Carcinogenesis. 2023 Apr 13. pii: bgad020. [Epub ahead of print]
Sulfasalazine (SAS) is a repurposed antitumor drug which inhibits the proliferation and survival of cancer cells by inhibiting the xCT cellular antioxidant system. Recent clinical studies have shown that, due to poor bioavailability, the antitumor effects of SAS monotherapy are minimal. Therefore, we hypothesized that DSF, another repurposed drug that has demonstrated anti-cancer effects, or its complex with copper (DSF-copper, DSF-Cu) could potentiate the anti-lung cancer effects of SAS. Exposure of non-small cell lung cancer (NSCLC) cells to therapeutically achievable concentrations of SAS induced low to moderate cytotoxic effects (20-40% reduction in cell viability) and, unexpectedly, induced the antioxidant protein NRF2 and its downstream effectors xCT and ALDH1A1. However, combinations of SAS and DSF-Cu, but not SAS and DSF, induced a significantly higher cytotoxic effect (64-88% reduction in cell viability), apoptosis and generation of mitochondrial reactive oxygen species (mROS) as compared to SAS or DSF-Cu alone. Moreover, DSF-Cu abrogated SAS-induced NRF2, xCT and ALDH1A1 expression. In a mouse model of lung tumor, SAS + DSF-Cu showed a higher efficacy than the individual drugs in reducing the number and size of tumors as well as the incidence and multiplicity of lung adenocarcinoma. Taken together, our findings indicate that the observed anti-lung cancer effects of SAS plus DSF-Cu are mediated, at least in part, via impairment of ROS defense and enhancement of oxidative stress and provide evidence for the preventive/therapeutic potential of this combinatorial approach against lung cancer.
Keywords: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); disulfiram (DSF); lung tumor; mice; sulfasalazine (SAS)