Ferroptosis and its novel role in cancer therapeutics

Andrea Janet D’Souza, JAIN (Deemed – to – be) University

Cancer is a disease that occurs due to uncontrolled cell division and an imbalance between cell proliferation and cell death. Programmed cell death or apoptosis can be induced in cancer cells through intrinsic and extrinsic pathways by the use of Caspases. Loss of apoptotic property of cancer cells leads to increased invasiveness during tumor progression and stimulates angiogenesis. This article deals with the role of ferroptosis, a novel cell death pathway that is quite promising as cancer therapeutic.

A brief overview of the study:

Ferroptosis is a novel cell death concept first studied in 2012 by Dixon which was induced by small molecules Erastin or RSL3. Over the last decade, continued research of ferroptosis in cancer has opened avenues for its use in cancer therapeutics. The mechanism is so named due to the involvement of large iron accumulation during the cell death process. Lipid peroxides accumulation and iron dependency are the main characteristics of ferroptosis.

Unlike autophagy and apoptosis, ferroptosis results in the reduction or disappearance of mitochondrial cristae, disruption of the mitochondrial membrane, and depletion of intracellular NADH but not ATP levels. This could lead to a loss of selective permeability of the plasma membrane due to lipid peroxidation reactions. Ferroptosis differs from necrosis in the fact that it involves mitochondrial shrinkage but necrosis involves degradation of plasma membrane integrity and chromatin condensation. Autophagy is the collection of proteins and organelles in autophagosomes and sent to lysosomes or suicide bags where they are degraded and in this way, it differs from ferroptosis.

Moreover, ferroptosis is not inhibited by RIP1/RIP3 or Cyclophilin D which regulates necrosis, and 3-MA which regulates autophagy.

Mechanism of action:

Ferroptosis is regulated by two mechanisms: First, the cysteine/glutathione (GSH) / glutathione peroxidase 4 (GPX4) axis and the NADPH/ferroptosis suppressor protein 1 (FSP1)/ Ubiquinone (CoQ10) axis. GPX4 controls ferroptosis, and its absence in some cells may lead to cell death.

P53 regulates ferroptosis in a cell. A large number of small molecules and drugs also regulate it in a Ras-dependent or independent way.

Conclusion and future prospects:

Ferroptosis has been detected in breast cancer, renal cell carcinoma, lung cancer, pancreatic cancer, lymphoma, and head and neck squamous carcinoma. 

Ferroptosis-based cancer therapeutics seem to have promising effects. It includes the use of nanoparticles, genetic modifications, exosomes, and small molecules. Nanoparticles could be used as drug-inducing ferroptosis and iron carriers in chemotherapy. As exosomes are more biocompatible and less immunogenic than nanoparticles, they could stand a better chance during clinical trials as drug delivery vectors. Genetic modifications for cancer treatments based on ferroptosis could be classified into gene knockdown and gene transfection technology. The genes which could commonly be targeted include p53, GPX4, ACSL4, and Nrf2.

Apart from cancer therapeutics, ferroptosis could also help address the problem of drug resistance and help in boosting the immune system.

Challenges:

Although significant research has been done on ferroptosis, there remain many unanswered questions about this new method of cell death, for instance, markers to label ferroptosis cell death in vivo have not been found. The exact cause as well as the specific role of iron in this process still has to be researched. Another challenge is that of ferroptosis induction by the GPX4 inhibitor which primarily helps in the development and functioning of the nervous system and kidney. The problem of ferroptosis resistance was also observed in HeLa cell lines after undergoing treatment with Erastin.

Also read: Everything you need to know about Prostate Cancer

Reference:

1. Bano, I., Horky, P., Abbas, S. Q., Majid, M., Bilal, A., Ali, F., Behl, T., Hassan, S., & Bungau, S.
   (2022). Ferroptosis: A New Road towards Cancer Management. Molecules (Basel, Switzerland),
   27(7), 2129. https://doi.org/10.3390/molecules27072129

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