Abstract
The development of novel therapeutic agents for oral squamous cell carcinoma (OSCC) remains an urgent clinical challenge. This study presents the synthesis and comprehensive biological evaluation of a new Cu complex derived from pyridoxal benzoylhydrazone. Single-crystal X-ray diffraction confirmed its distinct molecular structure. The complex demonstrated superior and selective cytotoxicity against a panel of cancer cell lines, particularly exhibiting potent activity against HSC-2 oral cancer cells, which was approximately 7.2-fold more potent than the clinical drug cisplatin. Notably, it showed a favorable selectivity index between that of HSC-2 and normal oral epithelial (HOK) cells. Mechanistic investigations revealed that the Cu complex exerts its potent anticancer effect through a pro-oxidant mechanism. It effectively disrupted redox homeostasis by depleting glutathione (GSH), elevating reactive oxygen species (ROS), and triggering a collapse of the mitochondrial membrane potential (ΔΨm). Consequently, these events led to the activation of the mitochondrial apoptotic pathway, as unequivocally confirmed by Annexin V-FITC/PI staining. These findings highlight the Cu complex as a highly promising candidate for targeted OSCC therapy, offering a new strategy to overcome cisplatin resistance via an ROS-mediated mechanism.