Oncotarget: Reversing oncogenic transformation with iron chelation

Oncotarget published "Reversing oncogenic transformation with iron chelation" which reported that cancer cells accumulate iron to supplement their aberrant growth and metabolism.

Depleting cells of iron by iron chelators has been shown to be selectively cytotoxic to cancer cells in vitro and in vivo. A plethora of studies have shown iron chelators can reverse some of the major hallmarks and enabling characteristics of cancer. Iron chelators inhibit signalling pathways that drive proliferation, migration and metastasis as well as return tumour suppressive signalling. Iron chelators target cancer cell metabolism, attenuating oxidative phosphorylation and glycolysis.

Dr. Gina Abdelaal from The Northumbria University said, "Iron is vital for normal cell growth and survival."

Iron is vital for normal cell growth and survival.

Cancer is an evolutionary maverick, which exploits its trademark genomic instability to drain environmental resources. As an enzyme cofactor, iron is responsible for many cellular processes including mitochondrial metabolism and DNA synthesis. As iron can drive cellular proliferation, cancer cells have an adapted iron metabolism allowing increased iron accumulation. The thiosemicarbazone class is a later stage of iron chelator evolution which manifested in 1992.

Unlike their predecessor DFO, thiosemicarbazone chelators are capable of inducing reactive oxygen species. Triapine is a thiosemicarbazone; its primary mode of action is thought to be ribonucleotide reductase inhibition with a higher potency than commonly used ribonucleotide reductase inhibitor, hydroxyurea. This approach is predicted to protect healthy tissues from the cytotoxic effects as the timing and place of the drug release can be controlled.

Encapsulating Dp44mT in PLGA nanoparticles enhanced its ability to induce apoptosis and improved its selectivity towards cancer cells.

At present many more classes of iron chelators are being taken into consideration as potential cancer therapy candidates.

Figure 1: The impact of iron chelators on the hallmarks of cancer. Iron chelators have been shown to reverse many oncogenic signalling pathways associated with each hallmark of cancer with NDRG1 being a common thread. Generated through BioRender.com [47, 48].

The Abdelaal Research Team concluded in their Oncotarget Research Output that based on the data presented in this review iron chelators could potentially reverse many of the key hallmarks of cancer. Stripping the cells of iron impacts many cellular targets with some targets still undiscovered. NDRG1 has been proven to be the common link between the ability of iron chelators to reverse many of the hallmarks of cancer as overexpression of NDRG1 mimics the impact of iron chelation on several signalling pathways. There are still many unanswered questions about the mechanism of action of iron chelators.

A consensus must be reached on the impact of iron chelation on angiogenesis through in vivo studies. As STAT3 is essential for VEGF gene expression and iron chelation attenuates STAT3 dimerisation and nuclear localisation. The cleaved isoform is only present in cancer cells and could potentially be oncogenic. Although many mechanistic studies have been undertaken iron chelators, the complexity of cell signalling remains a hurdle preventing the discovery of all cellular targets of iron chelation. A potential way of discovering new targets is combining iron chelators with well-characterised cancer therapeutics.

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DOI - https://doi.org/10.18632/oncotarget.27866

Full text - https://www.oncotarget.com/article/27866/text/

Correspondence to - Gina Abdelaal - gina.abdelaal@northumbria.ac.uk

Keywords - iron chelator, oncogenesis, selective cytotoxicity, hallmarks of cancer, NDRG1

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