title: Copper binding agents acting as copper ionophores lead to caspase inhibition and paraptotic cell death in human cancer cells.
abstract: We report a quantitative structure-activity relationship study of a new class of pyrazole-pyridine copper complexes that establishes a clear correlation between the ability to promote copper accumulation and cytotoxicity. Intracellular metal accumulation is maximized when ligand lipophilicity allows the complex to rapidly cross the membrane. Copper and ligand follow different uptake kinetics and reach different intracellular equilibrium concentrations. These results support a model in which the ligand acts as an ionophore for the metal ion, cycling between intra- and extracellular compartments as dissociated or complexed entities. When treating cancer cells with structurally unrelated disulfiram and pyrazole-pyridine copper complexes, as well as with inorganic copper, the same morphological and molecular changes were reproduced, indicating that copper overload is responsible for the cytotoxic effects. Copper-based treatments drive sensitive cancer cells toward paraptotic cell death, a process hallmarked by endoplasmic reticulum stress and massive vacuolization in the absence of apoptotic features. A lack of caspase activation, as observed in copper-treated dying cells, is a consequence of metal-mediated inhibition of caspase-3. Thus, copper acts simultaneously as an endoplasmic reticulum (ER) stress inducer and a caspase-3 inhibitor, forcing the cell into caspase-independent paraptotic death. The establishment of a mechanism of action common to different copper binding agents provides a rationale for the exploitation of copper toxicity as an anticancer tool.
authors: Dipartimento di Medicina Sperimentale, Sezione di Patologia Generale e Clinica, Via Volturno 39, 43100 Parma, Italy.
authors: Saverio
authors: S
authors: Tardito
authors: Irene
authors: I
authors: Bassanetti
authors: Chiara
authors: C
authors: Bignardi
authors: Lisa
authors: L
authors: Elviri
authors: Matteo
authors: M
authors: Tegoni
authors: Claudio
authors: C
authors: Mucchino
authors: Ovidio
authors: O
authors: Bussolati
authors: Renata
authors: R
authors: Franchi-Gazzola
authors: Luciano
authors: L
authors: Marchiò
mesh_terms: D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007476:Ionophores / Q000737:chemistry*; D008958:Models, Molecular
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007476:Ionophores; D003300:Copper; D020169:Caspases