Bio-molecular Fe(III) and Zn(II) complexes stimulate the interplay between PI3K/AKT1/EGFR inhibition and induce autophagy and apoptosis in epidermal skin cell cancer.

This study investigated the effectiveness and safety of a hybrid thiosemicarbazone ligand (HL) and its metal complexes (MnII-L, FeIII-L, NiII-HL, and ZnII-HL) against epidermoid carcinoma (A-431). The results indicated that FeIII-L is the most effective, with a high selectivity index of 8.01 and an IC50 of 17.49 ± 2.12 μM for FeIII-L. The study also revealed that the synthesized complexes effectively inhibited gene expression of the Phosphoinositide 3-kinases (PI3K), alpha serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR2) axis mechanism (P < 0.0001). Additionally, these complexes trigger a chain of events that include the inhibition of proliferating cell nuclear antigen (PCNA), transforming growth factor β1 (TGF β1), and topoisomerase II, and leading to a decrease in epidermoid cell proliferation. Furthermore, the inhibitory activity also resulted in the upregulation of caspases 3 and 9, indicating the acceleration of apoptotic markers, and the down regulation of miRNA221, suggesting a decrease in epidermoid proliferation. Molecular modeling of FeIII-L revealed that it had the best binding energy -8.02 kcal/mol and interacted with five hydrophobic π-interactions with Val270, Gln79, Leu210, and Trp80 against AKT1. Furthermore, the binding orientation of FeIII-L with Topoisomerase II was found to be the most stable, with a binding energy -8.25 kcal/mol. This stability was attributed to the presence of five hydrophobic π-interactions with His759, Guanin13, Cytosin8, and Ala465, and numerous ionic interactions, which were more favorable than those of doxorubicin and etoposide for new regimens of chemotherapeutic activities against skin cancer.