July 19th 2008 post. Our bodies need iron in order to function normally, but too much iron can increase the risk of developing cancer by promoting free radicals, and let’s also not forget that, once you have cancer, your cancer cells eagerly gobble up this metal, which is essential to their growth and wellbeing.
But too little iron can lead us to develop anaemia, which is one of the markers of active myeloma. Anaemia, in fact, is the “A” in the acronym “CRAB.” Can’t have too much..can’t have too little…
It just so happens that, according to my most recent (April) test results, my serum iron and ferritin (ferritin, by the way, is a protein that binds to and stores iron that the body can use when needed) are the lowest they have ever been, as far as I know. In May I went to see my fabulous family doctor who didn’t see that as a sign of the myeloma kicking up any dust. No worries. What is important, he remarked, is that my haemoglobin and haematocrit are normal (they are). By the way, he was very pleased with my overall results. So am I.
He told me to take an iron supplement to increase my serum iron levels, but, as stubborn as an Alpine goat, I decided to wait for my next test results (still haven’t taken them, by the way). The reason for my stubbornness will be clear at the end of this post.
I should mention that I have been intending to write about curcumin and its effect on body iron for quite some time now, but other things have been getting in the way. Today I was finally inspired to look over a draft that I wrote back in March (!), when an Italian blog reader (grazie!) left me a comment pointing to a study on curcumin that might provide an explanation for my low iron levels. Sherlock did not have access to that particular journal, but she was able to hunt down and send me a couple of other studies.
The first study deals specifically with curcumin and iron. It’s titled Iron chelation in the biological activity of curcumin and was published in “Free Radical Biology & Medicine” in 2006. You can read the abstract here: http://tinyurl.com/3q9zzu
But first, what is iron chelation? The body cannot metabolize some heavy metals such as mercury and lead, and an accumulation of too much of this stuff can cause toxic effects, interfere with regular body functions etc. Heavy metals can be removed from the body using what are called chelating agents that bind to metals, hold on tightly to ‘em and finally expel them.
Apparently that is what curcumin does. As we can read in the above-mentioned abstract, ferritin protein levels decreased in cultured liver cells when curcumin was present. And Mice that were fed diets supplemented with curcumin exhibited a decline in levels of ferritin protein in the liver.
And now for a look at the full study, without overloading the post with details that I can barely grasp myself. The first part examines the well-known chemopreventive action of curcumin, so skip skip skip.
Then we get to the ferritin-iron-curcumin discussion. The jargon in this part is quite convoluted, hard to translate into simpler language. I did my best. Oh, before I forget: I skipped the part about the increase in GST, or glutathione S-transferase, in cultured liver cells, since that would have made this post way too long. But if you are interested in GST, let me know, and I will be glad to forward the entire study to you. Back to business, now.
The researchers suggest that iron chelation may be a novel mechanism that contributes to the potent cancer chemopreventive activity of curcumin. In their tests, curcumin activated IRPs, or iron regulatory proteins. These thingies get activated when iron levels decrease, for instance as a result of treatment with iron chelators. So far, so good.
The team examined the effect of curcumin on mice whose diet also contained some iron. One group was fed more curcumin, another less, and then there was the usual control (no curcumin) group: ferritin H and L proteins were both reduced to approximately 50% of control in mice receiving 2.0% dietary curcumin. (“H” stands for heavy, “L” for light.) I would like to mention that in no case were any adverse effects or toxicity observed as a result of the administration of curcumin to the mice.
The team also found that curcumin induced ferritin mRNA but reduced ferritin protein in cultured liver cells. Ehhh? I know, I know. But I found a rather simple (?) explanation (the link to this UC Berkeley study that I used in my March draft doesn’t work anymore, sorry about that!) that may help us figure out the difference between the two types of ferritin: iron accumulates in tissues in a solid, slow release form thanks to the ferritin protein. Ferritin protein manages iron and oxygen.
