Acute myeloid leukemia (AML) is an aggressive malignancy that leads to a poor prognosis even with intensive chemotherapy. As the key feature of AML is the blockade of hematopoietic cell maturation, considerable attention has been paid to ‘differentiation therapy’ aimed at transforming AML cells into more mature, benign phenotypes using pharmacological agents. Here we report a hyaluronic acid–(−)-epigallocatechin-3-O-gallate (HA–EGCG) conjugate as a unique anti-leukemic agent, capable of selectively killing AML cells as well as promoting their terminal differentiation into monocytes and granulocytes. This ‘two-pronged’ effect of the HA–EGCG conjugate was demonstrated in two different AML cell lines (NB4 and HL60), but absent in a physical mixture (HA + EGCG), highlighting the importance of HA conjugation for targeting of EGCG moieties to AML cells. Moreover, administration of the HA–EGCG conjugate not only suppressed AML progression, but also prolonged survival in the HL60 xenograft mouse model. Our study suggests new opportunities for designing two-pronged anti-leukemic agents for more effective AML treatment.

中文翻译：

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基于透明质酸-绿茶儿茶素结合物的两管抗白血病剂，用于诱导靶向细胞死亡和终末分化。

急性髓细胞性白血病（AML）是一种侵袭性恶性肿瘤，即使进行密集的化疗也会导致不良的预后。由于AML的关键特征是对造血细胞成熟的阻断，因此人们对“分化疗法”给予了极大的关注，该疗法旨在使用药理学试剂将AML细胞转化为更成熟，良性的表型。在这里我们报告透明质酸-（-）-epigallocatechin-3- O-gallate（HA–EGCG）偶联物是一种独特的抗白血病药，能够选择性杀死AML细胞，并促进其最终分化为单核细胞和粒细胞。在两种不同的AML细胞系（NB4和HL60）中证明了HA-EGCG共轭物的这种“两管齐下”的作用，但在物理混合物（HA + EGCG）中却没有，这突显了HA共轭对于靶向EGCG部分的重要性AML细胞。此外，在HL60异种移植小鼠模型中，HA-EGCG偶联物的施用不仅抑制了AML的进展，而且还延长了其生存期。我们的研究表明，设计两管齐下的抗白血病药物以更有效地治疗AML的新机会。