Abstract：
The discovery of novel targeted agents for non-small cell lung cancer (NSCLC) remains an important research landscape due to the limited efficacy, side effects and drug resistance of current treatment options. Among many repurposed drugs, disulphiram (DSF) has shown the potential to target tumours. However, its unpleasant neurotoxicity greatly limits its use. A DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine (DS-NAC), was synthesised against NSCLC. The therapeutic effects, mechanism and toxicities of DS-NAC were evaluated in A549 and H460 cells and the mouse model of in situ lung cancer. The in vitro results exhibited that DS-NAC had potent anti-proliferation, apoptotic, anti-metastasis and epithelial-mesenchymal transition (EMT) inhibition effects. In the orthotopic lung cancer mouse model, therapeutic effects of DS-NAC were better than those of DSF and were similar to docetaxel (DTX). Also, results from western blot and immunohistochemistry showed that DS-NAC in combination with copper exerted therapeutic effects via regulating NF-κB signalling pathway and ROS-related proteins such as HIF-1α, Nrf2 and PKC-δ rather than regulating ROS level directly. Moreover, the safety evaluation study showed that DS-NAC had low haematologic and hepatic toxicities in comparison with DTX as well as low neurological toxicity compared with DSF. DS-NAC could be a promising anti-lung cancer agent with a favourable safety profile.
摘要：
由于疗效有限，发现非小细胞肺癌（NSCLC）的新型靶向药物仍然是重要的研究领域。目前治疗方案的副作用和耐药性。在许多重新利用的药物中，双硫仑（DSF）已显示出靶向肿瘤的潜力。然而,其令人不快的神经毒性极大地限制了它的使用。DSF导数，S-(N,N-二乙基二硫代氨基甲酰基-N-乙酰基-L-半胱氨酸(DS-NAC),针对NSCLC合成。治疗效果，机制，在A549和H460细胞以及原位肺癌小鼠模型中评估DS-NAC的毒性。体外实验结果表明,DS-NAC具有较强的抗增殖作用,凋亡，抗转移,和上皮-间质转化（EMT）抑制作用。在原位肺癌小鼠模型中，DS-NAC的疗效优于DSF，与多西他赛（DTX）相似。此外，Westernblot和免疫组织化学结果显示,DS-NAC与铜联合通过调节NF-κB信号通路和ROS相关蛋白如HIF-1α发挥治疗作用,Nrf2和PKC-δ，而不是直接调节ROS水平。此外，安全性评价研究显示,与DTX相比,DS-NAC的血液学和肝脏毒性较低,与DSF相比,其神经毒性较低.DS-NAC可能是一种有前途的抗肺癌药物，具有良好的安全性。
