Ferroptosis, a term coined in 2012, is being studied as a way of producing programmed cell death in cancer; it is biochemically distinct from other forms of regulated cell death such as necroptosis or apoptosis.
Ferroptosis is a unique form of cell death, dependent on iron and characterised by the accumulation of lipid peroxidation in the membranes. Many illnesses, but particularly degenerative diseases and organ injuries, exhibit lipid peroxidation (1). Various types of cancer, especially those where cancer stem cells are actively promoting metastasis, and those exhibiting drug resistance, seem particularly vulnerable to ferroptosis.
Lipid peroxidation is where free radicals steal electrons in a chain reaction causing oxidation of the fats in cell membranes. This is harmful to healthy cells. Membranes determine the integrity of a cell and what can and cannot pass through via receptor sites and the biochemical processes of the cell via cell signalling (2).
Ferroptosis is associated with smaller mitochondria, each with condensed mitochondrial membrane densities, and the rupture of their outer membrane.
Interest has grown recently because cancer cells supposedly never die; they also require iron and reduce levels in the blood supply. German researchers suggested that these immortal cells, however, could be susceptible to ferroptosis, where their iron content works against them, causing lipid peroxidation (3).
Ferroptosis is linked to cancer cell and tumour hypoxia (a state of extreme low oxygen) where cancer cells turn healthy cell metabolism to their advantage, for example, in blocking drug effectiveness.
In a recent review by a group of Chinese scientists (4), they showed that amino acid and iron metabolism might bring about free radical formation and cause lipid peroxidation of the cancer cells. At first it was thought that ferroptosis was controlled by glutathione-peroxidase 4; however, Ferroptosis Suppressor Protein 1 is now known to block ferroptosis, but a changed amino acid metabolism, control of glucose and lipid levels along with minerals such as selenium appear to invoke change.
Interestingly, researchers are trying to solve the conundrum of ferroptosis and glutathione. If healthy cells do not have enough glutathione, lipid peroxidation can damage them. In some cancers, for example renal cancer, it is known that ferroptosis can propagate the cancer. It’s early days yet, but maybe a drug-free metabolic solution to cancer could become reality after all.
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References
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Ferroptosis: mechanisms, biology, and role in disease; Nat Rev Mol Cell Biol; May 2021 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142022/
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Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066722/
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Ferroptosis in Cancer Cell Biology; Cancers (Basel); 2020, Jan 9 12(1):164; Chritine M. Bebber et al. https://pubmed.ncbi.nlm.nih.gov/31936571/#affiliation-1
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Ferroptosis: A New Strategy for Cancer Therapy; Yu Chen et al, Front Onco 2022, Feb 16, 12; https://pubmed.ncbi.nlm.nih.gov/35252001/#affiliation-1