Ferroptosis is one of the newly discovered programmed cell deaths. It differs from other known cell death forms, such as apoptosis, autophagy, and necrosis. This new discovery involves three primary metabolisms: iron, thiol, and lipid. Moreover, it leads to an iron-dependent production of lipid peroxidation. 

Recent studies say that ferroptosis plays a significant role in suppressing tumor growth and development. As a result, it opens new opportunities in cancer therapy and management. 

This blog post will highlight ferroptosis’ role in cancer therapy. So, read on if you want to understand ferroptosis better and how it works in cancer management. 

What is Ferroptosis?

Ferroptosis is a relatively new discovery of programmed cell death. It differs from the other known forms of cell death, such as necrosis, autophagy, and gene regulation, in terms of biochemistry and morphology. 

The Ferroptosis process does not require energy consumption. Moreover, it is not inhibited by inhibitors of apoptosis. In addition, it has no intracellular calcium overload. One of the markers of ferroptosis is a significant cytoplasmic iron and lipid ROS increase. It also has a decrease in the mitochondrial level and an increase in the bilayer membrane thickness. 

Not only does the discovery of ferroptosis give medical experts new ideas for treating cancer, but it also provides new solutions for managing drug resistance. 

Hallmarks of Ferroptosis

Below are the three primary hallmarks that define ferroptosis. 

They are: 

• The loss of lipid peroxide repair capability by the phospholipid hydroperoxide Glutathione peroxidase 4. 
• Redox-active iron availability
• The oxidation of polyunsaturated fatty acids (phospholipids that contain PUFA)

P53 and KEAP1/NRF2 activity can also determine the sensitivity of ferroptosis. It links ferroptosis to the pathways of key tumor suppressors. These discoveries in cancer biology emerge as significant finds in precision medicine discovery.

Mechanism of Ferroptosis

One characteristic of ferroptosis that defines its mechanism is the intracellular iron-dependent accumulation of lipid peroxides. This event is influenced by glutathione peroxidase 4 (GPX4) and iron ions, lipid reactive oxygen species (L-ROS). 

It is generally accepted that the excessive accumulation of L-ROS causes ferroptosis. Still, it depends on the catalysis of intracellular ions. Therefore, this process results in a break in the balance of the production and clearance of ROS, which finally leads to ferroptosis. Intracellular ROS are primarily produced by the mitochondrial respiratory chain. It can also be made by a series of chemical reactions in the endoplasmic reticulum and the reduced NADPH oxidase (NOX) and reduced nicotinamide adenine dinucleotide phosphate (NADPH).

The normal rate of the oxidation-antioxidant system maintains ROS in a certain range. Beyond the normal scope is considered to promote tumor development and progression. The nuclear factor-factor 2 (Nrf2) and the GPX4, heat shock factor-binding protein β1 (HSBP1), negatively regulate ferroptosis by limiting ROS production. Moreover, it reduces cellular iron uptake. On the contrary, the NADPH oxidase and P53 exert a positive regulation by inducing the production of ROS.

A similar mechanism for a cofactor working as a diffusible antioxidant was also discovered in the same year for tetrahydrobiopterin (BH4). It is a byproduct of the rate-limiting enzyme GCH1. The same study concluded that ferroptosis can be induced via the inhibition of GPX4. It is similar to the molecular mechanism of action of ML162, RSL3, and ML210. In some cells, the FSP1 compensates for the absence of GPX4 activity. Both GPX4 and FSP1 should be inhibited simultaneously to instigate ferroptosis.

Cancers Related to Ferroptosis

The preliminary studies hinted that ferroptosis is potentially efficient in killing tumor cells. Below are the types of cancers where it may produce positive outcomes.

• Renal cell carcinomas
• Breast
• Ovarian
• Acute myeloid leukemia
• Lung
• Pancreatic ductal adenocarcinoma
• Glioblastoma
• B-cell lymphoma

The World Health Organization (WHO) ranked cancer as the 2nd leading cause of death. In addition, it can affect any tissue or organ of the body. Studies say that inducing ferroptosis or utilizing ferroptosis activators, combined with cancer medication, plays a crucial role in prevention, intervention, and general cancer management.

The changes in iron metabolism mechanisms contribute to the metastasis and occurrence of cancer. 

The upregulation of iron levels also induced ferroptosis in breast cancer. Breast cancer cells showed vulnerability to ferroptosis through a combination of lapatinib and Siramesine. Both cells exhibited an autophagic cycle independent of ferroptosis activity. It indicates that the two different types of cell death can be managed to trigger at specific times after the treatment.  

Small Molecules that Inhibit Tumor Cell Growth via Ferroptosis

• Erastin
• Sulfasalazine
• Sorafenib
• (1S, 3R)-RSL3
• ML162
• ML210

Final Thoughts

Although ferroptosis cancer therapy is relatively new, it already showed potential. The discovery of ferroptosis’s role in cancer management shows great things ahead in oncology. Remember, cancer affects millions of people worldwide. We should support novel treatment methods to help those in need.

Safe and Efficient Cancer Management

Living with cancer is a life-long challenge. That’s why we offer safe and efficient cancer treatment and management. The Institute of Integrative BioOncology supports and practices innovative cancer management techniques like ferroptosis. 

We aim to provide safe and efficient cancer treatment to help you recover and live a happier life. 

Dr. Paul Zhang specializes in conventional and innovative cancer management therapies with years of experience and a positive track record. 

You can reach us by calling 7137971900 today.