摘要
急性髓细胞白血病(AML)中造血干细胞和祖细胞的分化堵塞导致血细胞减少和死亡的高风险。大多数AML患者由于缺乏有效的细胞毒性和促分化物而产生抗药性。高MN1表达使AML患者预后差,并诱导阿糖胞苷和全反式维甲酸(ATRA)诱导的抗分化。采用高通量筛选,我们确定了二氢叶酸还原酶(DHFR)拮抗剂乙胺嘧啶能有效的诱导小鼠和人白血病细胞株凋亡和分化。口服药物治疗在两个异种移植小鼠模型中是有效的,并且专门针对人类AML细胞株白血病细胞和原代细胞,而健康人的CD34+细胞不受影响。PMT的抗白血病的影响可以通过过量的叶酸部分减弱,提示在AML中叶酸代谢的致癌作用。因此,我们的研究确定了乙胺嘧啶作为候选药物,应进一步评估在AML的治疗。
关键词: AML,细胞凋亡,分化和DHFR,高通量药物筛选
Current Cancer Drug Targets
Title:Pyrimethamine as a Potent and Selective Inhibitor of Acute Myeloid Leukemia Identified by High-throughput Drug Screening
Volume: 16 Issue: 9
Author(s): Amit Sharma, Nidhi Jyotsana, Courteney K. Lai, Anuhar Chaturvedi, Razif Gabdoulline, Kerstin Görlich, Cecilia Murphy and Jan E. Blanchard, Arnold Ganser, Eric Brown, John A. Hassell, R. Keith Humphries, Michael Morgan, Michael Heuser
Affiliation:
关键词: AML,细胞凋亡,分化和DHFR,高通量药物筛选
摘要: Hematopoietic stem and progenitor cell differentiation are blocked in acute myeloid leukemia (AML) resulting in cytopenias and a high risk of death. Most patients with AML become resistant to treatment due to lack of effective cytotoxic and differentiation promoting compounds. High MN1 expression confers poor prognosis to AML patients and induces resistance to cytarabine and alltrans-retinoic acid (ATRA) induced differentiation. Using a high-throughput drug screening, we identified the dihydrofolate reductase (DHFR) antagonist pyrimethamine to be a potent inducer of apoptosis and differentiation in several murine and human leukemia cell lines. Oral pyrimethamine treatment was effective in two xenograft mouse models and specifically targeted leukemic cells in human AML cell lines and primary patient cells, while CD34+ cells from healthy donors were unaffected. The antileukemic effects of PMT could be partially rescued by excess folic acid, suggesting an oncogenic function of folate metabolism in AML. Thus, our study identifies pyrimethamine as a candidate drug that should be further evaluated in AML treatment.
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Cite this article as:
Amit Sharma, Nidhi Jyotsana, Courteney K. Lai, Anuhar Chaturvedi, Razif Gabdoulline, Kerstin Görlich, Cecilia Murphy and Jan E. Blanchard, Arnold Ganser, Eric Brown, John A. Hassell, R. Keith Humphries, Michael Morgan, Michael Heuser , Pyrimethamine as a Potent and Selective Inhibitor of Acute Myeloid Leukemia Identified by High-throughput Drug Screening, Current Cancer Drug Targets 2016; 16 (9) . https://dx.doi.org/10.2174/1568009616666160617103301
DOI https://dx.doi.org/10.2174/1568009616666160617103301 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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