Iron is needed for Ferroptosis but its availability can be inhibited.

Lynch’s No2 Hypothesis:  Iron is needed for Ferroptosis but its availability can be inhibited at many points. A broad scoping & attack approach is warranted to make iron available for ferroptopic action.

Abstract:  Cancers like Uveal / Ocular melanoma (OM) have a very poor prognosis when they spread. There is no known cure. A correlation between low iron has been noted with metastatic progression. Unusual OM remission cases have been connected with ferroptosis & ferroptopic inducers. Iron is needed for ferroptosis, here we explore the low availability of iron at the cellular level, what  the causes may be and possible therapeutic options.

Background: It is well know that iron deficiency or over exposure has noticeable effects on human health. Iron is an essential element for almost all living organisms as it participates in a wide variety of metabolic processes, including oxygen transport, deoxyribonucleic acid (DNA) synthesis, and electron transport [1].  Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages[2]. Enterocytes can be killed by rotavirus and suffer other injuries. Iron absorption into the plasma is controlled by ferroportin. 

Hepcidin is a circulating peptide hormone secreted by the liver that plays a central role in the regulation of iron homeostasis. It is the master regulator of systemic iron homeostasis, coordinating the use and storage of iron with iron acquisition [3].

Ferritin stores iron, representing iron status. Hepcidin binds to ferroportin, thereby inhibiting iron absorption/efflux. Inflammation in CKD increases ferritin and hepcidin independent of iron status, which reduce iron availability[4]. ccRCC is a sister clear cell cancer to OM and others. These cancers are susceptible to ferroptosis. In the absence of anything in the literature it is hypothesised that hepcidin acts the same way in these cancers and possibly more types.

Dysregulation of hepcidin can lead to iron disorders. In this paper we are primarily concerned with iron not being available at the cellular level for ferroptosis as needed in cancer cell control. It is hypothesised that hepcidin plays a key role and one that has not yet been tested on OM patients.

Increased hepcidin is associated with  chronic inflammation, antimicrobial activity (Escherichia coli (ML35P), Neisseria cinerea, Staphylococcus epidermidis, Staphylococcus aureus & Streptococcus agalactiae) and with action against the fungus Candida albicans. Interestingly hepcidin benefits from hypoxia.

Anecdotally OM patients have been observed with anaemia and others with high ferritin levels which is confusing. However if we consider the role of hepcidin we may hypothesise that both cohorts have reduced iron available for ferroptosis.

Inhibitors of hepcidin are erythroferrone [5] (no draggable candidate found in this search) and large doses of vitamin D (100,000 IU vitamin D2)  [6].

Iron excess can lead to the generation of reactive oxygen species (ROS) which can cause cellular oxidative stress and induce apoptosis in cancer cells. Lack of or lowered iron levels can inhibit  ROS an thus allow cancer cells to progress unchecked.

Iron is highly conserved by the body [7] with the main losses in women with excessive menstrual blood loss.  Major inhibitors of iron absorption are phytic acid, polyphenols, calcium, and peptides from partially digested proteins. Enhancers are ascorbic acid and muscle tissue which may reduce ferric iron to ferrous iron and bind it in soluble complexes which are available for absorption [8]. This an interesting point as ascorbic acid (vitamin C) is regularly injected into cancer patients for its ROS generating properties.
On the inhibitor side black tea has been identified as a polyphenol. Ireland is the second highest consumer of black tea in the world behind Turkey.

Another point of note is the competition with iron for absorption by other heavy metals. Of major interest here is lead. Lead is taken up by the iron absorption machinery (DTM1), and secondarily blocks iron through competitive inhibition. Ireland has areas where public tap water is up to 15 x the national safety limit. The WHO has stated that there are NO safe limits for lead in drinking water[9]. 

Iron deficiency can exist with or without anemia. Some functional changes may occur in the absence of anaemia, but the most functional deficits appear to occur with the development of anaemia. Even mild and moderate forms of iron deficiency anaemia can be associated with functional impairments affecting immunity mechanisms [10],

Testing for available iron levels in serum can be problematic. The WHO has recommended that haemoglobin and ferritin, a protein that is strongly correlated with iron stores in healthy people, are the most useful indicators of the impact of programmes to control iron deficiency. The main problem with ferritin lies in the fact that it is affected by inflammation due to infection and chronic disease, so it is less useful to assess the prevalence of iron deficiency than to estimate a change brought about by a programme. Because of this, the WHO recommended that to assess iron deficiency, the transferrin receptor, in addition to haemoglobin and ferritin, should be measured in places where infection is common[11].

Zinc protoporphyrin reflects the shortage of iron supply and can be detected by RBC fluorimetry.

Anaemia is where the number of RBCs in the blood are low. It is not a measure of iron but is more an indicator of low iron and disease process. Iron is the leading cause of anaemia but not the sole cause. Other causes can be chronic disease, active bleeding, kidney disease, pregnancy, low vitamin B12, A, folate ribiflavin and copper.  

Obesity may be connected to low haemoglobin concentration low serum iron, transferrin saturation band elevated serum ferritin. Obesity-related inflammation may increase hepcidin concentrations and reduce iron availability [12]

Other causes of anaemia are alcoholism, sickle cell, thalassemia, aplastic & hemoltic

Hypothesis:
It is hypothesised that:

    • Iron is necessary for ferroptosis in OM. 
    • That iron must be available at the cellular level.
    • Available Iron levels should be measured appropriately (WHO guidelines).
    • A supportive iron environment should be established.
    • Immediate response should go direct to parenteral iron treatment. 
    • Hepcidin a master iron controller should be managed aggressively.
    • Lead levels in the patient should be tested and addressed
    • In restoring the bodies natural iron pathway post primary treatments, causes of damage must be fully addressed. 

Failure to cover all the escapes & blocks will result in failure. To succeed treating physicians will have to be thorough. 

Declaration of Competing Interest:
The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The author:
Mr. Brendan Lynch is the surviving spouse and carer of a deceased uveal melanoma patient Ms. Belinda Honeyman-Lynch. He has continued the passionate search for a cure. He is an active member in the OM community at national and international levels. He is also a founding member of Ocular Melanoma Ireland (www.ocumirl.org). He is a retired civil servant who's only declared interest is the discovery of a cure for ocular melanoma. 

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