Structurally related hydrazone-based metal complexes with different antitumor activities variably induce apoptotic cell death.

Abstract

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)] 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)] are highly cytotoxic with EC50 values of 1.25 ± 0.01 μM and 20 ± 1 μM, 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 the caspase-independent cell death (CICD). In addition, an increased generation of reactive oxygen species (ROS) and a strong up-regulation of proteins responsive to oxidative stress suggest that alterations of the cellular redox metabolism likely contribute to the cytotoxicity of the Cu(ii) complex.

• Authors: Dominik A Megger, Kristin Rosowski, Christian Radunsky, Jutta Kösters, Barbara Sitek, Jens Müller
• Journal: Dalton transactions (Cambridge, England : 2003) (Dalton Trans) Vol. 46 Issue 14 Pg. 4759-4767 (Apr 05 2017) ISSN: 1477-9234 [Electronic] England
• PMID: 28338141 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Chlorides
• Coordination Complexes
• Hydrazones
• Ligands
• Manganese Compounds
• Proteome
• Pyridines
• Reactive Oxygen Species
• Zinc Compounds
• Copper
• zinc chloride
• Caspases
• manganese chloride
• cupric chloride

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Survival (drug effects)
• Chlorides (chemistry)
• Coordination Complexes (chemical synthesis, chemistry, pharmacology)
• Copper (chemistry)
• Dose-Response Relationship, Drug
• Hep G2 Cells
• Humans
• Hydrazones (chemistry)
• Ligands
• Manganese Compounds (chemistry)
• Molecular Structure
• Proteome (metabolism)
• Pyridines (chemistry)
• Reactive Oxygen Species (metabolism)
• Zinc Compounds (chemistry)