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MDM2抑制剂APG-115与ABT-199协同作用，诱导慢性淋巴细胞白血病细胞凋亡。

MDM2 inhibitor APG-115 synergizes with ABT-199 to induce cell apoptosis in chronic lymphocytic leukemia.

作者信息

Cui Ying, Shao Xiaoya, Yang Haiping, Xin Jingyi, Liu Yuanyuan, Zhang Mingxiao, Sun Chuanyue, Chen Ge, Shen Guomin, Meng Xueqiong, Chen Yixiang

机构信息

Henan International Joint Laboratory of Thrombosis and Hemostasis, School of Basic Medical Science, Henan University of Science and Technology, Luoyang, China.

The Second Affiliated Hospital, Henan University of Science and Technology, Luoyang, China.

出版信息

Front Pharmacol. 2024 Jul 31;15:1441383. doi: 10.3389/fphar.2024.1441383. eCollection 2024.

DOI:10.3389/fphar.2024.1441383
PMID:39144622
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11321975/
Abstract

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.

摘要

尽管几种获批的小分子抑制剂已使慢性淋巴细胞白血病（CLL）的临床疗效有了显著改善，但获得性耐药仍会出现，导致疾病进展并最终导致死亡。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功能已被视为治疗不同癌症的一种潜在策略。我们研究了新型MDM2抑制剂APG-115对CLL的影响。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，并使细胞周期停滞在G0/G1期。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（维奈克拉）联合使用，进一步抑制了BCL-2家族抗凋亡蛋白的表达，从而增强了细胞死亡。总体而言，本研究表明APG-115激活p53，从而抑制多种促生存机制，这为APG-115在CLL中诱导细胞凋亡的有效性提供了合理的解释。APG-115与ABT-199的协同作用提示了其在CLL治疗中的潜在联合应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/ba2293dcd124/fphar-15-1441383-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/d3868d6d5aee/fphar-15-1441383-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/4f90f0025da2/fphar-15-1441383-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/115d1c7dc744/fphar-15-1441383-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/63c8c217d93c/fphar-15-1441383-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/ac290d3d96ba/fphar-15-1441383-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/ba2293dcd124/fphar-15-1441383-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/d3868d6d5aee/fphar-15-1441383-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/4f90f0025da2/fphar-15-1441383-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/115d1c7dc744/fphar-15-1441383-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/63c8c217d93c/fphar-15-1441383-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/ac290d3d96ba/fphar-15-1441383-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b918/11321975/ba2293dcd124/fphar-15-1441383-g006.jpg

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