Head and neck squamous cell carcinomas (HNSCC) are one of the deadliest forms of cancer, and 90% of its origin is from squamous cells. NAD(P)H:quinone oxidoreductase 1 (NQO1), an enzyme overexpressed in squamous cell carcinoma, plays an important role in proliferation and chemoresistance. The main aims were to study the inhibitory effect of ß-lapachone (ARQ761 in clinical form) in HNSCC and to study the combinational effect of 5-FU and ß-lap in improving the therapeutic efficacy in HNSCC. Lipid bilayer-assembled mesoporous silica nanoparticles loaded with 5-FU/ß-lap were prepared and studied for its physicochemical and biological properties. ß-lap showed a concentration-dependent inhibition of NQO1 enzyme activity in Cal33 cells. Notably, significant inhibitory effect was observed at a dose of 20-50 μg/ml of ß-lap. Combination of 5-FU+ß-lap resulted in lower cell viability; most notably, 5-FU/ß-lap-loaded mesoporous silica nanoparticles (FNQ-MSN) exhibited significantly lower cell viability compared with that of any of the individual drug or physical combinations. ß-lap resulted in a decrease in the protein band of NQO1 compared with control; however, most notable decrease in the NQO1 level was observed in the FNQ-MSN-treated cell group. FNQ-MSN resulted in more than 60% of cell apoptosis (early and late apoptosis) and predominant nuclear fragmentation of cancer cells indicating the superior anticancer effect of a carrier-based combination regimen. Notable decrease in tumor volume was observed with the physical mixture of 5-FU+ß-lap; however, combined treatment of carrier-based 5-FU and ß-lap (FNQ-MSN) significantly delayed the tumor growth and prolonged the survival of tumor-bearing xenograft mice. These findings suggest the potential of NQO1 inhibitor in enhancing the chemotherapeutic potential of 5-FU in the treatment of HNSCC.

中文翻译：

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基于介孔二氧化硅纳米颗粒的 NQO1 抑制剂和 5-氟尿嘧啶组合，对头颈鳞状细胞癌 (HNSCC) 具有有效的抗肿瘤作用。

头颈鳞状细胞癌 (HNSCC) 是最致命的癌症之一，90% 的起源来自鳞状细胞。NAD(P)H：醌氧化还原酶1 (NQO1)，一种在鳞状细胞癌中过度表达的酶，在增殖和化疗耐药中发挥重要作用。主要目的是研究β-lapachone（临床形式的ARQ761）对HNSCC的抑制作用，以及研究5-FU和ß-lap联合使用以提高HNSCC的治疗效果。制备了负载 5-FU/ß-lap 的脂质双层组装介孔二氧化硅纳米粒子，并研究了其物理化学和生物学特性。ß-lap 对 Cal33 细胞中的 NQO1 酶活性具有浓度依赖性抑制作用。值得注意的是，β-lap 剂量为 20-50 μg/ml 时观察到显着的抑制作用。5-FU+ß-lap 的组合导致细胞活力降低；最值得注意的是，与任何单独的药物或物理组合相比，5-FU/ß-lap 负载的介孔二氧化硅纳米颗粒 (FNQ-MSN) 表现出显着较低的细胞活力。与对照相比，ß-lap导致NQO1蛋白条带减少；然而，在 FNQ-MSN 处理的细胞组中观察到 NQO1 水平最显着的下降。FNQ-MSN 导致超过 60% 的细胞凋亡（早期和晚期凋亡）和癌细胞的主要核碎裂，表明基于载体的联合方案具有卓越的抗癌效果。5-FU+ß-lap 的物理混合物观察到肿瘤体积显着减小；然而，基于载体的 5-FU 和 ß-lap (FNQ-MSN) 的联合治疗显着延迟了肿瘤生长并延长了荷瘤异种移植小鼠的生存期。这些发现表明 NQO1 抑制剂有可能增强 5-FU 在 HNSCC 治疗中的化疗潜力。