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 (Cu²⁺, Fe³⁺, Co²⁺, Ni²⁺). Two series of ligands were tested, the arylvinylquinolinic <b>L1–L8</b> and the arylethylenequinolinic <b>L9</b>–<b>L16</b>, which can all interact with metal ions by virtue of the N,O donor set of 8-HQ; however, only <b>L9</b>–<b>L16</b> are flexible enough to bind the metal in a multidentate fashion, thus exploiting the additional donor functions. <b>L1</b>–<b>L16</b> were tested for their cytotoxicity on HeLa cancer cells, both in the absence and in the presence of copper. Among them, the symmetric <b>L14</b> 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 <b>L14</b> complexed with other late transition metal ions (Fe³⁺, Co²⁺, Ni²⁺), although the biological response of HeLa cells is different. In fact, while Ni/<b>L14</b> and Co/<b>L14</b> exert a cytostatic effect, both Cu/<b>L14</b> and Fe/<b>L14</b> trigger a caspase-independent paraptotic process, which results from the induction of a severe oxidative stress and the unfolded protein response