Identification of 6-benzylthioinosine as a myeloid leukemia differentiation-inducing compound
Identification of 6-benzylthioinosine as a myeloid leukemia differentiation-inducing compound
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DOI：
10.1158/0008-5472.can-07-6559
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Tse, William
中科院分区：
文献类型：
--
作者：
Wald, David N.;Vermaat, Hanna M.;Tse, William
由于急性髓系白血病(AML)的病理生理过程涉及髓系成熟障碍，因此通过诱导白血病细胞成熟来提高疗效并避免传统化疗药物的副作用是一种理想的治疗策略。通过复合文库筛选，6-苄基硫代肌苷(6BT)被认为是一种很有前途的分化诱导剂。6BT诱导HL-60和OCI-AML3等髓系白血病细胞系以及原发患者样本的单核细胞分化，这一点通过形态学、免疫表型和四氮蓝还原试验得到证明。6BT不仅可诱导AML细胞分化，而且部分AML细胞系如MV4-11和HNT34可通过6BT诱导细胞死亡。尽管6BT可诱导某些白血病细胞死亡，但对成纤维细胞、正常骨髓和内皮细胞等几种非恶性细胞的毒性极低。这种毒性可能与6BT作为核苷转运蛋白ent1的抑制剂的功能有关，ent1被认为可以阻止6BT进入多种细胞类型。相反，6BT可能至少进入一些白血病细胞系，这从其分化活性所需的磷酸化表明。6BT还能够与目前使用的髓系分化药物如全反式维甲酸和地西他滨协同作用。早期的研究表明，该化合物的作用机制可能涉及导致生长抑制和随后的分化的ATP耗竭。除体外活性外，6BT还具有抑制HL-60和MV4-11裸鼠移植瘤生长的作用。6BT是一种具有明显白血病细胞特异性活性的新型单核细胞分化剂。
As the pathophysiology of acute myelogenous leukemia (AML) involves a block of myeloid maturation, a desirable therapeutic strategy is to induce leukemic cell maturation to increase the efficacy and to avoid the side effects of traditional chemotherapeutics. Through a compound library screen, 6-benzylthioinosine (6BT) was identified as a promising differentiation-inducing agent. 6BT induces monocytic differentiation of myeloid leukemia cell lines such as HL-60 and OCI-AML3, as well as primary patient samples as evidenced by morphology, immunophenotyping, and nitroblue tetrazolium reduction. Not only can 6BT induce differentiation but a subset of AML cell lines such as MV4-11 and HNT34 instead undergo 6BT-mediated cell death. Despite inducing cell death in some leukemic cells, 6BT exhibits extremely low toxicity on several nonmalignant cells such as fibroblasts, normal bone marrow, and endothelial cells. This toxicity profile may relate to the function of 6BT as an inhibitor of the nucleoside transporter, ent1, which is thought to prevent it from entering many cell types. In contrast, 6BT likely enters at least some leukemic cell lines as shown by its requirement for phosphorylation for its differentiation activity. 6BT is also able to synergize with currently used myeloid differentiation agents such as ATRA and decitabine. Early studies indicate that the mechanism of action of this compound may involve ATP depletion that leads to growth inhibition and subsequent differentiation. Besides in vitro activity, 6BT also shows the ability to impair HL-60 and MV4-11 tumor growth in nude mice. 6BT is a promising new monocytic differentiation agent with apparent leukemic cell-specific activity.