In a review paper published in Oncotarget in 2021, researchers discuss the impact of iron chelation on cancer cell survival and the underlying mechanisms of action.
Iron is essential for human life, however, this element can also become toxic in high doses. Contrary to iron anemia, iron overload occurs when the body accumulates more iron than it can use, and this excess iron is damaging to cells and tissues. Famous for their atypical growth patterns, cancer cells accumulate a surplus of iron to support their irregular growth and metabolism. Thus, the cancer-cell metabolism may be exploited by targeting their proclivity to require and retain iron.
“Iron chelators selectively deplete cancer cells of iron, exploiting cancer’s iron addiction – a trait displayed by a range of different cancers.”
Iron chelators are compounds that can bind to iron and facilitate iron wasting. Depriving cancer cells of iron using iron chelators has selectively cytotoxic effects in cancer cells. Some natural iron chelators include turmeric, quercetin, resveratrol, and green tea. Synthetic iron chelators include derivatives of 8-hydroxyquinoline, tachpyridine and deferoxamine. A considerable number of studies have shown that iron chelators can reverse some major catalysts and hallmarks of cancer—making iron chelators a promising treatment option for cancer patients.
Researchers Gina Abdelaal and Stephany Veuger from Northumbria University reviewed the available research literature about the impact of iron chelation on cancer cell survival and the underlying mechanisms of action. Their review paper was published by Oncotarget in 2021 and entitled, “Reversing oncogenic transformation with iron chelation.”
“This review aims to explore the underlying mechanisms of action behind iron chelator driven cytotoxicity in the context of the hallmarks of cancer established by Hanahan and Weinberg [47, 48] (see Figure 1, Supplementary Table 1). This will in turn support further research into iron chelators as a potential effective anti-cancer therapy.”
Iron Chelation Therapy
In the researchers’ review, they emphasize that iron chelation therapy has been shown to reverse multiple oncogenic hallmarks and is a promising treatment for many cancers. Studies have shown that iron chelation weakens cancer cell proliferation, induces cell cycle arrest, reactivates tumor suppressor genes, induces apoptotic signaling, inhibits stemness and Wnt/β-catenin signaling, prevents the initiation of metastasis through EMT and ROCK/MLC2 and NF-kB inhibition, and exploits and mimics genomic instability. While iron chelation has multiple targets within a cancer cell, the authors note that the NDRG1 gene has a critical role in inducing iron chelator-mediated cytotoxicity.
![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].](https://www.impactjournals.com/wp-content/uploads/2022/02/Screen-Shot-2022-02-09-at-8.58.35-AM-999x1024.png)
One of the main mechanisms by which iron chelators exert their cytotoxic effects is through their ability to induce autophagy. However, this effect may both suppress and facilitate tumorigenesis. The researchers wrote that further in vivo studies must be conducted to reach a consensus about the impact of iron chelation on angiogenesis.
“In cancer cells, autophagy suppresses tumorigenesis by inhibiting cancer-cell survival and inducing cell death, but it also facilitates tumorigenesis by promoting cancer-cell proliferation and tumor growth [8,9].”
Many natural and synthetic iron chelators are currently being researched and developed. However, some early-developed iron chelators, such as deferoxamine, are effective in only some cancer patients. This is due to deferoxamine having poor lipophilicity, rapid clearance by the kidneys and poor absorption in the small intestine. Other iron chelators, such as those in the thiosemicarbazone class, are capable of inducing reactive oxygen species, causing oxidative stress. However, these chelators have only been successful in blood cancers, not in solid tumors. The researchers also spotlighted a novel iron chelator—VLX600—for its ability to target oxidative phosphorylation and initiate metabolic reprogramming.
“Cancer cells undergo a metabolic transformation known as the Warburg effect, which shifts their source of energy from oxidative phosphorylation to glycolysis. This is another trait which is exploited by iron chelators. VLX600 diminishes the ability of MCF7 and HCT116 cells to undergo oxidative phosphorylation [38].”
Conclusion
“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.”
The authors point out that the full impact of iron chelators on two remaining hallmarks of cancer, inflammation and immune evasion, have yet to be established. Additionally, the ability of iron chelators to induce both a pro-survival and tumor suppressor response in cancer cells through autophagy must be addressed. The researchers suggest that combining iron chelators with other inhibitors may be worth examination.
“We propose a combinatorial study of iron chelators with immune checkpoint inhibitors as they have shown success in clinic and could uncover more mechanisms of action.”
Click here to read the full review paper published in Oncotarget.
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