Ferritin mRNA instead has to do with genes, as the “mRNA” part suggests: A special structure in ferritin mRNA controls the synthesis rate of ferritin protein when iron has entered the cell. Okay, this is probably still not completely obvious to anybody without a scientific background, like yours truly. But the point is: curcumin’s ability to distinguish between the two types of ferritin—increasing the levels of the one (ferritin mRNA) but decreasing the levels of the other (ferritin protein)—suggests that it acts as an iron chelator, since iron chelators do the exact same thing.
Let’s have a look at the study results: One mechanism of action of synthetic chemopreventive agents is the induction of cytoprotective proteins. These include ferritin, a protein that functions as a cytoprotective protein by virtue of its ability to bind iron and reduce oxidative stress. And, just like chemotherapy, curcumin increases the levels of both subunits of mRNA ferritin, H (heavy) and L (light).
But, in contrast with chemo drugs, the levels of regular ferritin protein H and L declined to approximately 65% of control in cells treated with curcumin. That is quite a drop. The team demonstrated, however, that it is possible to reverse the trend, since iron depletion causes decreased levels of ferritin: If iron depletion underlies the curcumin-dependent decrease in levels of ferritin protein, then it should be possible to reverse the effect of curcumin on ferritin by repleting cells with iron. That is exactly what happened, and the researchers found that iron blocks curcumin-dependent ferritin repression.
At the end of the study we get to a very interesting bit of news. The researchers suggest that the intake of iron as a dietary supplement may bind to and interfere with the beneficial activity of curcumin. Aha! And, in fact, earlier in the study they write that iron was recently shown to attenuate the cytotoxic effects of curcumin in cultured squamous cell carcinoma. So iron renders curcumin less effective. Makes sense.
Well, after reading this study, I will not be taking an iron supplement…for now, at least. I cannot and indeed should not avoid iron completely (it’s in a lot of foods, of course), but I certainly don’t want to take anything extra that might interfere with curcumin’s anticancer activities…no way!
UPDATE, November 7 2008 post: Another study on curcumin’s function as an iron chelator was published in “Blood” last month (abstract: http://tinyurl.com/5fhhwd). The interesting part is that these Wake Forest University NC researchers wanted To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, using mice whose diets contained graded concentrations of both iron and curcumin for 26 weeks. Well, after reading the full study, I have reached a couple of conclusions. But first, the study…
As we can read in the abstract, the researchers found that curcumin has the potential to affect systemic iron metabolism, particularly in a setting of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.
Hmmm, doesn’t sound too good, eh. Well, now for the full study (grazie Sherlock!).
As usual, it begins with info on how curcumin has been used traditionally, how human Phase I clinical trials of curcumin have yielded good results, such as almost no toxicity, and so on. It then discusses how curcumin works—inhibition of NF-kappaB and so on. Skip, skip. Skip.
Then the study mentions a 2006 study, which I discussed in a previous post (see my Page on curcumin and iron). In a nutshell, liver cells treated with curcumin showed a decrease in ferritin, raising the possibility that the chelator activity of curcumin might be sufficient to induce systemic iron depletion, potentially triggering or exacerbating subclinical or clinical iron deficiency.
The first thing that the researchers did was put groups of mice on either high or low iron diets. Then curcumin was added to the mix, up to the equivalent of 8-12 grams a day. No toxicity from the curcumin was observed, by the way. So far, so good.
Results: the addition of curcumin had no effect on the hematocrit, haemoglobin, serum iron or transferrin saturation of the “high-iron” mice BUT it did have a dramatic effect on the “low-iron” mice. All the above-mentioned values declined; the higher the curcumin dose, the lower the values.
However, before we freak out and toss our precious bottles of curcumin into the rubbish bin, let me say that the Discussion part of the study makes a few interesting points.
