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Abstract：
Amongst the most prevalent malignancies worldwide, head and neck squamous cell carcinoma (HNSCC) is characterized by high morbidity and mortality. The failure of standard treatment modalities, such as surgery, radiotherapy, and chemotherapy, demands the need for in-depth understanding of the complex signaling networks involved in the development of treatment resistance. A tumor\'s invasive growth and high levels of intrinsic or acquired treatment resistance are the primary causes of treatment failure. This may be a result of the presence of HNSCC\'s cancer stem cells, which are known to have self-renewing capabilities that result in therapeutic resistance. Using bioinformatics methods, we discovered that elevated expressions of MET, STAT3, and AKT were associated with poor overall survival in HNSCC patients. We then evaluated the therapeutic potential of our newly synthesized small molecule HNC018 towards its potential as a novel anticancer drug. Our computer-aided structure characterization and target identification study predicted that HNC018 could target these oncogenic markers implicated in HNSCC. Subsequently, the HNC018 has demonstrated its anti-proliferative and anticancer activities towards the head and neck squamous cell carcinoma cell lines, along with displaying the stronger binding affinities towards the MET, STAT3, and AKT than the standard drug cisplatin. Reduction in the clonogenic and tumor-sphere-forming ability displays HNC018\'s role in decreasing the tumorigenicity. Importantly, an vivo study has shown a significant delay in tumor growth in HNC018 alone or in combination with cisplatin-treated xenograft mice model. Collectively with our findings, HNC018 highlights the desirable properties of a drug-like candidate and could be considered as a novel small molecule for treating head and neck squamous cell carcinoma.
摘要：
在全世界最常见的恶性肿瘤中，头颈部鳞状细胞癌（HNSCC）的特点是发病率和死亡率高。标准治疗方式的失败，比如手术，放射治疗,和化疗，需要深入了解与治疗抗性发展有关的复杂信号网络。肿瘤的侵袭性生长和高水平的内在或获得性治疗抗性是治疗失败的主要原因。这可能是HNSCC的癌症干细胞的存在的结果，已知它们具有自我更新能力，导致治疗抗性。使用生物信息学方法，我们发现MET的表达升高，STAT3和AKT与HNSCC患者总体生存率低相关。然后，我们评估了我们新合成的小分子HNC018作为新型抗癌药物的潜力。我们的计算机辅助结构表征和靶标鉴定研究预测，HNC018可以靶向这些与HNSCC有关的致癌标记。随后，HNC018已证明其对头颈部鳞状细胞癌细胞系的抗增殖和抗癌活性，随着对MET表现出更强的结合亲和力，STAT3和AKT比标准药物顺铂。克隆形成和肿瘤球体形成能力的降低显示了HNC018在降低致瘤性中的作用。重要的是,一项体内研究显示,在HNC018单独或联合顺铂治疗的异种移植小鼠模型中,肿瘤生长显著延迟.结合我们的发现，HNC018突出了药物样候选物的理想特性，可以被认为是治疗头颈部鳞状细胞癌的新型小分子。
