Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T cells, frequently driven by MYC overexpression. A reciprocal activation between MYC and aurora B kinase (AURKB) is essential for leukemogenesis. Hesperadin, an AURKB inhibitor, is hypothesized to suppress T-ALL through MYC downregulation. Chidamide, a histone deacetylase (HDAC) inhibitor approved for T-cell lymphoma, has shown synergistic effects with other anti-leukemia agents. This study investigates the anti-leukemic potential of hesperadin alone or in combination with chidamide and explores the underlying mechanisms in T-ALL.

Methods: Cytotoxicity of hesperadin and chidamide was evaluated in T-ALL cell lines (CCRF-CEM, Jurkat, Molt-4) using CCK-8 assays. In vivo efficacy was assessed using T-ALL xenograft models. IC₅₀ values were calculated in GraphPad Prism, and drug synergy analyzed via CompuSyn. Flow cytometry and Western blot were used for evaluation of apoptosis, cell cycle changes, and key signaling pathways. MYC protein turnover was evaluated by cycloheximide pulse-chase assays.

Results: Hesperadin showed potent, time- and dose-dependent cytotoxicity in T-ALL cells (IC₅₀: 0.14–0.4 µM), inducing apoptosis via Bax upregulation and BCL2/MCL1 downregulation. It also caused G₂/M arrest with decreased CDK1 and Cyclin B levels. Hesperadin did not affect MYC mRNA but promoted MYC protein degradation and reduced its half-life. Combined with chidamide, hesperadin synergistically inhibited cell proliferation (CI < 1.0 in all lines) and further reduced MYC protein levels. The combination also significantly suppressed tumor growth in vivo.

Conclusion: Hesperadin synergizes with chidamide to inhibit T-ALL progression by promoting MYC degradation, supporting a promising combination strategy for T-ALL therapy.

Keywords: T cell acute lymphoblastic leukemia, hesperadin, c-MYC, chidamide, aurora kinase B

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2025
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