Zhang Siwei, Schneider Lina S, Vick Binje, Grunert Michaela, Jeremias Irmela, Menche Dirk, Müller Rolf, Vollmar Angelika M, Liebl Johanna
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany.
Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
Oncotarget. 2015 Dec 22;6(41):43508-28. doi: 10.18632/oncotarget.6180.
Prognosis for patients suffering from T-ALL is still very poor and new strategies for T-ALL treatment are urgently needed. Our study shows potent anti-leukemic effects of the myxobacterial V-ATPase inhibitor Archazolid A. Archazolid A reduced growth and potently induced death of leukemic cell lines and human leukemic samples. By inhibiting lysosomal acidification, Archazolid A blocked activation of the Notch pathway, however, this was not the mechanism of V-ATPase inhibition relevant for cell death induction. In fact, V-ATPase inhibition by Archazolid A decreased the anti-apoptotic protein survivin. As underlying mode of action, this work is in line with recent studies from our group demonstrating that Archazolid A induced S-phase cell cycle arrest by interfering with the iron metabolism in leukemic cells. Our study provides evidence for V-ATPase inhibition as a potential new therapeutic option for T-ALL.
T细胞急性淋巴细胞白血病（T-ALL）患者的预后仍然很差，因此迫切需要T-ALL治疗的新策略。我们的研究表明，粘细菌V-ATP酶抑制剂阿奇唑立德A具有强大的抗白血病作用。阿奇唑立德A可抑制白血病细胞系和人类白血病样本的生长，并有效诱导其死亡。通过抑制溶酶体酸化，阿奇唑立德A阻断了Notch信号通路的激活，然而，这并不是其抑制V-ATP酶从而诱导细胞死亡的机制。事实上，阿奇唑立德A对V-ATP酶的抑制作用降低了抗凋亡蛋白存活素的水平。作为潜在的作用模式，这项研究与我们团队最近的研究一致，即阿奇唑立德A通过干扰白血病细胞的铁代谢诱导S期细胞周期停滞。我们的研究为抑制V-ATP酶作为T-ALL潜在的新治疗选择提供了证据。
