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–Meier 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.

Chronic myeloid leukemia (CML) is driven by constitutive BCR–ABL1 activity and remains clinically challenging due to disease persistence and resistance to tyrosine kinase inhibitors (TKIs). SIRT1, a NAD⁺-dependent deacetylase, has been implicated in leukemic cell survival and chemoresistance through negative regulation of p53. In this study, we evaluated the antileukemic effects of the Sechium hybrid H387 extract and its impact on the SIRT1–p53 signaling axis in K562 CML cells. Cell proliferation was assessed using a crystal violet assay, while gene and protein expression were analyzed by RT-qPCR, immunofluorescence, and flow cytometry. Apoptosis was determined by Annexin V/7-AAD staining. The extract significantly inhibited K562 cell proliferation and downregulated SIRT1 expression, reducing its nuclear localization. These effects were associated with increased p53 acetylation at lysine 382 (Ac-K382-p53) and enhanced apoptosis. Notably, a higher percentage of apoptotic cells was observed following extract treatment than with imatinib under the experimental conditions used, although the two agents have distinct mechanisms of action. These findings suggest that the antileukemic activity of Sechium hybrid H387 extract is associated with modulation of the SIRT1–p53 axis and induction of apoptosis in K562 cells.