Oxidative Stress Induced by Copper and Iron Complexes with 8-Hydroxyquinoline Derivatives Causes Paraptotic Death of HeLa Cancer Cells

Abstract

Here, we report the antiproliferative/cytotoxic properties of 8-hydroxyquinoline (8-HQ) derivatives on HeLa cells in the presence of transition metal ions (Cu(2+), Fe(3+), Co(2+), Ni(2+)). Two series of ligands were tested, the arylvinylquinolinic L1-L8 and the arylethylenequinolinic L9-L16, which can all interact with metal ions by virtue of the N,O donor set of 8-HQ; however, only L9-L16 are flexible enough to bind the metal in a multidentate fashion, thus exploiting the additional donor functions. L1-L16 were tested for their cytotoxicity on HeLa cancer cells, both in the absence and in the presence of copper. Among them, the symmetric L14 exhibits the highest differential activity between the ligand alone (IC50 = 23.7 μM) and its copper complex (IC50 = 1.8 μM). This latter, besides causing a significant reduction of cell viability, is associated with a considerable accumulation of the metal inside the cells. Metal accumulation is also observed when the cells are incubated with L14 complexed with other late transition metal ions (Fe(3+), Co(2+), Ni(2+)), although the biological response of HeLa cells is different. In fact, while Ni/L14 and Co/L14 exert a cytostatic effect, both Cu/L14 and Fe/L14 trigger a caspase-independent paraptotic process, which results from the induction of a severe oxidative stress and the unfolded protein response.

Cytoplasmic vacuolization in cell death and survival

“…Current data indicate that cell death with ER vacuolization and mitochondrial swelling typical for IGF1R-induced paraptosis can be initiated by a number of other stimuli including oxidative stress [59–61], overexpression of TAJ/TROY receptors [62], epidermal growth factor (EGF) [63, 64], glucocorticoids [65], thiol reactive cyclopentenone prostaglandin 15d-PGJ2 [66] as well as various xenobiotics [16, 67–74]. At the same time, cell death triggered by these inducers relies on the mechanisms different from that of IGF1R-induced paraptosis (Table 2).…”

The effect of metalloprotein inhibitors on cellular metal ion content and distribution

“…It is well known that transition metal ions play a major role in the dynamic processes of disease. For example, intracellular free Cu must be strictly limited as the uncontrolled accumulation of Cu may lead to increased oxidative stress and damage to macromolecules (7–9). Similarly, metalloproteins are essential to numerous biological processes and represent a broad class of validated clinical targets (10, 11).…”

Metal Ions Effectively Ablate the Action of Botulinum Neurotoxin A

“…66–69 Although our results show negligible effects of copper complexes on cytotoxicity, the observed cell rounding indicates the inevitable off-target effects of copper in inducing an unfolded-protein response through proteasome inhibition or by direct interference in protein folding. 59, 70, 76–77 While ROS and proteasome inhibition play major roles in copper complexes as anticancer agents, they may still occur in our cell-based model but are unlikely to be involved in the copper-mediated inhibition of BoNT/A-induced SNAP-25 cleavage.…”