Kowolik Claudia M, Lin Min, Xie Jun, Overman Larry E, Horne David A
Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA.
Department of Chemistry, University of California, Irvine, CA 92697, USA.
Oncotarget. 2016 Dec 27;7(52):86186-86197. doi: 10.18632/oncotarget.13364.
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected. The IC50 values for NT1721 were significantly lower than those for clinically used AML drugs (i.e. cytarabine, sorafenib) in all tested AML cell lines regardless of their FLT3 mutation status. Moreover, combinations of NT1721 with sorafenib or cytarabine showed better antileukemic effects than the single agents in vitro. Combining cytarabine with NT1721 also attenuated the cytarabine-induced FLT3 ligand surge that has been linked to resistance to tyrosine kinase inhibitors. Mechanistically, NT1721 depleted DNA methyltransferase 1 (DNMT1) protein levels, leading to the re-expression of silenced tumor suppressor genes and apoptosis induction. NT1721 concomitantly decreased the expression of EZH2 and BMI1, two genes that are associated with the maintenance of leukemic stem/progenitor cells. In a systemic FLT3-ITD+ AML mouse model, treatment with NT1721 reduced tumor burdens by > 95% compared to the control and significantly increased survival times. Taken together, our results suggest that NT1721 may represent a promising novel agent for the treatment of AML.
急性髓系白血病（AML）是一种侵袭性恶性肿瘤，其特征是造血祖细胞发生异质性遗传和表观遗传变化，导致异常的自我更新和增殖。尽管初始缓解率较高，但大多数AML患者的预后仍然很差，尤其是那些在Fms相关酪氨酸激酶3（FLT3）中存在内部串联重复（ITD）突变的患者。在此，我们报告一种新型环缩二硫代二酮哌嗪NT1721能有效降低FLT3-ITD+ AML细胞系的细胞活力，其半数抑制浓度（IC50）值在低纳摩尔范围内，而对正常CD34+骨髓细胞基本无影响。在所有测试的AML细胞系中，无论其FLT3突变状态如何，NT1721的IC50值均显著低于临床使用的AML药物（即阿糖胞苷、索拉非尼）。此外，NT1721与索拉非尼或阿糖胞苷联合使用在体外显示出比单一药物更好的抗白血病效果。阿糖胞苷与NT1721联合使用还减弱了阿糖胞苷诱导的FLT3配体激增，这与对酪氨酸激酶抑制剂的耐药性有关。从机制上讲，NT1721降低了DNA甲基转移酶1（DNMT1）的蛋白水平，导致沉默的肿瘤抑制基因重新表达并诱导细胞凋亡。NT1721同时降低了EZH2和BMI1的表达，这两个基因与白血病干/祖细胞的维持有关。在系统性FLT3-ITD+ AML小鼠模型中，与对照组相比，NT1721治疗使肿瘤负荷降低了> 95%，并显著延长了生存时间。综上所述，我们的结果表明NT1721可能是一种有前景的新型AML治疗药物。
