虽然慢性淋巴细胞白血病 (CLL) 的临床结果在几种已批准的小分子抑制剂的作用下得到了极大改善，但获得性耐药确实发生，导致疾病进展并最终死亡。因此，需要努力探索新型抑制剂和联合治疗方案。抑制MDM2-p53相互作用以恢复p53功能被认为是治疗不同癌症的潜在策略。我们研究了新型 MDM2 抑制剂 APG-115 在 CLL 中的作用。我们发现 APG-115 处理在 mRNA 和蛋白质水平上调了 p53、MDM2 和 p21 的表达。 APG-115 抑制细胞增殖，诱导细胞凋亡，并将细胞周期阻滞在 G0/G1 阶段。此外，APG-115 抑制 BCL-2、BCL-xL 和 MCL-1 的表达，并抑制 AKT 和 ERK 信号通路的激活。 APG-115 与 BCL2 抑制剂 ABT-199 (venetoclax) 结合，可进一步抑制 BCL-2 家族抗凋亡蛋白的表达，从而增强细胞死亡。总的来说，这项研究表明 APG-115 激活 p53，从而抑制多种促生存机制，这为 APG-115 诱导 CLL 细胞凋亡的效率提供了合理的解释。 APG-115 与 ABT-199 的协同作用表明其在 CLL 治疗中的潜在联合应用。版权所有 © 2024 Cui、Shao、Yang、Xin、Liu、Zhang、Sun、Chen、Shen、Meng 和 Chen。

Although clinical outcomes in chronic lymphocytic leukemia (CLL) have greatly improved with several approved small molecular inhibitors, acquired resistance does occur, leading to disease progression and eventual death. Thus, the effort to explore novel inhibitors and combination therapeutic regimens is needed. The inhibition of MDM2-p53 interaction to restore p53 function has been regarded as a potential strategy for treating different cancers. We investigated the effects of novel MDM2 inhibitor APG-115 in CLL. We found that APG-115 treatment upregulated the expression of p53, MDM2, and p21 at the mRNA and protein level. APG-115 inhibited cell proliferation, induced apoptosis, and arrested the cell cycle at G0/G1 stage. Moreover, APG-115 inhibited the expression of BCL-2, BCL-xL, and MCL-1, and suppressed the activation of AKT and ERK signaling pathways. APG-115 combined with the BCL2 inhibitor, ABT-199 (venetoclax), led to further inhibition of the expression of BCL-2 family anti-apoptotic proteins and consequently enhanced cell death. Collectively, this study demonstrates that APG-115 activates p53 and thus inhibits multiple pro-survival mechanisms, which provides a rational explanation for APG-115 efficiency in inducing cell apoptosis in CLL. The synergistic effect of APG-115 with ABT-199 suggested a potential combination application in CLL therapy.Copyright © 2024 Cui, Shao, Yang, Xin, Liu, Zhang, Sun, Chen, Shen, Meng and Chen.