Romero-Trejo Daniel, Aguiñiga-Sánchez Itzen, Velasco-García Amanda, Rodríguez-Terán Katia Michell, Flores-Borja Fabian, Soto-Cruz Isabel, Legorreta-Herrera Martha, Macías-Zaragoza Víctor Manuel, Romero-López Ernesto, Weiss-Steider Benny, Miranda-Duarte Karen, Sandoval-Franco Claudia Itzel, Santiago-Osorio Edelmiro
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.
Department of Biomedical Sciences, School of Medicine, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, Mexico City 56410, Mexico.
Int J Mol Sci. 2025 Aug 1;26(15):7468. doi: 10.3390/ijms26157468.
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 IC 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.
对阿糖胞苷（Ara-C）的耐药性仍然是急性髓系白血病（AML）成功治疗的主要障碍。因此，调节对Ara-C的耐药性对于改善临床结果至关重要。我们之前证明，酪蛋白酸钠（SC）是一种从主要乳蛋白酪蛋白衍生而来的盐，可抑制化疗耐药细胞的增殖并调节Ara-C耐药相关基因的表达。然而，尚不清楚SC与抗肿瘤药物联合使用是否能增强细胞凋亡、调节化疗耐药相关基因，并延长植入化疗耐药细胞的荷瘤小鼠的生存期。在此，我们研究了SC与Ara-C或柔红霉素（DNR）联合使用对细胞增殖、凋亡、化疗耐药相关基因表达以及荷瘤小鼠生存期的影响。采用结晶紫测定、定量逆转录聚合酶链反应（qRT-PCR）、免疫荧光、流式细胞术和 Kaplan-Meier 生存曲线来评估联合用药对化疗耐药细胞的影响。我们证明，SC与抗白血病药物联合使用时的IC浓度，通过下调SIRT1和MDR1、上调ENT1和dCK的表达、增强细胞凋亡以及延长荷瘤WEHI-CR50小鼠的生存期，增加了化疗耐药的WEHI-CR50细胞对Ara-C的敏感性。我们的数据表明，SC与抗白血病药物联合使用可能是Ara-C耐药AML的一种有效辅助治疗方法。
