Like evolution vs. creation and the origins of life, there are two competing theories regarding the origins of cancer: Genetic mutation and metabolic dysfunction. Which of these is correct? It turns out, both are correct, and iron is at the very center. Iron dysregulation unifies the concepts embodied in both the genetic and metabolic theories of cancer. Something called the intracellular labile iron pool (LIP) acts as a central hub in the birth of cancer and links iron metabolism to traditional cancer hallmarks. Increases in the LIP create reactive oxygen species (ROS) which in turn induces mitochondrial (metabolic) dysfunction. Increases in the LIP also induce genomic instability. At the end of the day, iron may be the important issue that needs to be dealt with when it comes to fighting cancer.
The process by which normal cells are transformed into cancer cells involves iron dependency and ferroptosis resistance. Due to the higher rates of proliferation and DNA synthesis in cancer cells vs. normal cells, cancer cells have greater requirements for and contain much more iron than normal cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance, and immune evasion. Bottom line, the greater need for iron by cancer cells vs. normal cells is a distinct difference that can and should be exploited to gain the upper hand. In other words, turning cancer’s love of iron into its worst nightmare!
Besides apoptosis, one of the other mechanisms of cancer-cell death is ferroptosis. The term “ferroptosis” was first coined in 2012 to describe the iron-mediated overaccumulation of oxidatively damaged phospholipids called lipid peroxides that induce irreversible damage to cell membranes. Ferroptosis is a type of programmed or regulated necrosis of cells. As such, it is much more immunogenic than apoptosis. Due to the release of immune-attracting damage-associated molecular patterns (DAMPs), ferroptosis recruits and activates immune cells at tumor sites. Furthermore, ferroptosis has been found to target cancer stem cells.
In a recently published landmark study, scientists at the University of British Columbia believe they may be one step closer to defeating cancer after finding what they call the disease’s “Achilles’ heel.” Their study uncovered a protein that fuels cancer when tumor oxygen levels are low (tumor hypoxia). It enables cancer to adapt and survive and become more aggressive. This protein is called carbonic anhydrase IX (CAIX) and it helps cancer cells spread (metastasize) to other organs.
Cancer depends on the CAIX enzyme to survive by protecting it from ferroptosis-mediated cell death. The scientists found that inhibiting CAIX acidifies intracellular pH, disrupts redox homeostasis, and induces vulnerability to ferroptosis. By inhibiting CAIX, scientists believe we can effectively stop cancer cells from growing and spreading. According to one of the study authors, Dr. Shoukat Dedhar, “Combining inhibitors of CAIX, including SLC-0111, with compounds known to bring about ferroptosis results in catastrophic cell death and debilitates tumor growth.”
Comments from Dr. Thomas: If you have metastatic cancer and are in need of promising treatment options, do you wait a decade or more to see if the experimental compound SLC-0111 becomes an FDA-approved drug? Do you wait while approved drugs that induce ferroptosis are developed? I do not recommend it. Right now, we can use acetazolamide or spermidine to inhibit CAIX and stimulate autophagy to sensitize tumors to ferroptosis; and artemisinin, piperlongumine, and sodium selenite to promote ferroptosis and induce death of cancer cells and cancer stem cells.
The anti-tumor immune effect of ferroptosis can be enhanced by using Ganoderma lucidum (reishi mushroom extract) to increase the activity of dendritic cells, cytotoxic T-lymphocytes, B-lymphocytes, Natural Killer cells, and phagocytic macrophages. Additionally, because tumor hypoxia inhibits ferroptosis, to further sensitize tumors to ferroptosis, we can add pentoxifylline and transcutaneous carbon dioxide to promote tumor oxygenation. And to fully exploit the benefits of iron-mediated cell death, we can combine intravenous low-molecular-weight iron dextran with hyperthermia.
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