1. Compared to other chelators used for the treatment of iron overload, curcumin has a moderate chelator activity.
2. Indian diets are traditionally low in bio-available iron. This is important, since Indians consume quite a bit of curcumin via the spice from which it is extracted–turmeric. So, theoretically, Indians should be an anemic population en masse with their large consumption of turmeric and low iron intake, right? Hmmm…I doubt that that is the case…
On the negative side, the mice with the iron-deficient diet ended up with iron deficiency anemia, including a decline in serum iron, decreased hematocrit, decreased transferrin saturation and appearance of hypochromic red blood cells. “Hypochromic” red blood cells means “paler than usual” red blood cells = anemia (Werriam Webster definition: marked by or being red blood cells with deficient haemoglobin).
Then we read that Curcumin also decreased iron levels in the bone marrow and spleen. And that curcumin-mediated changes in the liver were extensive: curcumin reduced liver iron, activated IRP, repressed ferritin, blablabla.
This sounds really scary, but hey, after all I have been on a high dose of curcumin for almost three years, and I am not anemic. Yes, my haemoglobin is on the low end of normal but is still hanging in there. I just checked, and, as far back as 2005, my Hgb has never been super high. So, without meaning to sound flippant, I say, no big deal. My serum iron, though, took a plunge in February, after our (Sherlock’s and mine) failed Biocurcumax experiment. So far, it hasn’t recovered, and for the past three set of tests has been slightly below the normal range. I will keep an eye on it.
At any rate, at the end of the study, the researchers make a few important points: There are two important implications of these results. First, iron chelators have been shown to exert anti-tumor effects, both through the formation of redox-active iron complexes and by iron depletion. Thus, reduction in systemic iron resulting from the use of curcumin in the setting of a low iron diet may contribute to the anti-cancer activity of curcumin. Second, curcumin may have the potential to contribute to the development of anemia in patients with marginal iron status. This may be an important consideration when curcumin is used to treat patients with marginal or depleted iron stores or those exhibiting the anemia of cancer and chronic disease.
So if you are healthy but trying to prevent the development of cancer and your iron levels are normal or high, don’t worry about taking curcumin. However, you have to be more cautious if you are a cancer patient with low iron levels. Problem is, if we, the low-iron myeloma folks, add an iron supplement to our daily intake, we may end up inhibiting curcumin’s anticancer activity (again, see my Page on curcumin and iron)…sigh. Catch-22.
My own conclusions. Driving to work this morning, I decided to wait until I get my test results in mid December before taking any action on the iron front. I will begin taking an iron supplement in December if I see that my Hgb, serum iron and ferritin levels keep dropping compared to my July tests. If I do start taking iron, though, I will wait at least 12 hours before swallowing my curcumin, so as to minimize any possible interference.
In yesterday’s post I forgot to mention that a couple of weeks ago I came across a bottle of curcumin (in my medicine cabinet) that turns out not to be the C3 Complex curcumin that I usually take. No idea where it came from, my parents must have brought it with them last spring. Anyway, each capsule contains about 850 mg of curcumin, which means that I have to take only 10 capsules a day, not 16 (bonus!). And each capsule has a bit of bioperine in it, which is good. So I decided, what the heck?, and began taking this new curcumin. That was about ten days before I had my blood tests.
But the big decision of the past few days is that I have decided to begin taking feverfew, in its capsule form. The parthenolide content is rather low, but I hope it WILL work anyway. This weekend I am going to do some research on when and how to take it (at the same time as I take my curcumin or not?), etc.
Next tests in January. My parthenolide tests. Exciting!
UPDATE: after reading this post, Sherlock wrote me a private note reminding me that her Hgb is the same as it was one year ago (=before she began taking curcumin). However, get this: her serum iron and transferrin have actually gone UP since 2007. Now that is interesting. (Hmmm, my transferrin is high, incidentally…food for thought.)
The only value that has decreased in a year’s time for Sherlock is her ferritin. So, curcumin may have a different effect on different people. After all, we are not mice!