Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high-throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) β. ERβ expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERβ were sensitive, whereas cells with low ERβ were insensitive to diosmetin. Knockdown of ERβ confirmed resistance, whereas overexpression enhanced sensitivity to diosmetin, which was demonstrated to be mediated by reactive oxygen species signaling. In summary, these studies highlight targeting of ERβ with diosmetin as a potential novel therapeutic strategy for the treatment of AML. Mol Cancer Ther; 16(11); 2618–26. ©2017 AACR .

中文翻译：

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雌激素受体{beta}是急性髓细胞白血病的新型靶标

急性髓细胞性白血病（AML）是一种破坏性疾病，其特征是患者预后差且化疗效果欠佳。在此，高通量筛选确定了具有抗AML活性的薯os类黄酮（Diosmetin），一种柑橘类黄酮。薯met皂素在体外和体内均赋予针对白血病和白血病干细胞的选择性毒性，而对正常造血干细胞没有影响。从机理上讲，我们证明了薯os皂素可靶向雌激素受体（ER）β。ERβ表达赋予细胞敏感性，因为来自患者的ERβ高水平的AML细胞敏感，而具有低ERβ的细胞对Diosmetin不敏感。ERβ的敲低证实了耐药性，而过表达增强了对diosmetin的敏感性，这被证明是由活性氧信号介导的。总之，这些研究突出了用薯os皂素靶向ERβ作为一种潜在的新型AML治疗策略。分子癌疗法；16（11）; 2618–26。©2017 AACR。