Dr.Christopher R. Chitambar, MD | Professor of Medicine and Biophysics | Division of Hematology and Oncology | Medical College of Wisconsin explains how cancer cells are killed by Gallium Maltolate.
This is the trial of an agent that most people have not heard of. It’s called Gallium Maltolate. In the late 60s to early 70s, the Oakridge group was looking at radioisotopes for imaging purposes. They were looking at ways to image tumors and were experimenting by injecting lab animals with Gallium-67 a radioisotope. They found that Gallium-67 is concentrated and localized in tumors. That was the beginning of Gallium scans which is now been replaced by more modern-day imaging technologies. In many parts of the world, the Gallium scan is still being used to image tumors. In the 70s, when this imaging technology picked up steam, it was tested in a lot of tumors and went very quickly into application in humans.
In the early 70s, they did not have an understanding as to why and how this metal isotope was concentrated in the tumors. Subsequent studies show that Gallium bound to a protein, once it was injected into patients, the isotope bound avidly to transferrin. Transferrin is a protein in circulation. Its normally present in the human body, a protein that transports iron, around the body, to cells. It was found that transferrin bound Gallium and that led to targeting and rapid accumulation of Gallium in cancer cells. It was tested in many tumors and many patients.
For detection of residual or occult tumors what you are looking at on the left-hand side of the slide below, those dark areas are lymph nodes where Gallium has accumulated. This was the state of the art for many years for imaging.
Transferrin physiologically, about 1/3 of this protein in the blood is occupied by iron. There is no such thing as free-floating iron in the blood. There is, but it is bound to something, otherwise, it would become very toxic. Tumor cells have on their surfaces the transferrin receptors. Tumors such as lymphoma and other tumors including glioblastoma have very high densities of the transferrin receptors and as a result, they need more iron. Gallium very much mimics iron in its chemical properties except there is no need, our bodies need iron, but they don’t need Gallium, but Gallium will bind to transferrin and it will home in on transferrin receptor-bearing cells.
Gallium is a metal. It was discovered by French chemist Paul Emile Lecoq de Boisbourdran in 1875. It does share certain properties that are similar to iron, its ionic radius is 3+, and it binds to transferrin, and other iron-binding proteins in the circulation as well as ions inside the iron protein, inside the cells. It’s a unique metal and is a solid compound. When you place it on your hand, it kind of semi-liquefies.
Now, why is this all relevant to cancer?
A lot of research has been done into this. Early discoveries show that cancer cells have a far greater need for iron than normal cells. This is because there are lot of processes, metabolism, cell division, and so forth that are amplified in cancer cells. If you look at the image above Gallium is mimicking iron by binding to transferrin and you got this trojan horse approach here where the cancer cells think of taking up iron but in fact, it binds transferrin, but transferrin instead of containing iron contains Gallium. So, the cell thinks it’s taking up iron, through its transferrin receptor, for its utilization but in fact, it’s taking up transferrin Gallium. As a result, you’ve tricked this cancer cell into taking up the metal that in fact will disrupt iron homeostasis in the cancer cell, simply put.
Early studies show when Gallium scans were being developed for patient tumor imaging, it was showing that Gallium was taken up by glioblastoma and brain tumors. The point is that Gallium gets into the brain. The blood-brain barrier is a big obstacle to current chemotherapy. The brain protects itself from foreign agents getting in. It’s a protective mechanism, but the blood-brain barrier may be partially disrupted by brain tumors but it may also be partially intact.
Here’s an example of lymphoma in a patient, you can see that arrow pointing to the hot lymphoma spot in the brain, and after radiation therapy, which was a state of treatment for brain lymphoma in those days, and still involved chemotherapy, you see that complete disappearance making the point that Gallium gets into the brain.
In the first generation, when the discovery was made that radioactive Gallium was taken up by brain tumors, there was a lot of excitement. So, the questions were asked: What about non-radioactive Gallium? And what about stable Gallium salts?
A number of them were tested at the NCI (National Cancer Institute) and the first Gallium compound that was developed was Gallium Nitrate. It’s a soluble Gallium Citrate Nitrate complex and it was designated an investigational drug, in 1979. We’re going back quite a way here with Gallium Nitrate. There were several Phase 1 and phase 2 trials with Gallium Nitrate in a variety of different tumors.
What surfaced from all those phase 2 trials were the questions: Is this active in cancers? Was Gallium Nitrate found to have anti-tumor activity in lymphoma and bladder cancers, those were among the few tumors that were tested. The problem with Gallium Nitrate was it has to be given intravenously, it’s very cumbersome. There were different roles tried. It was given as an intravenous bolus, meaning given over 15-20 minutes and the pharmacokinetics of that was not the best and you had to give it to patients continuously over 24 hours for at least 5-7 days, so you can imagine how difficult that is and how inconvenient it was for patients. Everyone said it would be nice if we would have a tablet, an oral formulation.
