Cancer stem cells (CSC) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater antiproliferative effects on HNSCC cells compared with the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT). SVC112 preferentially inhibited cancer cells compared with patient-matched cancer-associated fibroblasts, whereas HHT was equally toxic to both. SVC112 reduced sphere formation by cell lines and CSCs. SVC112 alone inhibited the growth of patient-derived xenografts (PDX), and SVC112 combined with radiation resulted in tumor regression in HPV-positive and HPV-negative HNSCC PDXs. Notably, CSC depletion after SVC112 correlated with tumor response. SVC112 preferentially impeded ribosomal processing of mRNAs critical for stress response and decreased CSC-related proteins including Myc and Sox2. SVC112 increased cell-cycle progression delay and slowed DNA repair following radiation, enhancing colony and sphere formation radiation effects. In summary, these data demonstrate that SVC112 suppresses CSC-related proteins, enhances the effects of radiation, and blocks growth of HNSCC PDXs by inhibiting CSCs. SIGNIFICANCE: Inhibiting protein elongation with SVC112 reduces tumor growth in head and neck squamous cell carcinoma and increases the effects of radiation by targeting the cancer stem cell pool.

中文翻译：

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用SVC112抑制翻译延伸可抑制癌干细胞并抑制头颈部鳞状细胞癌的生长。

癌干细胞（CSC）驱动头颈部鳞状细胞癌（HNSCC）的生长，治疗耐药性和复发。蛋白质翻译的调控对正常干细胞和CSC至关重要。它的抑制作用可能会破坏茎的特性，但是由于毒性，翻译抑制剂在临床上受到限制。SVC112是Bouvardin（植物来源的翻译延伸抑制剂）的合成衍生物。与FDA批准的翻译抑制剂奥西他汀甲琥珀酸酯（HHT）相比，SVC112对HNSCC细胞具有更大的抗增殖作用。与患者匹配的癌症相关成纤维细胞相比，SVC112优先抑制癌细胞，而HHT对两者均具有同等毒性。SVC112减少了细胞系和CSC的球形成。单独使用SVC112可以抑制源自患者的异种移植物（PDX）的生长，SVC112与放射线结合可导致HPV阳性和HPV阴性HNSCC PDX中的肿瘤消退。值得注意的是，SVC112后的CSC耗竭与肿瘤反应相关。SVC112优先阻止对应激反应至关重要的mRNA的核糖体加工，并降低CSC相关蛋白（包括Myc和Sox2）的表达。SVC112增加了细胞周期进程的延迟，并减缓了放射后的DNA修复，从而增强了菌落和球体形成的放射效应。总之，这些数据表明，SVC112通过抑制CSCs抑制CSC相关蛋白，增强放射作用并阻止HNSCC PDXs的生长。意义：用SVC112抑制蛋白质伸长可降低头颈部鳞状细胞癌的肿瘤生长，并通过靶向癌症干细胞池增加放射作用。