveira, J.L., Amparo, J.A.O., Costa da Silva, K., Soares, J.R.P., Pitanga, B.P.S., Souza, C.d.S., and Lopes, G.P.d.F. (2019). The flavonoid rutin and its aglycone quercetin modulate the microglia inflammatory profile improving antiglioma activity. Brain Behav. Immun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jsps.2016.04.025","article-title":"The Pharmacological Potential of Rutin","volume":"25","author":"Ganeshpurkar","year":"2017","journal-title":"Saudi Pharm. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1080\/09168451.2018.1491286","article-title":"Identification and characterization of a rhamnosyltransferase involved in rutin biosynthesis in fagopyrum esculentum (common buckwheat)","volume":"82","author":"Koja","year":"2018","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chen, H., Miao, Q., Geng, M., Liu, J., Hu, Y., Tian, L., Pan, J., and Yang, Y. (2013). Anti-Tumor Effect of Rutin on Human Neuroblastoma Cell Lines through Inducing G2 \/ M Cell Cycle Arrest and Promoting Apoptosis. Sci. Worl J.","DOI":"10.1155\/2013\/269165"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.tifs.2017.07.008","article-title":"Rutin: A review on extraction, identification and purification methods, biological activities and approaches to enhance its bioavailability","volume":"67","author":"Moreira","year":"2017","journal-title":"Trends Food Sci. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12935-014-0124-6","article-title":"Rutin mediated targeting of signaling machinery in cancer cells","volume":"14","author":"Perk","year":"2014","journal-title":"Cancer Cell Int."},{"key":"ref_21","first-page":"244","article-title":"Bioavailability and metabolic pharmacokinetics of rutin and quercetin in rats","volume":"13","author":"Yang","year":"2005","journal-title":"J. Food Drug Anal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1517\/13543784.2013.805744","article-title":"Rutin: Therapeutic potential and recent advances in drug delivery","volume":"22","author":"Sharma","year":"2013","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Caparica, R., J\u00falio, A., Baby, A.R., Ara\u00fajo, M.E.M., Fernandes, A.S., Costa, J.G., and T\u00e2nia, S.d.A. (2018). Choline-Amino Acid Ionic Liquids as Green Functional Excipients to Enhance Drug Solubility. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10040288"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1080\/03639045.2017.1349788","article-title":"Choline- versus imidazole-based ionic liquids as functional ingredients in topical delivery systems: Cytotoxicity, solubility, and skin permeation studies","volume":"43","author":"Saraiva","year":"2017","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhang, X., Xing, H., Zhao, Y., and Ma, Z. (2018). Pharmaceutical dispersion techniques for dissolution and bioavailability enhancement of poorly water-soluble drugs. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10030074"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Caparica, R., J\u00falio, A., Rosado, C., and Santos, T. (2018). Applicability of Ionic Liquids in Topical Drug Delivery Systems\u202f: A Mini Review. J. Pharmacol. Clin. Res., 4.","DOI":"10.19080\/JPCR.2018.04.555649"},{"key":"ref_27","first-page":"96","article-title":"Influence of two choline-based ionic liquids on the solubility of caffeine","volume":"15","author":"Rosado","year":"2018","journal-title":"J. Biomed. Biopharm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lee, J.Y., Selfridge, K.M., Kohn, E.M., Vaden, T.D., and Caputo, G.A. (2019). Effects of Ionic Liquid Alkyl Chain Length on Denaturation of Myoglobin by Anionic, Cationic, and Zwitterionic Detergents. Biomolecules, 9.","DOI":"10.3390\/biom9070264"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ejpb.2015.05.027","article-title":"Pro et contra\u2019 ionic liquid drugs-Challenges and opportunities for pharmaceutical translation","volume":"94","author":"Balk","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.chemosphere.2016.04.042","article-title":"Assessing chemical toxicity of ionic liquids on Vibrio fischeri: Correlation with structure and composition","volume":"155","author":"Hidalgo","year":"2016","journal-title":"Chemosphere"},{"key":"ref_31","first-page":"483","article-title":"Studies on thermal stability of amino acid ionic liquids","volume":"70","author":"Ossowicz","year":"2016","journal-title":"Chemik"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Quraish, K.S., Bustam, M.A., Krishnan, S., Aminuddin, N.F., Azeezah, N., Ghani, N.A., Uemura, Y., and