Gallium Nitrate is not bio-available when it is given orally. It just isn’t absorbed. Several years later along came the compound Gallium Maltolate.
Gallium, what is it doing?
And this is the result of much research, looking at its mechanisms of action, it acts on the transferrin receptors, and it disrupts iron utilization, by tumors. It inhibits a key enzyme ribonucleic reductase that depends on iron. And it also blocks mitochondrial energy production and induces cell death. What is the precedent for the absorption of iron maltol? Iron maltol is used in Europe to treat iron deficiency, anemia. Orally Gallium Maltol, we’re not sure how it gets across the gut. That’s the entero side there. But it does. Because in the human trials that have been done so far, you can give an individual, oral Gallium Maltolate and then take samples from the blood, and it turns out, that Gallium is bound to transferrin. Just like the radioisotope when injected.
But oral Gallium 99% of it or 95% of it binds, to transferrin. It is mimicking iron transfer. If you look at our model below, how does this all work? If you look at the slide below, in the red or the brown, what you are looking at in the top part, is the microvascular circulation, of the brain. Endothelial cells. Outside of the brain, the endothelial cells of the blood vessels do not have transferrin receptors, but in the brain microvascular endothelial cells have transferrin receptors. That’s how they get their iron. As I said we are hijacking that system and what’s shown here, is the Immuno histochemistry, a slide from the biopsy of the brain.
The brown dot, brown staining, actually represents, the transferrin receptor staining, here. When you get inside the brain parenchyma, the cartoon here shows a glioblastoma. This again is a model, and glioblastomas, also have high levels of transferrin receptors if you look at Immuno histochemistry staining, you will see here, the brown stain representing dark brown and these are low power you can see that this is all positive, meaning, it expresses transferrin receptors. So, there’s a pathway for transferrin-bound iron to get into glioblastoma cells.
The red dots here, Gallium transferrin, is taken up at the same time, whereas once you look at the normal brain, that surrounds the brain tumor, the normal glial cells don’t have transferrin receptors. They get their iron differently. So, you have here a great setup, wherein the glioblastoma cell/tumor has a target, the transferrin receptor sitting in a sea of the brain, normal brain, it’s the island here. When you get to the enzyme that is inhibited.
Ribonucleotide reductase is an enzyme that’s expressed when in proliferating cells, glioblastoma cell is growing, they are proliferating the high-grade glioblastoma and the staining here shows again, the brown stain if you would zoom in here, where these red arrows are, actually stains for Ribonucleotide reductase specifically the M2 subunit that has an iron center.
So, what it’s telling us here is that GBM has a high expression of Ribonucleotide reductase which is a target for Gallium. We’ve shown in other studies that Gallium inhibits Ribonucleotide reductase in one of our early discoveries. Ribonucleotide reductase is not expressed in the normal brain. And why should it be, normal brain is not proliferating glioblastomas. We have a scenario here where you have a target, you have an enzyme that increases and you have a compound. Gallium or a metal that will trick cells into taking it up and blocking the enzyme. Now ferritin is where iron is stored and in glioblastoma, you can see that ferritin is markedly increased, the brown stain here compared to surrounding normal brain.
In short, what this model and the slide are depicting is that glioblastoma cells have a very high requirement for iron and transferrin receptors. We have found in cells that, see the green arrow, glioblastoma cells produce transferrin, secreted and they secrete it as a mechanism into the parenchyma, and they secrete it because they are trying to get more iron for their growth. And Gallium gets on that transferrin and that’s one more way. It’s a very highly proliferative tumor that requires iron and what we referred to as an autocrine mechanism which is trying to produce a substance to help it get iron and that substance happens to be transferrin.
Cancer cells require iron to proliferate. Transferrin, a protein in the human body transports iron into the cancer cells. Gallium Maltolate binds to transferrin mimicking iron and enters the cancer cells. The cancer cell receives Gallium Maltolate via transferrin instead of iron. Cancer cells cannot survive without iron. Thus, Gallium Maltolate assists in cancer cell death by depriving it of iron.
Gallium Maltolate comes in powder form and can be taken orally. Consult with your physician if Gallium Maltolate is right for you. Gallium Maltolate is available here.
P.S: There is an alternative method for disrupting the iron inside cancer cells. It is a slow method and is not suitable for late-stage cancers. In an upcoming article, we will be presenting information related to the non-invasive experimental method for iron disruption in cancer cells. Readers interested in the article can subscribe to our newsletter so that you will be notified as soon as the article is posted.