Table 2.

Examples of possible uses of chelating drugs and metal complexes in cancer treatment.

Effects of Metal Ion Mobilization

Inhibition of cancer cell growth and proliferation through deprivation of essential metal ions from

cancer cells or through metal ion removal from metal-transporting proteins by chelators.

Inhibition of transcription factors through zinc binding by chelators. About 2000 transcription

factors have been identified to be zinc-dependent.

The use of chelating drugs, chelators and metal–chelator complexes as metal theranostics against cancer.

Chelators used for the decorporation of radioactive metals, e.g., uranium, plutonium, and xenobiotic metals such as cadmium and nickel, which cause cancer formation and proliferation.

Inhibition of Key Proteins Involved in Iron Metabolism

Inhibition of the iron-containing enzyme ribonucleotide reductase, which is involved in the reduction

of ribonucleotides to deoxyribonucleotides in DNA synthesis.

Inhibition of transferrin receptor uptake of iron transferrin, which is up-regulated in many cancer types, e.g., breast cancer, prostate cancer and leukemia.

Inhibition of aconitase activity, which affects mitochondrial metabolism and function and is also crucial for tumor proliferation, survival and metastasis.

Inhibition of free radicals and other regulatory molecules produced during cycooxygenase and lipoxygenase activity.

Modulation by chelating drugs and other chelators of the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1), six-transmembrane epithelial antigen of prostate, family member 4” (STEAP4) protein, hypoxia-inducible factor (HIF) and similar biomolecules.

Inhibition of Free Radicals and Antioxidant Action

Inhibition of free radical cascade toxicity formed by iron and copper catalytic centers, causing damage and modification to DNA and other biomolecules.

Chelating drugs for preventing free radical toxicity including tissue damage following radiotherapy and chemotherapy.

Design of drugs and protocols, e.g. dexrazoxane and L1, for protection against cardiotoxicity of the anticancer drug doxorubicin.

Modulation of Ferroptosis and Associated Processes

Inhibition of ferroptosis by non-redox-active chelating drugs such as deferiprone and deferoxamine and other chelators with similar properties.

Induction of ferroptosis by redox-active lipophilic chelators and iron complexes

Induction of ferroptosis by redox-active lipophilic chelators and iron complexes in combination with reducing agents such as ascorbic acid.

Ferritin iron mobilization during ferritinophagy in ferroptosis.

Increased macrophage anticancer activity via iron mobilization from hemosiderin and ferritin in iron-laden macrophages.

Modulation of Targeting Activity

Design of chelators for cell cycle control and prevention of drug resistance and metastasis.

Design of new anticancer drugs of equivalent or greater efficacy in cytotoxic activity in comparison to existing drugs, e.g., omadine and derivatives.

Combination protocols of established anticancer drugs with chelating drugs. Synergistic effects and better efficacy overall in anticancer activity are observed in comparison to monotherapies.

Design of inactive prodrug that can be converted to active chelating drug for targeting specific active pathways in cancer cells but not normal cells.

Design of chelating drugs with different partition coefficients for the targeting of either lipophilic or hydrophilic compartments in cancers cells.

Therapeutic Effects Improving the Survival of Cancer Patients

Chelating drugs, e.g., deferiprone, deferoxamine and deferasirox, for preventing iron overload toxicity in regularly red-blood-cell-transfused cancer patients.

Chelating drugs for preventing infections in immunocompromised patients following chemotherapy and radiotherapy.

Chelator–iron complexes used as monotherapy, or in combination with erythropoietin, for the treatment of chronic anemia in cancer patients.