Disulfiram and disulfiram-loaded poly-[lactide-co-glycolic acid] nanoparticles modulate metastatic markers and proteasomal activity in hepatocarcinoma Hep3b cell line

Abstract

Abstract Hepatocellular carcinoma (HCC) results in significantly high mortality rates due to its subtle metastatic expressions. Exorbitant costs of anticancer drugs have lead to the concept of repositioning standard drugs for their anticancer potential. One such antialcoholic drug, disulfiram (DSF), has been reported to show significant cytotoxicity (IC50 6 μM) against hepatocarcinoma cells. Hence, we studied its antimetastatic and proteasome-inhibiting potential to ascertain its efficacy against metastatic hepatocarcinoma. In addition, we also studied the influence of the components of polysorbate 80-stabilised poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) on metastastatic markers and proteasome complexes. A significant reduction in antimigratory assays (0.1 μM) and gelatin zymography (0.5 μM) was observed. A Western blot analysis furthermore confirmed the modulation of metastatic markers. Chymotrypsin-like activity was significantly inhibited at 2 μM of DSF, and in silico docking studies show comparable gliding scores of DSF against standard antimetastatic drugs. Our experiments suggest a significant antimetastatic and proteasome-inhibiting potential of DSF and its loaded NPs. We also infer that polysorbate 80 and PLGA neither show interference with drug behaviour nor inhibit metastasis and proteasome activity, thus behaving as components of a neutral vector. However, they may potentially manipulate the pharmacokinetics of DSF for achieving maximum therapeutic efficacy, in addition to targeted drug delivery.