索拉非尼（Sor）是唯一获批治疗HCC的多激酶抑制剂。先前的研究表明，杏仁苷（Amy）对多种癌细胞系具有抗癌活性；我们推测这些化合物可能干扰AMPK/mTOR和BCL-2。因此，本研究使用综合体外和体内模拟方法来确定Amy和Sor在靶向AMPK/mTOR和BCL-2方面的可能协同作用，以用于抑制HepG2细胞的抗血管生成和凋亡细胞死亡。值得注意的是，与正常WI-38细胞相比，Amy对HepG2细胞表现出异常的细胞毒性选择性（IC50 = 5.21 mg/ml；141.25 mg/ml）。相反，WI-38细胞对Sor的毒性更敏感。观察到Amy和Sor之间存在显著的协同作用（CI50 = 0.56），该作用与细胞周期在S和G2/M阶段的停滞、增加的凋亡和潜在的坏死有关。Amy和Sor联合治疗导致最高的谷胱甘肽水平，并诱导AMPK、HGMB1、ATG5、Beclin 1和LC3等前自噬基因的表达，抑制mTOR和BCL2等抗凋亡基因的表达。最后，对接研究表明，Amy与AMPK酶的活性位点结合，从而抑制其活性。AMPK的抑制最终导致mTOR的抑制，从而在HepG2细胞中诱导凋亡。尽管需要更多使用动物模型进行的体内研究来确认这些发现，我们的研究结果有助于支持Amy作为治疗HCC的替代治疗选择的潜在抗癌有效性证据。© 2023. Springer Nature旗下BioMed Central Ltd.

Sorafenib (Sor) is the only approved multikinase inhibitor indicated for the treatment of HCC. Previous studies have shown that amygdalin (Amy) possesses anticancer activities against several cancer cell lines; we suggested that these compounds might disrupt AMPK/mTOR and BCL-2. Therefore, the current study used integrated in vitro and in silico approaches to figure out Amy and Sor's possible synergistic activity in targeting AMPK/mTOR and BCL-2 for anti-angiogenesis and apoptosis cell death in HepG2 cells.Notably, Amy demonstrated exceptional cytotoxic selectivity against HepG2 cells in comparison to normal WI-38 cells (IC50 = 5.21 mg/ml; 141.25 mg/ml), respectively. In contrast, WI-38 cells were far more sensitive to the toxicity of Sor. A substantial synergistic interaction between Amy and Sor was observed (CI50 = 0.56), which was connected to cell cycle arrest at the S and G2/M stages and increased apoptosis and potential necroptosis. Amy and Sor cotreatment resulted in the highest glutathione levels and induction of pro-autophagic genes AMPK, HGMB1, ATG5, Beclin 1, and LC3, suppressed the mTOR and BCL2 anti-apoptotic gene. Finally, the docking studies proposed that Amy binds to the active site of the AMPK enzyme, thus inhibiting its activity. This inhibition of AMPK ultimately leads to inhibition of mTOR and thus induces apoptosis in the HepG2 cells.Although more in vivo research using animal models is needed to confirm the findings, our findings contribute to the evidence supporting Amy's potential anticancer effectiveness as an alternative therapeutic option for HCC.© 2023. BioMed Central Ltd., part of Springer Nature.