Unveiling the potency of ZnO and CuO nanocomposites in combating hepatocellular carcinoma by inducing cell death and suppressing migration

Human hepatocellular carcinoma (HCC) is recognized as one of the leading causes of death globally and is resistant to several anticancer drugs. As a result, it is critical to identify more effective druggable therapies. Metal oxide nanoparticles (MO-NPs), especially nanocomposites, have recently received much attention owing to their potential applications in cancer therapy. In this study, we synthesized zinc oxide (ZnO) and copper oxide (CuO) nanocomposites in different ratios (N1, N2, and N3). We evaluated their cytotoxicity against two HCC cell lines (HepG2 and HuH-7) and one normal liver cell (BNL), compared with Sorafenib as a standard therapy. Then, we investigated the potential underlying mechanisms of anticancer action employing flow cytometry, migration assay, and western blot. The results showed that the nanocomposite with an equal ratio of both ZnO and CuO-NPs (N1) exhibited the highest cytotoxic activity on the HuH7 cell line while exerting no detrimental impact on normal rat liver epithelial cells. Further investigation into the toxicity mechanisms of N1 revealed three modalities of induced cell death (apoptotic, necrotic, and autophagic) along with S- and G2/M cell cycle arrest, suggesting mitotic catastrophe. Furthermore, N1 displayed potent anti-migratory activity, surpassing sorafenib, upregulated the protein level of autophagy marker beclin-1, while downregulated the protein level of EMT-marker vimentin. Overall, our findings showed that combining ZnO-NPs and CuO-NPs is more intriguing in combating HCC, providing prospective guidance for evolving liver cancer therapy employing bimetallic NPs.