{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T13:43:41Z","timestamp":1778247821423,"version":"3.51.4"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Renal cell carcinoma (RCC) is the 14<jats:sup>th<\/jats:sup> most incident cancer worldwide, and no curative therapeutic options are available for advanced and metastatic disease. Hence, new treatment alternatives are urgently needed to tackle disease management and drug resistance. Herein, we explored the use of MLo-1508 as an anti-tumoral agent in RCC and further assessed its combination with sunitinib for the treatment of papillary RCC. For that, different RCC cell lines were treated with both drugs, alone or in combination, and different phenotypic assays were performed. Moreover, global DNA methylation levels and specific DNMT3a activity were measured, and gene-specific CpG methylation and transcript levels were quantified after treatment. Finally, the combinatory potential of MLo-1508 and sunitinib were asses both in vitro and in vivo using the ACHN cell line. We found that MLo-1508 significantly decreased RCC cell viability while inducing apoptosis in a dose-dependent manner without cytotoxicity for non-malignant cells. Moreover, the treatment induced morphometric alterations and DNA damage in all RCC cell lines. MLo-1508 decreased <jats:italic>DNMT1<\/jats:italic> and <jats:italic>DNMT3A<\/jats:italic> transcript levels in 786-O and ACHN cells, inhibited DNMT3A activity, and reduced the global DNA methylation content of ACHN cells. When combined with sunitinib, a reduction in ACHN cell viability, as well as cell cycle arrest at G2\/M was observed. Importantly, MLo-1508 decreased the sunitinib effective anti-tumoral concentration against ACHN cell viability. In an <jats:italic>in vivo<\/jats:italic> ACHN CAM model, the combination induced cell necrosis. Thus, MLo-1508 might improve sensitivity to sunitinib treatment by decreasing the required concentration and delaying resistance acquisition.<\/jats:p>","DOI":"10.3389\/fonc.2025.1399956","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T11:11:34Z","timestamp":1742814694000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Combination of MLo-1508 with sunitinib for the experimental treatment of papillary renal cell carcinoma"],"prefix":"10.3389","volume":"15","author":[{"given":"\u00c2ngela","family":"Marques-Magalh\u00e3es","sequence":"first","affiliation":[]},{"given":"Filipa","family":"Moreira-Silva","sequence":"additional","affiliation":[]},{"given":"In\u00eas","family":"Gra\u00e7a","sequence":"additional","affiliation":[]},{"given":"Paula C.","family":"Dias","sequence":"additional","affiliation":[]},{"given":"Margareta P.","family":"Correia","sequence":"additional","affiliation":[]},{"given":"Maria Ana","family":"Alzamora","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[]},{"given":"Marie","family":"Lopez","sequence":"additional","affiliation":[]},{"given":"Paola B.","family":"Arimondo","sequence":"additional","affiliation":[]},{"given":"Vera","family":"Miranda-Gon\u00e7alves","sequence":"additional","affiliation":[]},{"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2012.06.003","article-title":"Genomics and epigenomics of renal cell carcinoma","volume":"23","author":"Maher","year":"2013","journal-title":"Semin Cancer Biol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2016.02.028","article-title":"The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs\u2014Part B: Prostate and Bladder Tumours","volume":"70","author":"Humphrey","year":"2016","journal-title":"Eur Urol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"17009","DOI":"10.1038\/nrdp.2017.9","article-title":"Renal cell carcinoma","volume":"3","author":"Hsieh","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1601333","article-title":"Systemic Therapy for Metastatic Renal-Cell Carcinoma","volume":"376","author":"Choueiri","year":"2017","journal-title":"New Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)67889-5","article-title":"Systemic therapy for renal cell carcinoma","volume":"163","author":"Motzer","year":"2000","journal-title":"J Urol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s11523-016-0463-4","article-title":"Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action","volume":"12","author":"Duran","year":"2017","journal-title":"Target Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1158\/2159-8290.Cd-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discovery"},{"key":"B9","doi-asserted-by":"publisher","first-page":"eaal2380","DOI":"10.1126\/science.aal2380","article-title":"Epigenetic plasticity and the hallmarks of cancer","volume":"357","author":"Flavahan","year":"2017","journal-title":"Sci (New York N.Y.)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-7-133","article-title":"Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors","volume":"7","author":"Costa","year":"2007","journal-title":"BMC Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2012.00094","article-title":"The epigenetics of renal cell tumors: from biology to biomarkers","volume":"3","author":"Henrique","year":"2012","journal-title":"Front Genet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/s13045-015-0180-y","article-title":"Role of DNA methylation in renal cell carcinoma","volume":"8","author":"Shenoy","year":"2015","journal-title":"J Hematol Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nrneph.2016.168","article-title":"The epigenetic landscape of renal cancer","volume":"13","author":"Morris","year":"2017","journal-title":"Nat Rev Nephrol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2009.01434.x","article-title":"Aberrant DNA methylation in contrast with mutations","volume":"101","author":"Ushijima","year":"2010","journal-title":"Cancer Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604374","article-title":"Proteins that bind methylated DNA and human cancer: reading the wrong words","volume":"98","author":"Lopez-Serra","year":"2008","journal-title":"Br J Cancer"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-04-2135","article-title":"Approval Summary: Azacitidine for Treatment of Myelodysplastic Syndrome Subtypes","volume":"11","author":"Kaminskas","year":"2005","journal-title":"Clin Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.21792","article-title":"Decitabine improves patient outcomes in myelodysplastic syndromes","volume":"106","author":"Kantarjian","year":"2006","journal-title":"Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0714.2002.00034.x","article-title":"DNA methylation: an epigenetic pathway to cancer and a promising target for anticancer therapy","volume":"31","author":"Worm","year":"2002","journal-title":"J Oral