Gold(I) complexes bearing EGFR-inhibiting ligands as anti-HCC agents through dual targeting of EGFR and TrxR.

Overexpression of epidermal growth factor receptor (EGFR) and thioredoxin reductase (TrxR) are commonly associated with an adverse prognosis in hepatocellular carcinoma (HCC). This makes them key targets for the treatment of HCC. Studies have shown that the clinical efficacy of the EGFR tyrosine kinase inhibitor gefitinib alone in treating HCC is limited. Herein, we developed a series of novel gold(I) complexes using a "dual-targeting strategy" by combining gold(I) complexes with different gefitinib derivatives. Among them, the best complex 6g exhibits significant antiproliferative activity against Huh7 cells and Huh7R (lenvatinib-resistant) cells. Remarkably, complex 6g inhibits the expression of phosphorylated EGFR while also effectively inhibiting intracellular TrxR activity. In addition, complex 6g causes a significant increase in the accumulation of reactive oxygen species (ROS), disrupts mitochondrial membrane potential (MMP), arrests the cell cycle in the G0/G1 phase, and induces apoptosis. Collectively, our findings demonstrate that complex 6g exhibits potential anti-HCC effects via dual-targeting of EGFR and TrxR.