3 things to know about copper in the treatment and prevention of cancer

Recent studies show that unmaintained copper homeostasis affects tumor growth, causing irreversible lesions. Cu can induce multiple forms of cell death, including apoptosis and autophagy, through various mechanisms such as accumulation of reactive oxygen species, proteasome inhibition and anti-angiogenesis, thereby showing a potential role in cancer prevention and therapy.

1. Mechanism of action of copper

Cu is a micronutrient essential for basic biological processes in all organisms. Cu is a redox active metal and has the ability to donate and accept electrons to change between reduced (Cu+) and oxidized (Cu2+) states. This property allows Cu to participate in an important biological process in redox reactions, by acting as a functional catalytic cofactor or structural component of many important enzymes.

In humans, examples of prominent enzymes that require Cu for their function include Cu/Zn superoxide dismutase (SOD) (free radical detoxification), cytochrome C oxidase (electron transfer enzyme involved in cellular respiration), ceruloplasmin by converting ferrous iron (Fe2+) to ferric iron (Fe3+), lysyl oxidase (LOX) (connective tissue synthesis) and tyrosinase (melanogenesis). However, free copper ions can generate highly reactive oxygen species (ROS) due to redox activity and can cause damage to lipids, proteins, nucleic acids and other biomolecules.

2. Copper and mechanism of cancer

Recent evidence has established a strong link between copper and both the development and progression of cancer. Preclinical studies have demonstrated that the administration of copper (CuSO4) by oral catheters or by providing Cu in drinking water significantly increased cancer growth in rodent models of mammary gland tumor, pancreatic islet cell carcinoma and lung cancer.

Likewise, severe Cu deficiency caused by a low copper diet suppressed the immune system in mice and resulted in a significantly increased cancer burden.

Further studies suggested that copper is central to the modulation of normal and malignant angiogenesis due to its ability to modulate multiple angiogenic responses. New blood vessel formation is required to deliver oxygen and nutrients to tumors larger than 1-2 millimeters.

The angiogenic role mediates copper through a variety of pathways including improving the growth and motility of vascular endothelial cells, regulating the synthesis and secretion of pro-angiogenic mediators (eg, fibroblast growth factors (FGF), interleukin-1-alpha (IL-1α) and vascular endothelial growth factor (VEGF)) and through direct binding to angiogenin (angiogenic growth factor) to enhance its performance.

Cu can also affect the ability of cancer cells to invade surrounding tissues and metastasize to distant organs. For example, the activities of both lysyl oxidase (LOX) and LOX-like proteins that contribute to the remodeling of the extracellular matrix and the establishment of a premetastatic drive are copper dependent.

Recently, Memo co-dependent protein was identified as a mediator of pre-metastasis in breast cancer and serves as a reliable prognostic marker for early distant metastases. The findings that copper acts as a limiting factor for many aspects of tumor progression have prompted the development of copper complexes as therapeutics and multiple anticancer strategies have appeared.

3. Copper complexes in cancer prevention

Anticancer contractile complexes can be classified into two main groups: Cu chelators and copper ionophores. Cu chelates sequester copper ions from cells in the body and thus aim to limit cancer progression by interfering with growth and malignancy.

In contrast, the Cu ionophore that transports copper into the cell increases the intracellular concentration and induces cytotoxicity through a variety of pathways.

Many Cu-releasing ionophores are incorporated in the intracellular reducing environment allowing Cu to become bioavailable (exchangeable) and such compounds are often more effective in killing cancer cells. Multiple Cu complexes have been used in the clinic for decades to treat other unrelated conditions (eg, clioquinol and disulfiram for diarrhea and alcoholism, respectively), but since the discovery of their anti-proliferative activities, many have been repurposed as anticancer therapies.

At the same time, structure-activity relationship studies have been performed on known Cu complexes allowing the development of novel complexes that are individually prepared. Cancer-specific analogues have enhanced antitumor activity, reduced toxicity to normal cells/tissues, and more favorable pharmacokinetics in preclinical and/or clinical studies. Major Cu complexes are reused (tetrathiomolybdate, clioquinol and disulfiram) for cancer treatment and several newly developed compounds (elesclomol and thiosemicarbazones) show promise as antineoplastic agents.

References:

1. Denoyer, S. A. S. Clatworthy, and M. A. Cater, “Copper Complexes in Cancer Therapy”, Met Ions Life Sci, vol. 18, tr /books/9783110470734/9783110470734-022/9783110470734-022.xml, February 2018, doi: 10.1515/9783110470734-022.
2. Y. Jiang, Z. Huo, X. Qi, T. Zuo, và Z. Wu, “Copper-induced tumor cell death mechanisms and antitumor theragnostic applications of copper complexes”, Nanomedicine (Lond), vol. 17, no. p.h 5, pp 303–324, February 2022, doi: 10.2217/nnm-2021-0374.

Article source: Nutrition Research and Development Institute (https://inrd.vn/)

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