L\u00e9v\u00eaque, J.M. (2017). Ionic liquids toxicity on fresh water microalgae, Scenedesmus quadricauda, Chlorella vulgaris & Botryococcus braunii; selection criterion for use in a two-phase partitioning bioreactor (TPPBR). Chemosphere, 642\u2013651.","DOI":"10.1016\/j.chemosphere.2017.06.037"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Agatemor, C., Ibsen, K.N., Tanner, E.E.L., and Mitragotri, S. (2018). Ionic liquids for addressing unmet needs in healthcare. Bioeng. Transl. Med., 7\u201325.","DOI":"10.1002\/btm2.10083"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.chemosphere.2013.10.055","article-title":"Toxicity of ionic liquids prepared from biomaterials","volume":"104","author":"Gouveia","year":"2014","journal-title":"Chemosphere"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"J\u00falio, A., Caparica, R., Lima, S.A.C., Fernandes, A.S., Rosado, C., Prazeres, D.M.F., Reis, S., and Santos de Almeida, T. (2019). Ionic Liquid-Polymer Nanoparticle Hybrid Systems as New Tools to Deliver Poorly Soluble Drugs. nanomaterials, 9.","DOI":"10.3390\/nano9081148"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1111\/cbdd.12979","article-title":"The APE1 redox inhibitor E3330 reduces collective cell migration of human breast cancer cells and decreases chemoinvasion and colony formation when combined with docetaxel","volume":"90","author":"Guerreiro","year":"2017","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"J\u00falio, A., Lima, S.A.C., Reis, S., De Almeida, T.S., and Fonte, P. (2019). Development of ionic liquid-polymer nanoparticle hybrid systems for delivery of poorly soluble drugs. J. Drug Deliv. Sci. Technol.","DOI":"10.1016\/j.jddst.2019.01.030"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Escudier, B., Porta, C., Schmidinger, M., Bex, A., Khoo, V., Gruenvald, V., and Horwich, A. (2016). Renal cell carcinoma\u202f: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 27.","DOI":"10.1093\/annonc\/mdw328"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1016\/j.biopha.2016.11.001","article-title":"Rutin inhibits proliferation, attenuates superoxide production and decreases adhesion and migration of human cancerous cells","volume":"84","author":"Sghaier","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Costa, J.G., Saraiva, N., Guerreiro, P.S., Louro, H., Silva, M.J., Miranda, J.P., Castro, M., Batinic-haberle, I., Fernandes, A.S., and Nuno, G. (2015). Ochratoxin A-induced cytotoxicity, genotoxicity and reactive oxygen species in kidney cells: An integrative approach of complementary endpoints. Food Chem. Toxicol.","DOI":"10.1016\/j.fct.2015.11.018"},{"key":"ref_41","first-page":"133","article-title":"p53 and CYCLIN B1 MEDIATE APOPTOTIC EFFECTS OF A PIGENIN AND RUTIN IN ERa + - BREAST CANCER MCF-7","volume":"1","author":"Hasani","year":"2018","journal-title":"J. Teknol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"37157","DOI":"10.1039\/C4RA05295A","article-title":"Toxicity of ionic liquids toward microorganisms interesting to the food industry","volume":"4","author":"Santos","year":"2014","journal-title":"RSC Adv."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ecoenv.2016.05.005","article-title":"Comparative in vitro study of cholinium-based ionic liquids and deep eutectic solvents toward fish cell line","volume":"131","author":"Slivac","year":"2016","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2018.00745","article-title":"Potential applications of nanotechnology in urological cancer","volume":"9","author":"He","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Rodrigues de Azevedo, C., Von Stosch, M., Costa, M.S., Ramos, A.M., Cardoso, M.M., Danhier, F., Pr\u00e9at, V., and Oliveira, R. (2017). Modeling of the burst release from PLGA micro - and nanoparticles as function of physicochemical parameters and formulation characteristics. Int. J. Pharm.","DOI":"10.1016\/j.ijpharm.2017.08.118"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/2\/233\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:54:39Z","timestamp":1760172879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/2\/233"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,4]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["biom10020233"],"URL":"https:\/\/doi.org\/10.3390\/biom10020233","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,4]]}}}