A nearly universal hallmark of cancer is its addiction to iron. Cancer cells and cancer stem cells have a much higher dependence on iron compared to normal cells. The reasons include:
- Increased proliferation: Cancer cells divide and grow rapidly, leading to a higher demand for iron, which is essential for DNA synthesis and cell division.
- Enhanced metabolic activity: Cancer cells have a high metabolic rate and require iron to produce energy through processes such as mitochondrial respiration and glycolysis.
- Iron-dependent enzymes: Cancer cells rely on iron-dependent enzymes, such as ribonucleotide reductase, for DNA replication and repair. Increased activity of these enzymes contributes to cancer cell survival and proliferation.
- Role in angiogenesis: Iron is necessary for the formation of new blood vessels (angiogenesis), which supply tumors with nutrients and oxygen, enabling their growth and spread.
- Immune evasion: High levels of iron can suppress the immune system, allowing cancer cells to evade immune surveillance and escape destruction by immune cells.
- Iron-dependent gene regulation: Iron can influence the expression of genes involved in cell growth, differentiation, and survival, contributing to cancer cell growth and maintenance.
- Role in epithelial-mesenchymal transition (EMT): Iron can promote EMT, a process through which cancer cells acquire invasive and metastatic properties.
Could cancer’s addiction to iron be its Achilles’ heel? If exploited, could this addiction prove to be cancer’s fatal weakness?
Gallium maltolate (GaM) is a compound consisting of gallium metal and maltol, a naturally occurring organic compound that enhances gallium’s bioavailability. Gallium maltolate has been explored for its potential anti-cancer properties. Gallium, the metal component of gallium maltolate, is similar to iron in its chemical properties. Because of this similarity, gallium can interfere with iron-dependent biological processes, which is the basis for its anti-cancer effects. Below are some of the mechanisms through which gallium maltolate can exert its effects:
- Iron mimicry: Gallium is able to bind to proteins and enzymes that normally bind iron. As an iron mimicker, enters the cancer cells like a “Trojan horse.” When gallium binds instead of iron, the proteins and enzymes often become non-functional or less efficient. For example, gallium can replace iron in the iron-dependent enzyme ribonucleotide reductase, which is crucial for DNA synthesis. This substitution inhibits the enzyme, thus disrupting the proliferation of cancer cells.
- Disruption of iron homeostasis: Gallium maltolate can disrupt iron homeostasis within cells. By acting as an iron mimetic, gallium can induce changes in the expression of iron regulatory proteins and transporters, leading to reduced iron availability within the cell. This can inhibit various iron-dependent metabolic pathways essential for cancer cell growth and survival.
- Induction of apoptosis: Similar to iron chelation, gallium maltolate can induce apoptosis, or programmed cell death, in cancer cells. By disrupting iron-dependent metabolic processes, gallium can lead to the generation of reactive oxygen species and the activation of cellular stress pathways, culminating in apoptosis.
- Anti-angiogenic effects: Gallium has been shown to exert anti-angiogenic effects, meaning it can inhibit the formation of new blood vessels. Tumors rely on angiogenesis to supply nutrients and oxygen for their growth. By inhibiting this process, gallium maltolate can limit the tumor’s ability to grow and spread.
- Immune modulation: Preliminary research suggests that gallium maltolate may have effects on the immune system, potentially altering the activity of macrophages and other immune cells in the tumor microenvironment.
- Synergistic effects with other therapies: Gallium maltolate may be used in combination with traditional chemotherapy or other cancer therapies. Its ability to inhibit DNA synthesis and disrupt iron homeostasis can make cancer cells more susceptible to the effects of other anti-cancer drugs.
Gallium shares striking similarities with iron in its highly oxidized (trivalent) state (Fe3+; ferric iron). However, unlike iron, which can readily transition between ferric and the less oxidized ferrous (divalent) state (Fe2+), gallium remains trivalent (Ga3+) under physiological conditions. As a result, gallium competes with ferric iron, which is essential for the activity of key enzymes. Furthermore, gallium does not integrate into hemoglobin or other crucial molecules containing ferrous iron (Fe2+). This lack of incorporation contributes to the low toxicity of gallium.
Orally administered gallium maltolate seems to utilize the standard iron uptake pathway. It has been administered in doses as high as 3,500 mg/day for numerous 28-day cycles, without any dose-limiting toxicity or significant drug-related side effects. The compound exhibits high oral bioavailability, and its elimination half-life is roughly 17 to 21 hours.
Absorption mainly occurs in the initial segment of the small intestine, where gallium detaches from the maltolate ligand and binds to transferrin present in blood plasma. Transferrin, the primary transport protein for iron, possesses two iron-binding sites per molecule, which can also accommodate gallium ions. Since only around a third of the binding sites are usually occupied by iron, there is ample availability for gallium binding.
Gallium maltolate therapy can be specifically directed toward patients whose cancers demonstrate a preferential uptake of gallium in a gallium-67 citrate nuclear medicine scan, as this would demonstrate high iron stores in the tumors. These patients are more likely to exhibit a positive response to gallium maltolate treatment.
References:
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