Pathol Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1134\/s0006297915080027","article-title":"Natural compounds: Role in reversal of epigenetic changes","volume":"80","author":"Aggarwal","year":"2015","journal-title":"Biochem (Mosc)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/tcr.201800133","article-title":"Natural Products and Chemical Biology Tools: Alternatives to Target Epigenetic Mechanisms in Cancers","volume":"18","author":"Lascano","year":"2018","journal-title":"Chem Rec"},{"key":"B21","doi-asserted-by":"publisher","first-page":"515","DOI":"10.3390\/nu8080515","article-title":"Natural Polyphenols for Prevention and Treatment of Cancer","volume":"8","author":"Zhou","year":"2016","journal-title":"Nutrients"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/79.5.727","article-title":"Polyphenols: food sources and bioavailability","volume":"79","author":"Manach","year":"2004","journal-title":"Am J Clin Nutr"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111681","article-title":"Anti-neoplastic and demethylating activity of a newly synthetized flavanone-derived compound in Renal Cell Carcinoma cell lines","volume":"141","author":"Marques-Magalh\u00e3es","year":"2021","journal-title":"BioMed Pharmacother"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111829","article-title":"Synthesis of novel 3-halo-3-nitroflavanones and their activities as DNA methyltransferase inhibitors in cancer cells","volume":"186","author":"Pechalrieu","year":"2020","journal-title":"Eur J Med Chem"},{"key":"B25","doi-asserted-by":"publisher","first-page":"670","DOI":"10.3390\/ph14070670","article-title":"Hydralazine and Panoninostat Attenuate Malignant Properties of Prostate Cancer Cell lines","volume":"14","author":"Pacheco","year":"2021","journal-title":"Pharm (Basel)"},{"key":"B26","volume-title":"ComboSyn","author":"Chou","year":"2005"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113031","article-title":"G9a inhibition by CM-272: Developing a novel anti-tumoral strategy for castration-resistant","volume":"150","author":"Moreira-Silva","year":"2022","journal-title":"BioMed Pharmacother"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2022.06.009","article-title":"Epigenetically-regulated miR-30a\/c-5p directly target TWF1 and hamper ccRCC cell aggressiveness","volume":"249","author":"Outeiro-Pinho","year":"2022","journal-title":"Trans Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2023.100929","article-title":"Sunitinib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers","volume":"67","author":"Jin","year":"2023","journal-title":"Drug Resist Updates"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s40291-018-0337-9","article-title":"The Role of DNA Methylation in Renal Cell Carcinoma","volume":"22","author":"Lasseigne","year":"2018","journal-title":"Mol Diagn Ther"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-08-2196","article-title":"Decitabine Effect on Tumor Global DNA Methylation and Other Parameters in a Phase I Trial in Refractory Solid Tumors and Lymphomas","volume":"15","author":"Stewart","year":"2009","journal-title":"Clin Cancer Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-06-0883","article-title":"Phase I Trial of Sequential Low-Dose 5-Aza-2\u2032-Deoxycytidine Plus High-Dose Intravenous Bolus Interleukin-2 in Patients with Melanoma or Renal Cell Carcinoma","volume":"12","author":"Gollob","year":"2006","journal-title":"Clin Cancer Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-09-0567","article-title":"A Phase I Dose-Finding Study of 5-Azacytidine in Combination with Sodium Phenylbutyrate in Patients with Refractory Solid Tumors","volume":"15","author":"Lin","year":"2009","journal-title":"Clin Cancer Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s13148-021-01154-x","article-title":"DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application","volume":"13","author":"Hu","year":"2021","journal-title":"Clin Epigenet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/srep15623","article-title":"Structural and functional analysis of cell adhesion and nuclear envelope nano-topography in cell death","volume":"5","author":"Kwon","year":"2015","journal-title":"Sci Rep"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1039\/c6ib00139d","article-title":"Morphological single cell profiling of the epithelial\u2013mesenchymal transition","volume":"8","author":"Leggett","year":"2016","journal-title":"Integr Biol (Camb)"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1042\/bj20102162","article-title":"ATR signalling: more than meeting at the fork","volume":"436","author":"Nam","year":"2011","journal-title":"Biochem J"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1505917","article-title":"Comprehensive molecular characterization of papillary renal-cell carcinoma","volume":"374","author":"Linehan","year":"2016","journal-title":"N Engl J Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s13148-021-01154-x","article-title":"DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application","volume":"13","author":"Hu","year":"2021","journal-title":"Clin Epigenet"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/mc.20866","article-title":"Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: in vitro and in vivo study","volume":"51","author":"Pandey","year":"2012","journal-title":"Mol Carcinog"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-013-9486-2","article-title":"Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer","volume":"15","author":"Ting","year":"2013","journal-title":"AAPS J"},{"key":"B42","article-title":"Green tea polyphenol epigallocatechin 3-gallate, contributes to the degradation of DNMT3A and HDAC3 in HCT 116 human colon cancer cells","volume":"33","author":"Moseley","year":"2013","journal-title":"Anticancer Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1186\/1868-7083-3-4","article-title":"Dietary phytochemicals, HDAC inhibition, and DNA damage\/repair defects in cancer cells","volume":"3","author":"Rajendran","year":"2011","journal-title":"Clin Epigenet"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.09.014","article-title":"ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma","volume":"32","author":"Powles","year":"2021","journal-title":"Ann Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1399956\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T11:11:37Z","timestamp":1742814697000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1399956\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,24]]},"references-count":44,"alternative-id":["10.3389\/fonc.2025.1399956"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1399956","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,24]]},"article-number":"1399956"}}