A cisplatin and disulfiram co-loaded inclusion complex overcomes drug resistance by inhibiting cancer cell stemness in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) accounting for about 80-85% of all lung cancer cases is one of the fastest-growing malignancies in terms of incidence and mortality worldwide and is commonly treated with cisplatin (DDP). Although treatment may initially be effective, the DDP therapy often leads to the development of chemoresistance and treatment failure. Disulfiram (DSF), an old alcohol-aversion drug, has been revealed to help reverse drug resistance in several cancers. In addition, several studies have shown a close relationship between drug resistance and cancer cell stemness. In this study, DDP and DSF were embedded in hydroxypropyl-β-cyclodextrin (CD) to prepare a co-loaded inclusion complex of DDP and DSF (DDP-DSF/CD) with enhanced solubility and therapeutic effects. The effects and mechanism of DSF on the DDP resistance from the perspective of cancer cell stemness were determined. Our data show that DDP-DSF/CD increased cytotoxicity and apoptosis of DDP-resistant A549 (A549/DDP) cells, inhibited stem cell transcriptional regulatory genes and drug resistance-associated proteins and reversed the DDP resistance in vitro and in vivo. Overall, DDP-DSF/CD could be a promising formulation for the reversal of DDP resistance in NSCLC by inhibiting cancer cell stemness.