Department of Otorhinolaryngology Head and Neck Surgery, Lihuili Hospital affiliated to Ningbo University, Ningbo, 315040, Zhejiang, China.
School of Medicine, Ningbo University, Ningbo, China.
Eur J Med Res. 2023 Sep 9;28(1):326. doi: 10.1186/s40001-023-01289-y.
Head and neck squamous carcinoma (HNSCC) is the seventh most common cancer worldwide. Targeted therapeutic drugs for HNSCC are still being explored. Among them, (S)-10-hydroxycamptothecin (10-HCPT), a specific inhibitor of TOP1, functions by DNA double-strand breaks that can inhibit DNA replication and trigger apoptotic cell death subsequently. Previous studies have reported that MLN4924 exerts potent anti-tumor effects by inhibiting cullin-RING ligases and causing substrate accumulation in a variety of cancers. Here, we show that MLN4924 effectively causes dose-dependent accumulation of topoisomerase I (TOP1) and blocks TOP1 ubiquitination. Importantly, neddylation inhibition with MLN4924 acts synergistically with 10-HCPT to suppress cell growth, migration and apoptosis in HNSCC cells. Mechanistically, transcriptome sequencing shows that the cytotoxic effects of the combination of MLN4924 and 10-HCPT may involve activation of the NFKB1 pathway. Taken together, our results suggest that combined treatment with MLN4924 and 10-HCPT may be an effective strategy in HNSCC.
头颈部鳞状细胞癌（HNSCC）是全球第七大常见癌症。目前仍在探索用于治疗 HNSCC 的靶向治疗药物。其中，（S）-10-羟基喜树碱（10-HCPT）是 TOP1 的特异性抑制剂，通过 DNA 双链断裂发挥作用，可抑制 DNA 复制并随后引发细胞凋亡。先前的研究表明，MLN4924 通过抑制泛素连接酶 cullin-RING 并导致多种癌症中的底物积累，发挥强大的抗肿瘤作用。在这里，我们表明 MLN4924 可有效引起拓扑异构酶 I（TOP1）的剂量依赖性积累并阻止 TOP1 泛素化。重要的是，用 MLN4924 抑制 neddylation 与 10-HCPT 协同作用，抑制 HNSCC 细胞的生长、迁移和凋亡。从机制上讲，转录组测序表明 MLN4924 和 10-HCPT 联合使用的细胞毒性作用可能涉及 NFKB1 途径的激活。综上所述，我们的研究结果表明，MLN4924 和 10-HCPT 的联合治疗可能是 HNSCC 的一种有效策略。
