Updated project metadata. Three new complexes bearing the tridentate hydrazone-based ligand 2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)pyridine (L) were synthesized and structurally characterized. Biological tests indicate that the Zn(II) complex [ZnCl2(L)] • 0.5 H2O is of low cytotoxicity against the hepatocellular carcinoma cell line HepG2. In contrast, the Cu(II) and Mn(II) complexes [CuCl2(L)] and [MnCl2(L)(OH2)] • H2O are highly cytotoxic with EC50 values of 1.25  0.01 M and 20  1 M, respectively. A quantitative proteome analysis reveals that treatment of the cells with the Cu(II) complex leads to a significantly altered abundance of 102 apoptosis-related proteins, whereas 38 proteins were up- or down-regulated by the Mn(II) complex. A closer inspection of those proteins regulated only by the Cu(II) complex suggests that the superior cytotoxic activity of this complex is likely to be related to an initiation of caspase-independent cell death (CICD).