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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1441383
This article is part of the Research Topic The Future of Hematologic Malignancy Treatment: Novel Target Discovery and Epigenetic Drug Development View all 5 articles

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

Provisionally accepted
Ying Cui Ying Cui 1Xiaoya Shao Xiaoya Shao 2Haiping Yang Haiping Yang 3Jingyi Xin Jingyi Xin 3Yuanyuan Liu Yuanyuan Liu 1Mingxiao Zhang Mingxiao Zhang 4Chuanyue Sun Chuanyue Sun 1Ge Chen Ge Chen 4Guomin Shen Guomin Shen 1Xueqiong Meng Xueqiong Meng 4Yixiang Chen Yixiang Chen 4*
  • 1 Henan University of Science and Technology, Luoyang, China
  • 2 Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan Province, China
  • 3 The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan Province, China
  • 4 Luoyang Polytechnic, Luoyang, Henan Province, China

The final, formatted version of the article will be published soon.

    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, , 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.

    Keywords: chronic lymphocytic leukemia, APG-115, Apoptosis, ABT-199, combination

    Received: 31 May 2024; Accepted: 16 Jul 2024.

    Copyright: © 2024 Cui, Shao, Yang, Xin, Liu, Zhang, Sun, Chen, Shen, Meng and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Yixiang Chen, Luoyang Polytechnic, Luoyang, Henan Province, China

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