COPPER CHELATION

Introduction

Copper is a crucial microelement that plays an important role during a big variety of biological processes. more than Copper plays a crucial role within the etiopathogenesis of the genetic disorder Wilson's syndrome, in neurodegenerative pathologies like Alzheimer's and Parkinson's diseases, in diabetes, and in several sorts of cancer. Copper chelating agents are the foremost promising tools to take care of copper concentration at physiological levels.

The majority of copper concentration within the body is found in organs with high metabolic activity, like the liver, kidneys, heart, and brain. Unbound Copper behaves as a potent oxidant, catalyzing the formation of highly reactive hydroxyl radicals resulting in DNA, protein, and lipid damage. Therefore, cellular copper concentration must be finely regulated by complex homeostatic mechanisms of absorption, excretion, and bioavailability.

A chelator may be a compound ready to bind at a selected site, thanks to its structure, with the formation of a stable complex ring-like structure. Copper is an important catalytic cofactor in biochemistry. The copper dyshomeostasis resulting in its unpaired distribution has been linked with several disorders, including diabetes, neurological disorders and cancer.

Different sorts of chelating drugs are shown to modulate copper levels by different mechanisms like trientine, penicillamine, and dimercaptosuccinic acid form complexes which are excreted within the urine, while tetrathiomolybdate promotes Copper biliary excretion. A study shows that the utilization of Copper chelating drugs like trientine in cancer patients has been considered safe.

Chelating drugs require a prescription because it carries a risk of side effects; therefore, it should be taken only as directed by a healthcare professional who will monitor their use.

Copper chelation in Cancer

Increased copper content has been determined in tissue and serum samples from patients with different types of cancer colorectal cancer, carcinoma, brain cancer and carcinoma organic phenomenon analysis revealed multiple alterations during a sort of copper-binding or copper-sensitive proteins in colorectal and carcinoma s, suggesting that deregulation of copper homeostasis might contribute to cancer pathogenesis, development and metastasis. The researchers have proved that copper chelation therapy is usually well tolerated. the rationale behind that's copper chelation agents act on cancer cells selectively, which have increased copper content, exerting little toxicity to normal cells.

Copper Chelation Combination Therapy in cancer:

1.Copper Chelation and Cancer Chemotherapy-

Chemotherapy drugs are widely used against solid cancers, but as many cancer cells are sensitive to chemotherapy, they'll develop resistance over time. Copper transport proteins play a task in cisplatin, the foremost used platinum-based chemotherapeutic drug. CTR1 regulates the Cellular copper homeostasis and is liable for specific copper cellular uptake into cells. Copper chelation therapy, reducing cellular copper content and, in turn, increasing CRT1 levels, enhances cellular accumulation and efficacy of chemotherapy drugs. There are different clinical trials are performed to assess copper chelation therapy as a tool to urge the higher platinum-based drug resistance in cancer patients.

Another promising class of metal complexes suitable for anticancer therapy is represented by Cu(II) chelate complexes

2.Copper Chelation and Radiotherapy-

Increased efficacy of radiotherapy of cancer against primary tumours with reduced side effects is often achieved when combined with antiangiogenic agents. An additive effect of radiotherapy and copper chelation therapy has been observed within the carcinoma mouse model.

3.Copper Chelation and Monoclonal Antibodies Immunotherapy-

The antibody, which binds specifically to the EGFR (epidermal protein receptor) by blocking the transmission of the relative proliferative signalling pathways, is an immunotherapeutic agent.The mixture therapy has been evaluated, but no statistically significant differences were observed between single and combined treatments. That's why more investigations are needed to work out the clinical significance of mixing copper chelation and monoclonal antibodies-mediated immunotherapy.

4.Copper Chelation and Immune Activation-

Copper chelation has been suggested in conjunction with immune activation for cancer immunotherapy. The strategy of nanoparticle-based copper chelation and immune stimulation effectively inhibits breast tumour growth and metastasis in experimental models both in vitro and in vivo.

5.Copper Chelation and Immune Checkpoint Inhibitors-

An important strategy for cancer immunotherapy targets the interactions between the immune checkpoints programmed necrobiosis protein 1 (PD-1) and therefore the programmed necrobiosis ligand 1 (PD-L1) using specific antibodies. A direct correlation between the copper transport protein CTR1 and PD-L1 expression has been observed in neuroblastoma and glioblastoma tumour cells.

6.Copper Chelation and Oncolytic Virotherapy-

Oncolytic vectors selectively replicate and promote lysis of cancer cells triggering the patient's system against tumour antigens. The tumour microenvironment changes in response to induced oncolysis may limit the efficacy of oncolytic virotherapy. Therefore, it's been hypothesized that a mixture of copper chelation therapy, which affects both tumour microenvironment and angiogenesis, may promote the efficacy of oncolytic virotherapy