Abstract
Conventional cancer therapies suffer from severe off-target effects because most of them target critical facets of cells that are generally shared by all rapidly proliferating cells. The development of new therapeutic agents should aim to increase selectivity and therefore reduce side effects. In addition, these agents should overcome cancer cell resistance and target cancer stem cells. Some copper ionophores have shown promise in this direction thanks to an intrinsic selectivity in preferentially inducing cuproptosis of cancer cells compared to normal cells. Here, Cu ionophores are discussed with a focus on selectivity towards cancer cells and on the mechanisms responsible for this selectivity. The proposed strategies, to further improve the targeting of cancer cells by copper ionophores, are also reported.
Highlights
Copper (Cu) is an essential mineral nutrient for all living organisms as it is fundamental in a huge number of biological processes including mitochondrial respiration, iron uptake, antioxidant/ detoxification processes (Ruiz et al, 2021)
It suffices to note that two new terms “cuproplasia” and “cuproptosis” have been recently used to indicate unique biological processes triggered by Cu action
Cu ionophores that could selectively induce cuproptosis may well succeed in overcoming the limits of traditional anticancer drugs
Summary
Copper (Cu) is an essential mineral nutrient for all living organisms as it is fundamental in a huge number of biological processes including mitochondrial respiration, iron uptake, antioxidant/ detoxification processes (Ruiz et al, 2021). There is some evidence that Cu could have a role in the etiology, severity, and progression of cancer disease (Ishida et al, 2013; Shanbhag et al, 2021). This hypothesis is, for example, supported by the enhanced incidence of hepatocarcinoma in Wilson’s disease patients, the correlation between the stage and Cu levels in colorectal and breast cancer, the link between Cu exposure, pancreatic and prostate cancer (Gupta et al, 1993; Sharma et al, 1994; Ishida et al, 2013; Gunjan et al, 2017; Vella et al, 2017). Some mechanisms, involved in Cu-dependent growth and progression of tumors, have been recently found and summarized elsewhere (Lelièvre et al, 2020; Ge et al, 2021; Ruiz et al, 2021). Cu ionophores are discussed with a focus on the selectivity towards cancer cells, the mechanisms responsible for the selectivity (Figure 1), and the strategies proposed to further increase the targeting of cancer cells by copper ionophores
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