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Abstract：
Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy.
摘要：
糖酵解代谢的改变与急性髓性白血病（AML）的化学耐药有关。然而,还有一些方面需要澄清，以及如何在治疗中探索这些代谢改变。在本研究中,我们旨在阐明葡萄糖代谢在AML细胞对阿糖胞苷(Ara-C)获得性耐药中的作用,并探讨其作为治疗靶点的作用.通过逐步暴露AML细胞以增加浓度的Ara-C诱导抗性。对Ara-C抗性细胞的生长能力进行了表征，遗传改变,代谢概况，以及对不同代谢抑制剂的敏感性。抗Ara-CAML细胞系,KG-1Ara-R,和MOLM13Ara-R呈现不同的代谢谱。KG-1Ara-R细胞比亲本细胞表现出更明显的糖酵解表型，对3-溴丙酮酸（3-BP）的急性反应较弱，但在48小时后灵敏度更高。KG-1Ara-R细胞也显示出呼吸速率增加，并且对苯乙双胍比亲本细胞更敏感。另一方面,MOLM13Ara-R细胞表现出与亲本细胞相似的葡萄糖代谢曲线，以及对糖酵解抑制剂的敏感性。这些结果表明AML对Ara-C的获得性抗性可能涉及代谢适应，可以在对治疗产生耐药性的AML患者中进行治疗性探索。
