Lv Huaiyou, Yang Huatian, Duan Yifei, Sha Hongyu, Zhao Zhongxi
Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
Key University Laboratory of Pharmaceutics &, Drug Delivery Systems of Shandong Province, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Jul;397(7):4747-4760. doi: 10.1007/s00210-023-02906-7. Epub 2023 Dec 26.
The exploration of novel anti-lung cancer small-molecule drugs is important for drug resistance and adverse effects of chemotherapeutic drugs in current clinics. Disulfiram (DSF), as an antidote, has been proven to have excellent antitumor effects in combination with copper (Cu). However, the risk for potential neurotoxicity and hepatotoxicity in clinical use, as well as its poor water solubility, limits its use. In this study, we identified a DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine, which could greatly increase the water solubility by converting it to a calcium salt (DS-NAC). The anti-lung cancer pharmacodynamic studies in vitro of DS-NAC were evaluated and a mouse model of lung cancer in situ was established to explore the therapeutic effects of DS-NAC compared with DSF and oxaliplatin (OXA). The results demonstrated that DS-NAC combined with Cu had superior cytotoxicity to DSF and OXA in the CCK8 assay against lung cancer cells, and exhibited potent anti-metastatic, epithelial-mesenchymal transition inhibition. In addition, DS-NAC showed better antitumor effects than DSF and comparable effects to OXA in lung cancer in situ model. In terms of the antitumor mechanism, we discovered that DS-NAC in combination with Cu exerted a greater inhibitory effect on the Notch pathway than DSF, which may account for its excellent antitumor effects. Finally, we verified the safety of DS-NAC in vivo, showing lower hepatotoxicity and neurotoxicity compared with DSF and OXA. DS-NAC is a promising anti-lung cancer drug with a favorable safety profile.
探索新型抗肺癌小分子药物对于解决当前临床化疗药物的耐药性和不良反应问题具有重要意义。双硫仑（DSF）作为一种解毒剂，已被证明与铜（Cu）联合使用时具有出色的抗肿瘤作用。然而，其临床使用中存在潜在神经毒性和肝毒性风险，以及水溶性差的问题，限制了其应用。在本研究中，我们鉴定出一种DSF衍生物，S-(N,N-二乙基二硫代氨基甲酰基)-N-乙酰-L-半胱氨酸，通过将其转化为钙盐（DS-NAC）可大大提高其水溶性。对DS-NAC进行了体外抗肺癌药效学研究，并建立了肺癌原位小鼠模型，以探讨DS-NAC与DSF和奥沙利铂（OXA）相比的治疗效果。结果表明，在CCK8法检测中，DS-NAC与Cu联合使用对肺癌细胞的细胞毒性优于DSF和OXA，并表现出强大的抗转移、抑制上皮-间质转化作用。此外，在肺癌原位模型中，DS-NAC显示出比DSF更好的抗肿瘤效果，与OXA效果相当。在抗肿瘤机制方面，我们发现DS-NAC与Cu联合使用对Notch通路的抑制作用比DSF更大，这可能是其具有出色抗肿瘤效果的原因。最后，我们在体内验证了DS-NAC的安全性，与DSF和OXA相比，其肝毒性和神经毒性更低。DS-NAC是一种具有良好安全性的有前景的抗肺癌药物。
