ArticleJournal of translational medicine2023
Antileukemic effect of venetoclax and hypomethylating agents via caspase-3/GSDME-mediated pyroptosis.
Article in Journal of translational medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 16 citations in OpenAlex.
- Targeting cell death pathways in acute myeloid leukemia: Molecular mechanisms and clinical implications (Review).Oncology reports · 2025Review
- Venetoclax synergizes with Wnt/β-catenin inhibitor C-82 in acute myeloid leukemia by increasing the degradation of Mcl-1 protein.Cancer cell international · 2025Article
- Chidamide triggers pyroptosis in T-cell lymphoblastic lymphoma/leukemia via the FOXO1/GSDME axis.Chinese medical journal · 2025Article
- 5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia.Journal of nanobiotechnology · 2025Article
- FGFC1 overcomes Ara-C resistance in acute myeloid leukemia by inducing apoptosis and pyroptosis.Frontiers in pharmacology · 2025Article
- Therapeutic Drug Monitoring: A New Hope for Individualised Treatment with Venetoclax.Current drug targets · 2025Review
- TREM2, a critical activator of pyroptosis, mediates the anti‑tumor effects of piceatannol in uveal melanoma cells via caspase 3/GSDME pathwayInternational journal of molecular medicine · 2024Article
- Article
- [Research Progress on the Role of GSDME-mediated Pyroptosis in the Treatment of Lung Cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2024Review
- Gasdermin-mediated pyroptosis confers anticancer immunity.Journal for immunotherapy of cancer · 2024Article
- Case report: Clinical features of pediatric acute myeloid leukemia presenting with cardiac tamponade: a case series study and literature review.Frontiers in oncology · 2024Article
- Venetoclax and Hypomethylating Agent Combination in Myeloid Malignancies: Mechanisms of Synergy and Challenges of Resistance.International journal of molecular sciences · 2023Review
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8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe identifying of B-cell lymphoma 2 (Bcl-2) as a therapeutic target has led to a paradigm shift in acute myeloid leukemia (AML) treatment. Pyroptosis is a novel antitumor therapeutic mechanism due to its cytotoxic and immunogenic effects. The combination of venetoclax and hypomethylating agents (HMAs) has been shown to lead to durable responses and significantly improve prognosis in patients with AML. However, our understanding of the mechanisms underlying this combinatorial activity is evolving.
methodsWe investigated whether the Bcl-2 inhibitor venetoclax induces AML cell pyroptosis and identified pyroptosis effector proteins. Via using western blotting, immunoprecipitation, RNA interference, CCK8 assays, and LDH assays, we explored the mechanism underlying the pyroptotic effect. The relationship between the expression of the pyroptosis effector protein GSDME and AML prognosis was investigated. The effect of GSDME demethylation combined with venetoclax treatment on pyroptosis was investigated and confirmed in mouse models and clinical samples.
resultsVenetoclax induces pyroptosis that is mediated by caspase-3-dependent GSDME cleavage. Mechanistically, venetoclax upregulates caspase-3 and GSDME cleavage by activating the intrinsic apoptotic pathway. GSDME is downregulated in AML by promoter methylation, and low GSDME expression is significantly associated with poor prognosis, based on public databases and patient sample analysis. In vivo and in vitro experiments showed that GSDME overexpression or HMAs-mediated restoration of GSDME expression significantly increased venetoclax-induced pyroptosis in AML.
conclusionGSDME-mediated pyroptosis may be a novel aspect of the antileukemic effect of Bcl-2 inhibitors. This finding offers new insights into potential biomarkers and therapeutic strategies, identifying an important mechanism explaining the clinical activity of venetoclax and HMAs in AML.
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