Department of Surgery, University of Michigan, USA.
Department of Otolaryngology Head & Neck Surgery, University of Michigan, USA.
Neoplasia. 2017 Dec;19(12):1003-1011. doi: 10.1016/j.neo.2017.09.003. Epub 2017 Nov 6.
Advanced head and neck squamous cell carcinoma (HNSCC) remains a therapeutic challenge due to the development of therapy resistance. Several studies have implicated the development of cancer stem cells as a possible mechanism for therapy resistance in HNSCC. Heat shock protein 90's (Hsp90's) molecular chaperone function is implicated in pathways of resistance in HNSCC. Therefore, in the present study, we investigated the efficacy of novel C-terminal Hsp90 inhibitors (KU711 and KU757) in targeting HNSCC cancer stem cells (CSCs). Treatment of HNSCC human cell lines MDA1986, UMSCC 22B, and UMSCC 22B cisplatin-resistant cells with the KU compounds indicated complete blockage of self-renewal for the resistant and parent cell lines starting from 20 μM KU711 and 1 μM KU757. Dose-dependent decrease in the cancer stem cell markers CD44, ALDH, and CD44/ALDH double-positive cells was observed for all cell lines after treatment with KU711 and KU757. When cells were treated with either drug, migration and invasion were downregulated greater than 90% even at the lowest concentrations of 20 μM KU711 and 1 μM KU757. Western blot showed >90% reduction in client protein "stemness" marker BMI-1 and mesenchymal marker vimentin, as well as increase in epithelial marker E-cadherin for both cell lines, indicating epithelial to mesenchymal transition quiescence. Several CSC-mediated miRNAs that play a critical role in HNSCC therapy resistance were also downregulated with KU treatment. In vivo, KU compounds were effective in decreasing tumor growth with no observed toxicity. Taken together, these results indicate that KU compounds are effective therapeutics for targeting HNSCC CSCs.
高级头颈部鳞状细胞癌（HNSCC）仍然是一个治疗挑战，因为治疗耐药性的发展。几项研究表明，癌症干细胞的发展可能是 HNSCC 治疗耐药性的一种机制。热休克蛋白 90 的（Hsp90 的）分子伴侣功能在 HNSCC 的耐药途径中被牵连。因此，在本研究中，我们研究了新型 C 端 Hsp90 抑制剂（KU711 和 KU757）在靶向 HNSCC 癌症干细胞（CSC）中的疗效。用 KU 化合物处理 HNSCC 人细胞系 MDA1986、UMSCC 22B 和 UMSCC 22B 顺铂耐药细胞，结果表明，从 20 μM KU711 和 1 μM KU757 开始，耐药和亲本细胞系的自我更新完全被阻断。在用 KU711 和 KU757 处理后，所有细胞系的癌症干细胞标记物 CD44、ALDH 和 CD44/ALDH 双阳性细胞均呈剂量依赖性减少。当用任一药物处理时，即使在 20 μM KU711 和 1 μM KU757 的最低浓度下，迁移和侵袭也下调超过 90%。Western blot 显示，两种细胞系的客户蛋白“干性”标记物 BMI-1 和间充质标记物波形蛋白的减少超过 90%，以及上皮标记物 E-钙粘蛋白的增加，表明上皮-间充质转化静止。几种在 HNSCC 治疗耐药性中起关键作用的 CSC 介导的 miRNA 也随着 KU 治疗而下调。在体内，KU 化合物可有效抑制肿瘤生长，无明显毒性。综上所述，这些结果表明 KU 化合物是靶向 HNSCC CSC 的有效治疗药物。
