The head and neck squamous cell carcinoma (HNSCC) constitute about 90% of all head and neck cancers. HNSCC falls in the top 10 cancers in men globally. Epoxyazadiradione (EPA) and Azadiradione (AZA) are the limonoids derived from the medicinal plant Azadirachta indica (popularly known as Neem). Whether or not the limonoids exhibit activities against HNSCC and the associated mechanism remains elusive. Herein, we demonstrate that EPA exhibits stronger activity in HNSCC in comparison to AZA. The limonoids obeyed the Lipinski’s rule of 5. EPA exhibited activities in a variety of HNSCC lines like suppression of the proliferation and the induction of apoptosis. The limonoid suppressed the level of proteins associated with anti-apoptosis (survivin, Bcl-2, Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9). Further, the expression of proapoptotic Bax and caspase-9 cleavage was induced by the limonoid. Exposure of EPA induced reactive oxygen species (ROS) generation in the FaDu cells. N-acetyl-L-cysteine (ROS scavenger) abrogated the down-regulation of tumorigenic proteins caused by EPA exposure. EPA induced NOX-5 while suppressing the expression of programmed death-ligand 1 (PD-L1). Further, hydrogen peroxide induced NF-κB-p65 nuclear translocation and EPA inhibited the translocation. Finally, EPA modulated the expression of lncRNAs in HNSCC lines. Overall, these results have shown that EPA exhibit activities against HNSCC by targeting multiple cancer related signalling molecules. Currently, we are evaluating the efficacy of this molecule in mice models.

头颈部鳞状细胞癌 (HNSCC) 约占所有头颈部癌症的 90%。HNSCC 属于全球男性癌症的前 10 名。Epoxyazadiradione (EPA) 和 Azadiradione (AZA) 是来自药用植物Azadirachta indica的柠檬苦素（俗称印楝）。柠檬苦素是否对 HNSCC 表现出活性以及相关机制仍然难以捉摸。在此，我们证明与 AZA 相比，EPA 在 HNSCC 中表现出更强的活性。柠檬苦素遵循Lipinski 法则5。EPA 在多种HNSCC 细胞系中表现出活性，如抑制增殖和诱导细胞凋亡。柠檬苦素抑制与抗细胞凋亡（存活蛋白、Bcl-2、Bcl-xL）、增殖（细胞周期蛋白 D1）和侵袭（MMP-9）相关的蛋白质水平。此外，柠檬苦素还能诱导促凋亡 Bax 和 caspase-9 切割的表达。暴露于 EPA 诱导 FaDu 细胞中的活性氧 (ROS) 生成。N-乙酰-L-半胱氨酸（ROS 清除剂）消除了由 EPA 暴露引起的致瘤蛋白的下调。EPA 诱导 NOX-5，同时抑制程序性死亡配体 1 (PD-L1) 的表达。此外，过氧化氢诱导 NF-κB-p65 核易位，EPA 抑制易位。最后，EPA 调节了 HNSCC 系中 lncRNA 的表达。总体而言，这些结果表明 EPA 通过靶向多种癌症相关信号分子而表现出抗 HNSCC 的活性。目前，我们正在评估这种分子在小鼠模型中的功效。