Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia.
Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia.
复制标题
DOI：
10.1016/j.exphem.2017.09.007
复制
发表时间：
2018-03
影响因子：
2.6
通讯作者：
DeGregori J
中科院分区：
文献类型：
--
作者：
Gregory MA;Nemkov T;Reisz JA;Zaberezhnyy V;Hansen KC;D'Alessandro A;DeGregori J
急性髓性白血病（AML）是一种血液癌症，对传统的细胞毒性化疗反应不良，AML的诊断通常是致命的。迫切需要更有效和耐受性更好的AML治疗方法。FMS样酪氨酸激酶3（FLT 3）的激活突变是AML中最常见的遗传缺陷之一。FLT 3抑制剂在临床试验中显示出令人印象深刻的抗白血病活性;然而，使用这些抑制剂作为单药治疗尚未实现持续缓解。我们以前的研究表明，FLT 3抑制剂引起的谷氨酰胺代谢受损是导致AML细胞死亡的主要因素。在这项研究中，我们采用了代谢通量分析，以检查FLT 3抑制对谷氨酰胺利用FLT 3突变的AML细胞使用稳定的同位素示踪剂的影响。我们发现，FLT 3抑制剂AC 220抑制谷氨酰胺流入抗氧化因子谷胱甘肽深刻由于缺陷谷氨酰胺输入。我们还发现，谷氨酰胺酶抑制剂CB-839通过有效地阻断谷氨酰胺流入谷氨酸，类似地损害谷胱甘肽的产生。此外，AC 220与CB-839的组合协同消耗谷胱甘肽，诱导线粒体活性氧，并通过凋亡性细胞死亡导致活力丧失。在体内，CB-839抑制转氨酶促进了AC 220对白血病细胞的清除，并显著改善了患者来源的异种移植AML小鼠模型的存活率。因此，靶向丙氨酸氨基转移酶与FLT 3联合可能代表了改善FLT 3突变AML治疗的有效治疗策略。
Acute myeloid leukemia (AML) is a blood cancer that is poorly responsive to conventional cytotoxic chemotherapy and a diagnosis of AML is usually fatal. More effective and better-tolerated therapies for AML are desperately needed. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are one of the most frequently observed genetic defects in AML. FLT3 inhibitors have shown impressive anti-leukemic activity in clinical trials; however, sustained remissions using these inhibitors as monotherapy have not been achieved. Our previous studies have implicated impaired glutamine metabolism in response to FLT3 inhibitors as a dominant factor causing AML cell death. In this study, we have employed metabolic flux analysis to examine the effects of FLT3 inhibition on glutamine utilization in FLT3-mutated AML cells using stable isotope tracers. We found that the FLT3 inhibitor AC220 inhibited glutamine flux into the antioxidant factor glutathione profoundly due to defective glutamine import. We also found that the glutaminase inhibitor CB-839 similarly impaired glutathione production by effectively blocking flux of glutamine into glutamate. Moreover, the combination of AC220 with CB-839 synergized to deplete glutathione, induce mitochondrial reactive oxygen species, and cause loss of viability through apoptotic cell death. In vivo, glutaminase inhibition with CB-839 facilitated leukemic cell elimination by AC220 and improved survival significantly in a patient-derived xenograft AML mouse model. Therefore, targeting glutaminase in combination with FLT3 may represent an effective therapeutic strategy for improving treatment of FLT3-mutated AML.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-14-2146
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Alvarez-Calderon F;Gregory MA;Pham-Danis C;DeRyckere D;Stevens BM;Zaberezhnyy V;Hill AA;Gemta L;Kumar A;Kumar V;Wempe MF;Pollyea DA;Jordan CT;Serkova NJ;Graham DK;DeGregori J
通讯作者：
DeGregori J
影响因子：
--
作者：
D'Alessandro A;Amelio I;Berkers CR;Antonov A;Vousden KH;Melino G;Zolla L
通讯作者：
Zolla L
影响因子：
12.8
作者：
De Kouchkovsky I;Abdul-Hay M
通讯作者：
Abdul-Hay M
影响因子：
20.3
作者：
Jacque, Nathalie;Ronchetti, Anne Marie;Bouscary, Didier
通讯作者：
Bouscary, Didier
影响因子：
20.3
作者：
Willems, Lise;Jacque, Nathalie;Bouscary, Didier
通讯作者：
Bouscary, Didier