Bafilomycin A1

Bafilomycin A1, a macrolide antibiotic isolated from the Streptomyces species, is an inhibitor of vacuolar H ATPase (V-ATPase). Bafilomycin A1 has been used to study the autophagy as an inhibitor of autophagosomes-lysosomes fusion and as an inhibitor of lysosomal degradation.[1] It binds to the V0 sector subunit c of the V-ATPase complex and inhibits H translocation which cause an accumulation of H in the cytoplasm of treated cells. Bafilomycin A1 inhibits cell growth and leads to apoptosis and differentiation. These anticancer effects of Bafilomycin A1 are considered to be attributable to the intracellular acidosis caused by V-ATPase inhibition.^[2]

In vitro study of Bafilomycin A1 indicated that Bafilomycin A1 preferentially inhibits in vitro growth of pediatric B-cell acute lymphoblastic leukemia cells. A various of leukemia cell lines including 697, Nalm-6, RS4;11, NB4, HL-60, K562 and BV173 representing B-ALL (697, Nalm-6, RS4;11), acute myeloid leukemia (NB4, HL-60), and chronic myeloid leukemia (K562, BV173) were used to investigate the effect of Bafilomycin A1. Cells were cultured in the presence of increasing concentrations of Bafilomycin A1 (0 nM, 0.5 nM, 1 nM). Cell proliferation was measured using an MTT assay. Results showed that Bafilomycin A1 has frequently been used as an inhibitor to block the autophagosomes-lysosomes fusion, or to inhibit lysosomal activity at high doses (0.1–1 mμ). While low concentration of Bafilomycin A1 (1 nM) cpuld effectively and specifically inactivate autophagy and activate apoptosis at multiple targets in pediatric B-ALL cells.^[3]

In vivo study demonstrated that Bafilomycin A1 can extend survival in the Bafilomycin A1-treated B-ALL mice with advanced disease compared with control mice. The red blood cell counts, hemoglobin concentration, and platelet counts in the B-ALL model group were extremely reduced, however they were normalized in the Bafilomycin A1-treated group. The mice in the B-ALL model group had severe hepatosplenomegaly compared with the control group. However, the size and weight of livers and spleens in the Bafilomycin A1-treated group were normalized compared with those in the disease model group. Results showed that Bafilomycin A1 dramatically inhibits pediatric B-ALL cell engraftment by targeting leukemia cells in vivo.^[3]

References:
[1]. Yamamoto A, et al. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct. 1998;23(1):33–42.
[2] Bowman EJ, et al. The bafilomycin/concanamycin binding site in subunit c of the V-ATPases from Neurospora crassa and Saccharomyces cerevisiae. J Biol Chem. 2004;279(32):33131–33138.
[3]. Yuan N, et al. Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia. Haematologica. 2015 Mar;100(3):345-56.

巴菲霉素A1是一种大环内酯类抗生素，从链霉菌属中分离出来，它是真空泡H ATPase（V-ATPase）的抑制剂。巴菲霉素A1已被用于研究自噬作为自噬体-溶酶体融合的抑制剂和溶酶体降解的抑制剂[1]。它结合到V-ATPase复合物的V0部门亚单位c上，并抑制H转运，导致处理细胞质中H积累。巴菲霉素A1可以抑制细胞生长并导致凋亡和分化。这些对癌症的治疗效果被认为归因于由V-ATPase抑制引起的细胞内酸中毒。^[2]

在体外研究中，巴非霉素A1表明其更倾向于抑制儿童B细胞急性淋巴细胞白血病的体外生长。使用多种白血病细胞系，包括代表B-ALL（697、Nalm-6、RS4;11）、急性髓系白血病（NB4、HL-60）和慢性髓系白血病（K562、BV173）的细胞株进行了对巴非霉素A1的影响的调查。将这些细胞培养在不断增加浓度的巴非霉素A1存在下（0 nM，0.5 nM，1 nM）。使用MTT试验来测量细胞增殖情况。结果显示，在高剂量下（0.1–1 mμ），巴非霉素A1经常被用作阻止自噬体与溶酶体融合或抑制溶酶体活动的抑制剂。而低浓度下（1 nM），巴非霉素A1可以有效且特异地失活自噬并激活小儿B-ALL细胞中多个靶点上的凋亡。^[3]

实验结果表明，与对照组相比，Bafilomycin A1可以延长治疗过的B-ALL小鼠的生存期。在B-ALL模型组中，红细胞计数、血红蛋白浓度和血小板计数极其降低，但在接受Bafilomycin A1治疗的组中得到了恢复。与对照组相比，B-ALL模型组的小鼠肝脾显著增大。然而，在接受 Bafilomycin A1 治疗的组中，肝脾大小和重量与疾病模型组相当。结果显示，在体内靶向白血病细胞时， Bafilomycin A1 可以显着抑制儿童 B-ALL 细胞移植。^[3]