Isobavachalcone, a natural sirtuin 2 inhibitor, exhibits anti‐triple‐negative breast cancer efficacy in vitro and in vivo

• DOI: 10.1002/ptr.8143
• Publication Date: 2024-02-13T12:26:08Z
• Authors: Ya‐li Ren; Jie‐ting Lei; Ting‐rui Zhang; Peng Lu; Dan‐dan Cui; Bo Yang; Gui‐ying Zhao; Fu Peng; Zhi‐xing Cao; Cheng Peng; Yu‐zhi Li
• Keywords: SIRT2; Triple-negative breast cancer

Abstract Triple‐negative breast cancer (TNBC) is the most aggressive and lethal clinical subtype lacks effective targeted therapies at present. Isobavachalcone (IBC), main active component of Psoralea corylifolia L., has potential anticancer effects. Herein, we identified IBC as a natural sirtuin 2 (SIRT2) inhibitor characterized mechanisms underlying inhibition TNBC. Molecular dynamics analysis, enzyme activity assay, cellular thermal shift assay were performed to evaluate combination SIRT2. The therapeutic effects, mechanism, safety analyzed in vitro vivo using xenograft models. effectively inhibited SIRT2 with an IC 50 value 0.84 ± 0.22 μM by forming hydrogen bonds VAL233 ALA135 within its catalytic domain. In environment, bound stabilized SIRT2, consequently inhibiting proliferation migration, inducing apoptosis cell cycle arrest disrupting SIRT2/α‐tubulin interaction downstream Snail/MMP STAT3/c‐Myc pathways. model, 30 mg/kg markedly tumor growth targeting interaction. Furthermore, exerted effects tissues was well‐tolerated. alleviated TNBC triggering reactive oxygen species ROS/β‐catenin/CDK2 axis. It promising lead compound for future development SIRT2‐targeting drugs.