BH3模拟剂通过抑制抗凋亡BCL2蛋白发挥抗癌活性。然而，越来越多的证据表明，这些药物的非靶效应严密调节它们的抗癌活性。本研究中，我们调查了BCL2L1抑制剂A-1331852是否通过非BCL2L1靶向效应诱导U937急性髓系白血病 (AML) 细胞的死亡。A-1331852引起U937细胞的凋亡特征包括增加的ROS产生，MCL1的下调以及线粒体膜电位的丧失。MCL1的外源表达减轻了A-1331852引起的U937细胞线粒体去极化和细胞毒性。A-1331852诱导ROS的产生增加了p38 MAPK的磷酸化并抑制了MCL1的转录。p38 MAPK激活的抑制恢复了A-1331852处理的细胞中的MCL1表达。A-1331852触发的p38 MAPK介导的Cullin 3下调进一步增加了PP2Acα的表达，从而降低了CREB的磷酸化。A-1331852减少了CREB与MCL1启动子的结合，导致了CREB介导的MCL1转录的抑制。此外，A-1331852与BCL2抑制剂ABT-199在通过抑制MCL1表达诱导U937和ABT-199抗药性U937细胞死亡方面表现出协同作用。类似现象导致A-1331852引起的MCL1下调和对HL-60细胞的细胞毒性。总的来说，我们的数据表明，A-1331852显示了抑制MCL1转录的非靶效应，最终导致了U937和HL-60细胞的死亡。版权所有 © 2023. Elsevier Inc. 出版

BH3 mimetics exert anticancer activity by inhibiting anti-apoptotic BCL2 proteins. However, accumulating evidence indicates that the off-target effects of these drugs tightly modulates their anticancer activities. In this study, we investigated whether the BCL2L1 inhibitor A-1331852 induced the death of U937 acute myeloid leukemia (AML) cells through a non-BCL2L1-targeted effect. A-1331852-induced apoptosis in U937 cells was characterized by increased ROS production, downregulation of MCL1, and loss of mitochondrial membrane potential. Ectopic expression of MCL1 alleviated A-1331852-induced mitochondrial depolarization and cytotoxicity in U937 cells. A-1331852-induced ROS production increased p38 MAPK phosphorylation and inhibited MCL1 transcription. Inhibition of p38 MAPK activation restored MCL1 expression in A-1331852-treated cells. A-1331852 triggered p38 MAPK-mediated Cullin 3 downregulation, which in turn increased PP2Acα expression, thereby reducing CREB phosphorylation. A-1331852 reduced the binding of CREB to the MCL1 promoter, leading to the inhibition of CREB-mediated MCL1 transcription. Furthermore, A-1331852 acted synergistically with the BCL2 inhibitor ABT-199 to induce U937 and ABT-199-resistant U937 cell death by inhibiting MCL1 expression. A similar phenomenon caused A-1331852-induced MCL1 downregulation and cytotoxicity in AML HL-60 cells. Collectively, our data suggest that A-1331852 shows an off-target effect of inhibiting MCL1 transcription, ultimately leading to U937 and HL-60 cell death.Copyright © 2023. Published by Elsevier Inc.