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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

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[Inhibition of NF-kB Activation Decreases Resistance in Acute Myeloid Leukemia Cells to TRAIL-induced Apoptosis in

R S Fadeev, M E Solovieva, D A Slyadovskiy

    Biofizika
    |February 5, 2016
    PubMed

    Insights

    Small molecule inhibitors targeting nuclear factor-kappa B (NF-kB) activation suppressed resistance in acute myeloid leukemia cells within multicellular aggregates to TRAIL-induced apoptosis. These compounds reduced cell resistance by inhibiting NF-kB signaling pathways.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cell Biology

    Context:

    • Acute myeloid leukemia (AML) cells exhibit resistance to TRAIL-induced apoptosis, particularly within multicellular aggregates.
    • Nuclear factor-kappa B (NF-kB) signaling is implicated in mediating this resistance.
    • Multicellular aggregate formation presents a unique microenvironment that can influence drug response.

    Purpose:

    • To investigate the efficacy of small molecule inhibitors of NF-kB activation in overcoming TRAIL resistance in AML cells.
    • To determine if inhibiting NF-kB signaling can sensitize AML cells in multicellular aggregates to recombinant protein izTRAIL.
    • To elucidate the role of NF-kB pathway activation, specifically RelA (p65) phosphorylation, in TRAIL resistance.

    Summary:

    • Non-toxic concentrations of NF-kB Activation Inhibitor IV and JSH-23 were used to treat AML cells in multicellular aggregates.
    • Both inhibitors successfully reduced the resistance of AML cells to the cytotoxic effects of recombinant protein izTRAIL.
    • Treatment with these inhibitors led to decreased phosphorylation of RelA (p65), a key marker of NF-kB activation.

    Impact:

    • This study highlights a potential therapeutic strategy to enhance the effectiveness of TRAIL-based therapies in AML by targeting NF-kB.
    • Understanding the mechanisms of resistance in multicellular aggregates can inform the development of more effective AML treatments.
    • The findings suggest that combination therapies involving NF-kB inhibitors and TRAIL agonists may be beneficial for overcoming drug resistance in AML.

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