Yuan Na, Song Lin, Zhang Suping, Lin Weiwei, Cao Yan, Xu Fei, Fang Yixuan, Wang Zhen, Zhang Han, Li Xin, Wang Zhijian, Cai Jinyang, Wang Jian, Zhang Yi, Mao Xinliang, Zhao Wenli, Hu Shaoyan, Chen Suning, Wang Jianrong
Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China
Haematologica. 2015 Mar;100(3):345-56. doi: 10.3324/haematol.2014.113324. Epub 2014 Dec 15.
B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H(+)-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia.
B细胞急性淋巴细胞白血病是儿童白血病最常见的类型。尽管缓解率有所提高，但目前用于儿童B细胞急性淋巴细胞白血病的治疗方案常常伴有不良反应和中枢神经系统复发，因此需要更有效、更安全的药物。巴佛洛霉素A1是一种液泡H(+)-ATP酶抑制剂，常用于高浓度阻断晚期自噬。在此，我们表明低浓度（1 nM）的巴佛洛霉素A1能有效且特异性地抑制并杀死儿童B细胞急性淋巴细胞白血病细胞。它通过激活雷帕霉素靶蛋白信号、解离Beclin 1-Vps34复合物以及抑制自溶酶体的形成来靶向自噬途径的早期和晚期阶段，所有这些都减弱了功能性自噬。巴佛洛霉素A1还靶向线粒体，并通过诱导凋亡诱导因子从线粒体转位至细胞核来诱导非半胱天冬酶依赖性凋亡。此外，巴佛洛霉素A1诱导Beclin 1与Bcl-2结合，这进一步抑制自噬并促进凋亡性细胞死亡。在儿童B细胞急性淋巴细胞白血病患者的原代细胞和异种移植模型中，巴佛洛霉素A1特异性地靶向白血病细胞，同时不损伤正常细胞。一项体内小鼠毒性试验证实巴佛洛霉素A1是安全的。因此，我们的数据表明巴佛洛霉素A1是治疗儿童B细胞急性淋巴细胞白血病的一种有前景的候选药物。
