In the previous essay, I talked about the incredible synergy between Dexamethasone, an anti-inflammatory steroid, and curcumin, a natural medicine derived from the spice turmeric. Multiple myeloma, a fatal bone marrow lymphoma, was largely erradicated in one month using only Dexamethasone and curcumin. I am an expert on the pharmacology of glucosteroids, such as Dexamethasone. This expertise goes back 30 years. I know what I am talking about.
Dexamethasone is a synthetic glucosteroid which is at least ten times more powerful than the natural glucosteroid cortisol (hydrocortisone). This anti-inflammatory steroid is used to treat an almost endless variety of inflammatory diseases. Unfortunately, over time steroid resistance develops, thereby reducing the effectiveness of this remarkable anti-inflammatory drug.
In this essay, I am going to discuss the biochemistry of Dexamethasone and curcumin and how they synergize or help one another. It appears that what Dexamethasone or curcumin cannot therapeutically accomplish alone they can certainly accomplish when used together.
The combination of Dexamethasone and curcumin would be extremely useful in the treatment of diseases including lymphomas, leukemias, arthritis, asthma, and a host of other inflammatory diseases. This combination CANNOT be used in the treatment of sarcoma or carcinoma cancers. More on this topic some other time.
Let's start at the beginning.
Glucosteroids such as Dex are well known to inhibit the activation of the pro-inflammatory genetic factor NF-kappaB. I have written extensively about the pharmacology of the NF-kappaB genetic factor and its relationship to the development of inflammatory diseases and cancer.
http://grouppekurosawa.com/blog/2006/03/nf-kappab-holy-grail-of-cancer.htm
http://grouppekurosawa.com/blog/2005/09/nf-kappab-immunity-inflammation-and.htm
Although these blog essays refer primarily to the activation of NF-kappaB and cancer cell survival, activated NF-kappaB is linked to a LONG list of inflammatory diseases. Dexamethasone is a well known inhibitor of NF-kappaB activation.
If NF-kappaB inactivation becomes impaired, the anti-inflammatory capacity of Dex and similar steroids rapidly declines.
Glucosteroid resistance is a complicated phenomenon which takes many different forms. Since glucosteroids are a mainstay of medical treatment, especially for asthma, arthritis, and lymphoma/leukemia. Unfortunately, the chronic use of glucosteroids usually results in the establishment of resistance. If we can find ANYTHING that enhances the anti-inflammatory efficacy of glucosteroids, it will be a tremendous advance in clinical medicine.
First, let's take a look at the two glucosteroid receptors.
Glucosteroids have two cellular receptors. The first is GRalpha, the primary receptor that modulates the anti-inflammatory capacity of glucosteroids. The second is GRbeta, a receptor which actually antagonizes the anti-inflammatory capabilities of GRalpha. The expression of GRbeta over GRalpha induces steroid resistance.
TNF, tumor necrosis factor, a mis-named pro-inflammatory hormones stimulates the synthesis of GRbeta. This induces steroid resistance. Other immune hormones can do the same. Glucosteroid resistance is very common in sites of chronic inflammation.
Interestingly, not all glucosteroids are equally sensitive to the inhibitory affects of over expressed GRbeta receptors. Methylprednisolone apparently continues to function as an anti-inflammatory hormone in the presence of elevated concentrations of GRbeta. This is an important observation because it means that methylprednisolone is THE glucosteroid of choice for therapeutic treatment applications.
Now lets talk about the GRalpha receptor itself. NF-kappaB and the GRalpha/hormone complex play directly opposite roles in the body. NF-kappaB is pro-inflammatory while GRalpha stimulates an anti-inflammatory response. NF-kappaB and the GRalpha glucosteroid receptor directly interact. This interaction is fundamental to the mutual antagonism reported for these two genetic factors. While the GRalpha protein can physicially interact with NF-kappaB, thereby inhibiting its ability to activate pro-inflammatory genes, NF-kappaB can equally inhibit the activity of the GRalpha pathway. If the NF-kappaB pathway is highly activated in a cell, it is certain that GRalpha signaling will be impaired.
There is more.
The GRalpha glucosteroid receptor is reversibly acetylated. When acetylated, the GRalpha complex cannot bind and inhibit the activity of NF-kappaB. The GRalpha complex binds the histone deacetylase HDAC2. This deacetyase keeps the GRalpha complex in a NON-acetylated form, thereby preserving its anti-inflammatory capacity.
Steroid resistance is caused by a failure of HDAC2 to bind and deacetylate GRalpha.
The enzyme that acetylates GRalpha is not absolutely known, but it is probably CBP/p300, an acetyltransferase which is associated with the GRalpha complex.
The control of inflammatory gene expression is controlled by the acetylation of histones. Hyperacetylation of histones activates gene expression. Hypoacetylation inactivates gene expression. Anti-inflammatory drugs like glucosteroids block the activation of inflammatory related genes, such as immune hormones, by preventing excessive histone acetylation. This results in gene inactivation.
Glucosteroids inhibit histone acetylation in two ways. First, they inhibit the activity of the CBP/p300 acetyltransferase. Second, they promote the migration of the histone deacetylase HDAC2 to specific genes. First and foremost, this inhibits the NF-kappaB mediated activation of pro-inflammatory genes.
How can curcumin synergize with glucosteroids for the treatment of disease? Consider the following.
1. Both curcumin and glucosteroids inhibit the CBP/p300 acetyltransferase. This turns OFF pro-inflammatory genes.
2. The inhibition of CBP/p300 acetyltransferase by curcumin also, no doubt, promotes the association of the GRalpha complex with NF-kappaB, resulting in the inactivation of NF-kappaB activated pro-inflammatory genes.
3. Keep in mind that that the GRalpha/NF-kappaB interaction occurs in the nucleus at the site of specific genes. Glucosteroids do not prevent the activation of NF-kappaB or the migration of NF-kappaB into the nucleus. But curcumin does.
4. Curcumin prevents the activation of NF-kappaB in the cytoplasm of the cell.
Obviously, the curcumin-mediated inhibition of NF-kappaB activation in the cytoplasm is going to tremendously enhance the anti-NF-kappaB role of glucosteroids in the nucleus. High amounts of NF-kappaB in the nucleus can completely overwhelm the ability of glucosteroids to inhibit pro-inflammatory gene expression.
5. The proteasome, an enzyme complex in the cell that degrades and processes proteins, degrades the GRalpha receptor. This is a method of routine feedback inhibition of excessive glucosteroid activity.
Curcumin is a proteasome inhibitor. The inhibition of proteasome activity enhances glucosteroid bioactivity.
This is a general essay on the synergy between glucosteroids and curcumin in the alleviation of inflammatory gene expression. As such, we concentrated on the inactivation of NF-kappaB gene activation by both curcumin and GRalpha. This is a good start. But there is MUCH more.
Stay tuned...
Grouppe Kurosawa, Medicine in the Public Interest
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