S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine for the Treatment of Non-Small Cell Lung Cancer through Regulating NF-κB Signaling Pathway without Neurotoxicity.

AbstractThe 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, disulfiram (DSF) has shown the potential to target tumors. However, its unpleasant neurotoxicity greatly limits its use. A DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine (DS-NAC), was synthesized against NSCLC. The therapeutic effects, mechanism, and toxicities of DS-NAC were evaluated in A549 and H460 cells and the mouse model of <italic>in-situ</italic> lung cancer. The <italic>in-vitro</italic> 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 that of DSF and were similar to docetaxel (DTX). Also, results from western blot and immunohistochemistry showed that DS-NAC in combination with copper exerted the therapeutic effects via regulating NF-κB signaling 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 hematologic and hepatic toxicities in comparision with DTX as well as low neurological toxicity compared with DSF. DS-NAC could be a promising anti-lung cancer agent with a favorable safety profile. [ABSTRACT FROM AUTHOR]