{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T19:09:23Z","timestamp":1787857763722,"version":"build-2784847793"},"reference-count":55,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"General Directorate of Academic Personnel Affairs, National Autonomous University of Mexico","award":["IN229820"],"award-info":[{"award-number":["IN229820"]}]},{"name":"General Directorate of Academic Personnel Affairs, National Autonomous University of Mexico","award":["IN222023"],"award-info":[{"award-number":["IN222023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Resistance to cytarabine (Ara-C) remains a major obstacle to the successful treatment of acute myeloid leukemia (AML). Therefore, modulating Ara-C resistance is indispensable for improving clinical outcomes. We previously demonstrated that sodium caseinate (SC), a salt derived from casein, the principal milk protein, inhibits proliferation and modulates the expression of Ara-C resistance-related genes in chemoresistant cells. However, it remains unclear whether the combination of SC with antineoplastic agents enhances apoptosis, modulates chemoresistance-related genes, and prolongs the survival of tumor-bearing mice implanted with chemoresistant cells. Here, we investigated the effects of SC in combination with Ara-C or daunorubicin (DNR) on cell proliferation, apoptosis, the expression of chemoresistance-associated genes, and the survival of tumor-bearing mice. Crystal violet assays, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, flow cytometry, and Kaplan\u2013Meier survival curves were used to evaluate the effects of combinations in chemoresistant cells. We demonstrate that the IC25 concentration of SC, when combined with antileukemic agents, increases the sensitivity of chemoresistant WEHI-CR50 cells to Ara-C by downregulating SIRT1 and MDR1, upregulating the expression of ENT1 and dCK, enhancing apoptosis, and prolonging the survival of WEHI-CR50 tumor-bearing mice. Our data suggest that SC in combination with antileukemic agents could be an effective adjuvant for Ara-C-resistant AML.<\/jats:p>","DOI":"10.3390\/ijms26157468","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T15:56:16Z","timestamp":1754409376000},"page":"7468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sodium Caseinate Induces Apoptosis in Cytarabine-Resistant AML by Modulating SIRT1 and Chemoresistance Genes, Alone or in Combination with Cytarabine or Daunorubicin"],"prefix":"10.3390","volume":"26","author":[{"given":"Daniel","family":"Romero-Trejo","sequence":"first","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"},{"name":"Department of Biomedical Sciences, School of Medicine, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 56410, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1692-8287","authenticated-orcid":false,"given":"Itzen","family":"Agui\u00f1iga-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"},{"name":"Department of Biomedical Sciences, School of Medicine, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 56410, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Velasco-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5197-8862","authenticated-orcid":false,"given":"Katia Michell","family":"Rodr\u00edguez-Ter\u00e1n","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0881-8822","authenticated-orcid":false,"given":"Fabian","family":"Flores-Borja","sequence":"additional","affiliation":[{"name":"Centre for Oral Immunobiology and Regenerative Medicine, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5115-3654","authenticated-orcid":false,"given":"Isabel","family":"Soto-Cruz","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5985-7365","authenticated-orcid":false,"given":"Martha","family":"Legorreta-Herrera","sequence":"additional","affiliation":[{"name":"Molecular Immunology Laboratory, Computational Chemistry Research Unit, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7799-866X","authenticated-orcid":false,"given":"V\u00edctor Manuel","family":"Mac\u00edas-Zaragoza","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"},{"name":"Department of Biomedical Sciences, School of Medicine, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 56410, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Romero-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4893-530X","authenticated-orcid":false,"given":"Benny","family":"Weiss-Steider","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8584-8955","authenticated-orcid":false,"given":"Karen","family":"Miranda-Duarte","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2851-7814","authenticated-orcid":false,"given":"Claudia Itzel","family":"Sandoval-Franco","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4876-0688","authenticated-orcid":false,"given":"Edelmiro","family":"Santiago-Osorio","sequence":"additional","affiliation":[{"name":"Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 09230, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16010","DOI":"10.1038\/nrdp.2016.10","article-title":"Acute Myeloid 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