The copper complex A0: license to kill without apoptosis

The copper(II)complex A0 emerged from a screening for metal-based anticancer compounds. The N,S coordinating thioxotriazole ligand confers the ability to kill human cancer cells to the metal with a potency comparable to that of cisplatin, while the pyridil and the thioamido groups were identified as potency determinants. Cells treated with A0 did not show any biochemical and morphological feature of apoptosis. Rather, the copper complex inhibits the activity of the apoptosis executor caspase-3 and induces a massive vacuolization originating from endoplasmic reticulum (ER). This alteration, which constitutes the paradigmatic feature of A0-induced toxicity, is also the hallmark of a newly identified cell death process named paraptosis. The mechanism of action of A0 was partially characterized: sensitive cells accumulate a great amount of copper, thus facing oxidative unbalance that, in turn, compromises protein folding. ER involvement in A0-induced paraptotic cell death was also demonstrated by the analysis of the transcriptome of treated cells, which induce typical ER-stress genes. Biochemical studies, while confirming the occurrence of an Unfolding Protein Response, indicated a pro-paraptotic role for eIF2α phosphorylation. Further elucidation of the molecular events that regulate A0-induced cell death will favour the assessment of the therapeutic potential of copper complexes and paraptosis.