Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo
Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo
复制标题
DOI：
10.1182/blood-2006-06-032250
复制
发表时间：
2007-04-15
期刊：
影响因子：
20.3
通讯作者：
Chen, Zhu
中科院分区：
文献类型：
--
作者：
Zhou, Guang-Biao;Kang, Hui;Chen, Zhu
研究表明，从草药中提取的一种化合物oriidonin具有潜在的抗肿瘤活性。然而，奥立冬甲素是否可以用于血液学/肿瘤学的选定环境仍然不清楚。在这里，我们报道了冬凌草苷诱导t（8;21）急性髓系白血病（AML）细胞凋亡。有趣的是，在白血病发生中起关键作用的t（8;21）产物AML1-ETO （AE）融合蛋白会随着分解代谢片段的产生而降解，而AE靶基因的表达模式可能会被重新编程。AE的异位表达增强了冬甲素对U937细胞的凋亡作用。用半胱天冬酶抑制剂预孵育可以阻断鸢尾草素引发的AE的裂解，而在融合的ETO部分的第188个残基上用Ala取代Asp则可以消除AE的降解。此外，冬凌草苷延长了携带截断的表达ae的白血病细胞的C57小鼠的寿命，而不抑制骨髓或减少动物的体重，并与阿拉伯糖胞嘧啶合用时发挥协同作用。在接种t(8;21)-载体Kasumi-1细胞的裸鼠中，oriidonin还能抑制肿瘤的生长。这些结果提示，oridonin可能是一种潜在的靶向AE癌蛋白D188残基的抗白血病药物，不良反应低，可能有助于治疗t(8;21)AML患者。
Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21)AML.