Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent
Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent
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DOI：
10.1182/blood-2015-07-660506
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发表时间：
2016-10-06
期刊：
影响因子：
20.3
通讯作者：
Frank, David A.
中科院分区：
文献类型：
--
作者：
Xiang, Michael;Kim, Haesook;Frank, David A.
致癌转录因子信号转导子和转录激活子 3 (STAT3) 在多种血液癌和实体癌中经常被不当激活，但临床上缺乏针对 STAT3 的可用疗法。使用计算策略来识别与 STAT3 基因表达特征相反的化合物，我们发现阿托伐醌 (Mepron)（美国食品和药物管理局批准的一种抗菌药物）是一种有效的 STAT3 抑制剂。我们发现，在人血浆中临床上常规达到的药物浓度下，阿托伐醌可抑制 STAT3 磷酸化、STAT3 靶基因的表达以及 STAT3 依赖性血液癌细胞的活力。用阿托伐醌治疗从急性髓性白血病或急性淋巴细胞白血病患者分离的原发细胞时也观察到了这些效应。 Atovaquone 不是激酶抑制剂，而是快速且特异性地下调细胞表面糖蛋白 130 的表达，而糖蛋白 130 是多种情况下 STAT3 激活所必需的。在多发性骨髓瘤小鼠模型中，给小鼠口服阿托伐醌可抑制肿瘤生长并延长生存期。最后，在接受造血干细胞移植治疗的急性髓性白血病患者中，长期使用阿托伐醌预防肺孢子虫与改善无复发生存率相关。这些发现确立了阿托伐醌作为一种新型的、临床上可用的 STAT3 抑制剂，并在动物模型和人类中均具有抗癌功效。
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron), an antimicrobial approved by the US Food and Drug Administration, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130, which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically accessible STAT3 inhibitor with evidence of anticancer efficacy in both animal models and humans.