S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine for the treatment of non-small cell lung cancer through regulating NF-κB signalling pathway without neurotoxicity

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.

Keywords:

• Disulphiram derivative
• S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine
• Neurotoxicity
• NF-κB
• ROS
• NSCLC

Ethical approval

All animal treatments were performed in accordance with the institutional guidelines of the Animal Care and Use Committee of Shandong University (No. 2016020, Jinan, China).

Author contributions

Huaiyou Lv: conceptualisation, methodology, validation, investigation, formal analysis and writing – original draft. Huatian Yang: visualisation and writing – review and editing. Yifei Duan: formal analysis. Chongzheng Yan: validation. Genju Li: resources (synthesise DS-NAC). Guozhi Zhao: validation. Fengqin Sun: investigation. Yafei Feng: investigation. Yuhan Li: investigation. Yaqing Fu: investigation. Yizhe Li: investigation. Xiumei Jia: supervision. Zhongxi Zhao: funding acquisition, writing – review and editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

Additional information

Funding

This work was partially funded by the Key R&D Programs of Shandong Province, China (Grant Nos. 2018CXGC1411 and 2021CXGC010514).