Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Clin Cancer Res. 2017 Dec 15;23(24):7558-7568. doi: 10.1158/1078-0432.CCR-17-1231. Epub 2017 Oct 3.
BCR-ABL B-ALL leukemic cells are highly dependent on the expression of endogenous antiapoptotic MCL-1 to promote viability and are resistant to BH3-mimetic agents such as navitoclax (ABT-263) that target BCL-2, BCL-X, and BCL-W. However, the survival of most normal blood cells and other cell types is also dependent on Despite the requirement for MCL-1 in these cell types, initial reports of MCL-1-specific BH3-mimetics have not described any overt toxicities associated with single-agent use, but these agents are still early in clinical development. Therefore, we sought to identify approved drugs that could sensitize leukemic cells to ABT-263. A screen identified dihydroartemisinin (DHA), a water-soluble metabolite of the antimalarial artemisinin. Using mouse and human leukemic cell lines, and primary patient-derived xenografts, the effect of DHA on survival was tested, and mechanistic studies were carried out to discover how DHA functions. We further tested and whether combining DHA with ABT-263 could enhance the response of leukemic cells to combination therapy. DHA causes the downmodulation of MCL-1 expression by triggering a cellular stress response that represses translation. The repression of MCL-1 renders leukemic cells highly sensitive to synergistic cell death induced by ABT-263 in a mouse model of BCR-ABL B-ALL both and Furthermore, DHA synergizes with ABT-263 in human Ph ALL cell lines, and primary patient-derived xenografts of Ph ALL in culture. Our findings suggest that combining DHA with ABT-263 can improve therapeutic response in BCR-ABL B-ALL. .
BCR-ABL B-ALL 白血病细胞高度依赖内源性抗凋亡 MCL-1 的表达来促进生存，并且对靶向 BCL-2、BCL-X 和 BCL-W 的 BH3 模拟物（如 navitoclax [ABT-263]）耐药。然而，大多数正常血细胞和其他细胞类型的存活也依赖于 MCL-1。尽管这些细胞类型需要 MCL-1，但最初关于 MCL-1 特异性 BH3 模拟物的报告并未描述与单一药物使用相关的任何明显毒性，但这些药物仍处于临床开发的早期阶段。因此，我们试图确定可使白血病细胞对 ABT-263 敏感的已批准药物。筛选确定二氢青蒿素（DHA），一种抗疟青蒿素的水溶性代谢物。使用小鼠和人类白血病细胞系以及原发性患者来源的异种移植物，测试了 DHA 对存活的影响，并进行了机制研究以发现 DHA 的作用方式。我们进一步测试了 和 与 ABT-263 联合使用 DHA 是否可以增强白血病细胞对联合治疗的反应。DHA 通过触发抑制翻译的细胞应激反应导致 MCL-1 表达下调。MCL-1 的抑制使白血病细胞对 ABT-263 诱导的协同细胞死亡高度敏感，这在 BCR-ABL B-ALL 的小鼠模型中得到了证实。此外，DHA 与 ABT-263 在人 Ph ALL 细胞系和 Ph ALL 的原发性患者来源异种移植物的培养物中协同作用。我们的研究结果表明，将 DHA 与 ABT-263 联合使用可以改善 BCR-ABL B-ALL 的治疗反应。
