MDM2 inhibitor APG-115 synergizes with ABT-199 to induce cell apoptosis in chronic lymphocytic leukemia
Ying Cui1, Xiaoya Shao2, Haiping Yang3
1Henan International Joint Laboratory of Thrombosis and Hemostasis, School of Basic Medical Science, Henan University of Science and Technology, Luoyang, China.
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.
Insights
Novel MDM2 inhibitor APG-115 shows promise for chronic lymphocytic leukemia (CLL) therapy by activating p53, inducing apoptosis, and enhancing cell death. Combination with ABT-199 (venetoclax) further boosts efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chronic lymphocytic leukemia (CLL) treatment faces challenges due to acquired resistance to existing therapies.
- Restoring p53 tumor suppressor function by inhibiting MDM2-p53 interaction is a potential therapeutic strategy for cancers.
Purpose of the Study:
- To investigate the efficacy of the novel MDM2 inhibitor APG-115 in chronic lymphocytic leukemia (CLL).
- To explore the combination therapy of APG-115 with the BCL2 inhibitor ABT-199 (venetoclax) in CLL.
Main Methods:
- Treatment of CLL cells with APG-115 to assess effects on p53, MDM2, p21 expression, cell proliferation, apoptosis, and cell cycle.
- Analysis of anti-apoptotic protein expression (BCL-2, BCL-xL, MCL-1) and signaling pathways (AKT, ERK).
- Evaluation of combined APG-115 and ABT-199 treatment on CLL cell death.
Main Results:
- APG-115 upregulated p53, MDM2, and p21, inhibited proliferation, induced apoptosis, and caused G0/G1 cell cycle arrest.
- APG-115 suppressed pro-survival proteins BCL-2, BCL-xL, MCL-1 and inhibited AKT/ERK pathways.
- Combination of APG-115 and ABT-199 enhanced CLL cell death synergistically.
Conclusions:
- APG-115 activates p53, inhibiting pro-survival mechanisms and inducing apoptosis in CLL.
- The synergistic effect of APG-115 and ABT-199 suggests a promising combination therapy for CLL.
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