Iron and Copper Intracellular Chelation as an Anticancer Drug Strategy

Abstract

A very promising direction in the development of anticancer drugs is inhibiting the molecular pathways that keep cancer cells alive and able to metastasize. Copper and iron are two essential metals that play significant roles in the rapid proliferation of cancer cells and several chelators have been studied to suppress the bioavailability of these metals in the cells. This review discusses the major contributions that Cu and Fe play in the progression and spreading of cancer and evaluates select Cu and Fe chelators that demonstrate great promise as anticancer drugs. Efforts to improve the cellular delivery, efficacy, and tumor responsiveness of these chelators are also presented including a transmetallation strategy for dual targeting of Cu and Fe. To elucidate the effectiveness and specificity of Cu and Fe chelators for treating cancer, analytical tools are described for measuring Cu and Fe levels and for tracking the metals in cells, tissue, and the body.

Brassica incana Ten. (Brassicaceae): Phenolic Constituents, Antioxidant and Cytotoxic Properties of the Leaf and Flowering Top Extracts

“…The greater activity of the flowering top extract may depend on its strong ferrous ions chelating properties. Indeed, it has been shown that some metals, such as copper and iron, play a significant role in the rapid proliferation of cancer cells [50].…”

Advances on Chelation and Chelator Metal Complexes in Medicine

“…Specificity in cancer cell targeting is also important and such approaches are considered to have a better therapeutic outcome. The efficacy and risk/benefit assessments of such combination approaches which may involve metal ions and chelators is in progress, with some of these at an investigational level and others in different stages of clinical development and use [1,4,5].…”

“…The therapeutic strategies for targeting cancer cell growth and proliferation by chelators may involve the modulation of protein function or other associated pathways such as the inhibition of key enzymes e.g., the iron containing ribonucleotide reductase involved in DNA synthesis, incorporation of xenobiotic metals such as Ga which could bind to nucleotide substrates and also disrupt iron and other essential metal metabolic pathways and lysosomic damage by redox active metal complexes (Table 1) [1,[4][5][6]. Chelating drugs could also be used in many other anticancer approaches such as modulation of macrophage anticancer function and also in the protection from the cardiotoxicity of anticancer drugs [7][8][9].…”

Isoxazole‐Derived Aroylhydrazones and Their Dinuclear Copper(II) Complexes Show Antiproliferative Activity on Breast Cancer Cells with a Potentially Alternative Mechanism Of Action

“…[54] Intracellular chelation as a strategy to induce cancer cell death was particularly studied during the last years. [55] Consequently, the discovery of new compounds with such a transchelation ability becomes an alternative strategy to develop potent anticancer drugs.…”

“…To sum up, we suggest that the notable cytotoxic activity of the compounds could be due, at least partially, to the dysregulation of iron and/or copper homeostasis which, in turn, could induce, for example, perturbation of cell cycle and reactive oxygen species (ROS) generation. [55]…”