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December 8, 2025BloodOpen Access

TP53 activation by the natural quassinoid brusatol enhances venetoclax efficacy and overcomes resistance in myeloid leukemias

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Authors

SKShin‐ichiro KawaguchiNTNorihito TakayamaHHHiroko Hayakawa

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Overview

In vitro analysis shows brusatol synergizes with venetoclax to induce apoptosis in AML, indicating a novel approach to overcome drug resistance.

Key Points

  • To investigate how brusatol enhances venetoclax efficacy and overcomes resistance in acute myeloid leukemia (AML).
  • Utilized five human AML cell lines including MOLM-14 and HL60 for experiments.
  • Generated a venetoclax-resistant MOLM-14 variant for comparative analysis.
  • Conducted RNA-seq after treatment with venetoclax, brusatol, or their combination.
  • Established cell line-derived xenograft models to assess in vivo efficacy.
  • Brusatol induced apoptosis in AML cell lines, notably enhancing venetoclax efficacy.
  • Synergy analysis confirmed significant interaction between brusatol and venetoclax against resistant AML cells.
  • The combination therapy improved survival in xenograft models compared to single agents.

Cite This Study

Kawaguchi et al. (2025) studied this question.

synapsesocial.com/papers/69362f604fa91c937236dcd9https://doi.org/10.1182/blood-2025-1491
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance2026
  2. 2Synergistic antitumor effects and mechanisms of KPT-330 combined with venetoclax in Acute Myeloid Leukemia2025
  3. 3ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells2024 · 6 citations
  4. 4The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells2019 · 381 citations
  5. 5Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl pyrophosphate2025 · 1 citations