Exploring the effect of copper on the bioactivity of 8-quinolines: an <i>in vitro</i> and <i>in vivo</i> study

Current anticancer therapy is challenged by the adaptability and resistance of tumor cells as well as limited drug selectivity that causes severe side effects. The scientific community maintains high interest in metal-based chemotherapeutic agents due to their unique interactions with cancer cells, potentially overcoming resistance mechanisms and exploiting the physiopathology of the tumour tissues. Copper, in particular, plays a dual role in cancer, both facilitating tumor progression and triggering cuproptosis, a copper-induced cell death mechanism. A better understanding of these processes has revived interest in copper-based therapies as a promising strategy against cancer. This work contributes to this field by investigating 8-aminoquinoline (8AQ) in combination with copper as an anticancer agent. Given its structural similarity to 8-hydroxyquinoline (8HQ), a known copper ionophore, we investigated whether the presence of Cu could influence its antitumor activity. For comparison purposes, we also studied 8-nitroquinoline (8NQ), which binds copper with lower affinity but may undergo selective reduction in those tumor tissues overexpressing the nitroreductase enzyme. 8AQ alone exhibits poor anticancer activity (in the human cancer cell lines explored here: A549, HepG2, and HCT116), but in the presence of copper ions, its effectiveness nearly doubles. <i>In vivo</i> experiments on zebrafish (<i>Danio rerio</i>) embryos confirmed the <i>in vitro</i> results, highlighting no toxicity <i>in vivo</i> and no cytotoxicity <i>in vitro</i> for 8NQ in parallel with stronger effects recorded with 8AQ both alone and in combination with copper. Our chemical and biological findings provide valuable insights into the pharmacological profile of the 8AQ-copper system, paving the way to further investigations and offering new experimental models to advance copper-based therapeutic strategies.