Copper-based Approaches in the War Against Cancer: Taking Advantage of Inorganic Physiopathology

Among various medical challenges, cancer remains the leading cause of death worldwide. The development of new effective therapies should aim to reduce side effects, increasing the selectivity of the administrated drugs. In addition, these agents should overcome cancer cell resistance and target cancer stem cells. Since the key role exerted by Cu in the etiology, severity, and progression of cancer diseases, it could be a vulnerable point to target for arresting cancer development (1). Some copper-involving agents (i.e. Cu ionophores, Cu complexes, Cu chelators and Cu nanosystems) have revealed anticancer activity, boding well for the development of new agents that can overcome cancer drug resistance (2). Here we report some systems based on the quinoline scaffold that, when co-administered with copper ions, can trigger cancer cell death, probably through a Cu-dependent mechanism, recently reported as cuproptosis (3). On the other hand, cuproplasia is copper-dependent cell growth and proliferation and some strong copper chelators based on quinoline scaffold can arrest cancer growth, suggesting that copper depletion and copper supplementation may be viable approaches for developing novel anticancer therapies. We also evaluated a series of strategies to increase the selectivity of our copper-binding compounds, for example, designing and evaluating stimulusresponsive systems of 8-substituted quinolines.