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Abstract：
Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients.
摘要：
液泡ATP酶（V-ATPase）被认为是癌症治疗中可能的靶标。它在原发性急性髓性白血病细胞（AML）中表达，但该表达在患者之间有所不同，对于强化化疗后预后良好的患者最高。因此，我们研究了两种V-ATPase抑制剂（巴弗洛霉素A1，康卡霉素A）对来自80例连续患者的原代AML细胞的功能作用。V-ATPase抑制剂显示出剂量依赖性的抗增殖和促凋亡作用，在患者之间差异很大。显示V-ATPase抑制的弱抗增殖作用和强抗增殖作用的原代AML细胞的蛋白质组学比较显示了参与细胞内运输/细胞骨架功能的蛋白质的差异表达。和等效的磷酸化蛋白质组比较显示了调节RNA加工/功能的蛋白质的差异表达以及酪蛋白激酶2的活性增加。继发性AML患者，即，具有一般不良预后和先前的细胞毒性治疗的异质子集，骨髓增生性肿瘤或骨髓增生异常综合征，其特征在于V-ATPase抑制的强抗增殖作用以及V-ATPase相互作用蛋白的特定mRNA表达谱。此外，V-ATPase抑制改变了几种可溶性介质的组成型细胞外释放(例如，趋化因子,白细胞介素,蛋白酶，蛋白酶抑制剂)，然后观察到在支持AML的骨髓间充质干细胞存在下介质水平升高，尤其是继发性AML患者。最后,动物研究表明，V-ATPase抑制剂巴弗洛霉素具有有限的毒性，即使与阿糖胞苷联合使用。最后，抑制V-ATP酶在AML中具有抗白血病作用，但是这种效果因患者而异。
