Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

Abstract

Copper (Cu) is a vital element required for cellular growth and development; however, even slight changes in its homeostasis might lead to severe toxicity and deleterious medical conditions. Cancer patients are typically associated with higher Cu content in serum and tumor tissues, indicating increased demand of cancer cells for this micronutrient. Cu is known to readily cycle between the +1 and +2 oxidation state in biological systems. The mechanism of action of Cu complexes is typically based on their redox activity and induction of reactive oxygen species (ROS), leading to deadly oxidative stress. However, there are a number of other biomolecular mechanisms beyond ROS generation that contribute to the activity of anticancer Cu drug candidates. In this review, we discuss how interfering with intracellular Cu balance via either diet modification or addition of inorganic Cu supplements or Cu-modulating compounds affects tumor development, progression, and sensitivity to treatment modalities. We aim to provide the rationale for the use of Cu-depleting and Cu-overloading conditions to generate the best possible patient outcome with minimal toxicity. We also discuss the advantages of the use of pre-formed Cu complexes, such as Cu-(bis)thiosemicarbazones or Cu-N-heterocyclic thiosemicarbazones, in comparison with the in situ formed Cu complexes with metal-binding ligands. In this review, we summarize available clinical and mechanistic data on clinically relevant anticancer drug candidates, including Cu supplements, Cu chelators, Cu ionophores, and Cu complexes.

Cuproptosis-Associated lncRNA Establishes New Prognostic Profile and Predicts Immunotherapy Response in Clear Cell Renal Cell Carcinoma

“…In addition, these agents should target cancer stem cells, thus, overcoming the resistance of cancer cells. Cancer cells are usually preferentially induced by cuproptosis compared to normal cells, and some copper ionophores have shown promise in this direction (Li, 2020;Steinbrueck et al, 2020;Babak and Ahn, 2021;Michniewicz et al, 2021;Shanbhag et al, 2021). Therefore, cuproptosisrelated studies are urgently needed for a deeper understanding.…”

Evaluation of the Safety and Toxicity of the Original Copper Nanocomposite Based on Poly-N-vinylimidazole

“…In this regard, the literature discusses the possibility to regulate the mitochondrial CcO functioning and the oxidative phosphorylation activity in general by introducing chelators or, conversely, additional amounts of copper into the cells, modulating the intensity of cellular metabolism and intracellular processes dependent on energy metabolism. This approach can be effective in the development of drugs targeted to the treatment of oncological diseases (by chelation of Cu) as well as the regulation of cell proliferation and differentiation in regenerative medicine (by addition of Cu) [ 6 , 86 , 87 ].…”

Downregulated Copper Homeostasis-Related Gene FOXO1 as a Novel Indicator for the Prognosis and Immune Response of Breast Cancer

“…Cu chelators are aimed at combining with Cu and weakening its relative bioavailability. Its representative examples are Tetrathiomolybdate (TM), D-penicillamine (D-pen), and trientine [ 27 ]. In the past, Cu chelators were mainly used for the treatment of Wilson disease to bind accumulated Cu in the liver [ 28 ].…”