Therapeutic potential of curcumin and curcumin analogues in rheumatology

The use of alternative medicine is widespread worldwide and is on the rise in the United States. Americans spent about $34 billion out of pocket on complementary and alternative medicine in 2007(1). Patients with autoimmune disorders have increasingly sought alternative medicine as a complementary and primary means of ameliorating disease.

The phytochemical curcumin, (1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione), the principal component in the curry spice turmeric obtained from the rhizome of Curcuma longa, is a widely used alternative medicine that has been studied extensively in a variety of inflammatory disorders. The history of the use of turmeric (curcuma longa) as a food spice and as a treatment for a variety of ailments goes back 5000 years(2). Turmeric has been used as a coloring agent in several foods such as mustards, cheeses, spices, cereals, potato flakes, soups, pickles, ice creams, and yogurts in the US(3). Even though curcumin has been studied extensively in a variety of disorders, the phytochemical is plagued with the problem of very poor bioavailability, owing to its lack of aqueous solubility and rapid biotransformation processes during first pass through the liver.

Sharma et al administered 440–2200 mg of curcuma extract per day (containing 36–180 mg of curcumin) for up to 29 days to subjects with advanced colorectal cancer, but failed to detect curcumin or curcumin metabolites in their blood or urine (4). Cheng et al, 2001 (5) discovered that doses under 4 g were barely measurable. Lao et al, 2006 (6) found no curcumin in the sera of volunteers administered 0.5, 1.0, 2.0 4.0, 6.0, or 8.0 g curcumin. However, these authors observed curcumin levels of only 50.5 and 51.2 ng/mL by 4 h in the sera of two subjects given 10 and 12 g of curcumin, respectively. Yet another study (7) revealed levels of only 22–41 ng/mL in plasma even when a dose of 8 g curcumin/day was supplied orally. While up to 12 g/day is non-toxic in human studies, the potential clinically utility of curcumin is limited by its insolubility.

Commercial curcumin, contains pure curcumin compound (77%), demethoxycurcumin (17%) and bisdemethoxycurcumin (3%). Curcumin compound, demethoxycurcumin and bisdemethoxycurcumin differ from each other structurally by the presence and position of a methoxy group. However, commercial curcumin is largely insoluble in water, rendering it poorly bioavailable. In addition, curcumin compound undergoes rapid metabolism. These concerns have sent investigators searching for (a) new methods to solubilize commercial curcumin, (b) new methods to improve drug delivery systems and (c) methods to synthesize novel synthetic analogues of curcumin.

Work has shown increased solubility (twelve-fold) of commercial curcumin in water using heat, without compromising its structural integrity and function (8). By administering heat/pressure solubilized curcumin or turmeric to MRL-lpr/lpr mice as the sole drinking fluid source, this group has demonstrated amelioration of systemic lupus erythematosus and Sjögren’s syndrome like condition in these mice (8, 9) compared to MRL-lpr/lpr mice administered water only. Conjugation of curcumin with polyethylene glycol (35 kD) has also improved its solubility in water (10).

In order to establish novel systems for curcumin delivery, investigators have developed (with increases in solubility and bioavailability up to 5.2 fold) (a) stabilized curcumin micelles by using surfactants such as Tween 80, Triton-X100 etc. (b) formulations of stable nanosuspensions of curcumin using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) (c) polyethylene glycosylated (PEGylated) curcumin analogs with increased solubility and (d) liposomal formulations of curcumin (curcumin encapsulated in dextransulfate–chitosan NPs or complexing curcumin with β-cyclodextrin or its derivatives (11).

Curcumin analogues have also been prepared by altering structural motif of curcumin. Such structural modifications help slow down its metabolism while increasing potency. Changes made include modification of (a) aryl side chain (b) diketo functionality (c) double bond (d) active methylene functionality and (e) metal complexation property of curcumin. Curcumin mimics with various chromophores, capable of targeting proteins important for tumor survival, have also been synthesized. Analogues of curcumin show therapeutic effect modulating several signaling pathways important for several diseases, including rheumatoid arthritis (11).

In this issue Ka-Heng et al report the use of BDMC33 (2,6-bis[2,5-dimethoxybenzylidene]cyclohexanone), a new curcumin-like diarylpentanoid analogue (without the active methylene group and b-diketone moiety of curcumin) to overcome the poor pharmacokinetic properties of curcumin (12). BDMC33 has been shown to have increased anti-inflammatory properties compared to curcumin. In this in vitro study using synovial fibroblast stimulated by phorbol-12- myristate acetate, the authors report that BDMC33 modulates matrix metalloproteinase (gelatinase and collagenase) activity, the enzyme responsible for degradation of extracellular matrix in joint tissues. By reducing the activity and expression of these enzymes as well as other inflammatory molecules like IL-6 and cyclooxygenase-2 partially through disruption of the NF-κB signaling pathway, BDMC33 has the potential to reduce inflammation in rheumatoid arthritis. However, as the authors suggest, BDMC33 needs to undergo pharmacokinetic and toxicity testing before it’s real therapeutic utility can be determined (12). While, curcumin analogues have not been studied in human rheumatoid arthritis, some studies have shown the potential therapeutic effect of curcumin in this disorder.

Curcumin treatment down-regulated Bcl-2 and Bcl-xL, up-regulated Bax, activated caspases-3 and 9 while degrading poly(ADP-ribose) polymerase (PARP) in the synovial fibroblasts of rheumatoid arthritis patients (13). Cyclooxygenase-2 suppression and blockade of prostaglandin E2 production by curcumin has also been shown to inhibit the inflammatory response in synovial fibroblasts (14). By treating 50 osteoarthritis patients with curcumin, a clinical study found that curcumin provided protection from joint inflammation via down-regulation of cyclooxygenase-2 and lipoxygenase enzymes as well as NFκB and STAT3 inflammatory transcription factors (15). In a randomized pilot study, subjects with active rheumatoid arthritis were given curcumin (500 mg, 14 patients) or curcumin with diclofenac sodium (50 mg, 12 patients). Disease Activity Score and American College of Rheumatology score showed that the subjects who took just the curcumin fared better than those who took curcumin plus diclofenac sodium (16). The efficacy of curcumin and its analogues stems from their ability to modulate cell signaling pathways.

The activation by toll-like receptor 3 and 4 of MyD88-dependent signaling pathway leads to activation of NF-κB, thereby inducing secretion of inflammatory molecules like cytokines and cyclooxygenase-2. Curcumin modulates this inflammatory response by inhibiting NF-κB, via inhibition of IKKβ kinase in MyD88 pathway, as well as inhibiting dimerization of TLR 4 receptor complex (essential for downstream signaling pathway activation)(17). The phytochemical also down-regulates several inflammation associated cell surface adhesion molecules. Immense amount of work has been carried out to investigate the mechanism by which curcumin exerts its anti-inflammatory effect.

Curcumin inhibits autoantigen-autoantibody interaction, an effect thought to be mediated by its direct interaction with the proteins involved(18). Curcumin binds directly also to different inflammatory molecules like tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-1, COX-2, human α1-acid glycoprotein, and myeloid differentiation protein 2 and thereby bring about anti-inflammatory effect(19).

Curcumin has been shown to be beneficial in human rheumatoid arthritis, while curcumin analogues have been investigated in in vitro studies. It would be of interest to investigate the in vitro use of BDMC33 alongside curcumin solubilized in dimethylsulfoxide or with heat/pressure (8) to directly compare the efficacy between the different forms of curcumin. Finally, pharmacokinetic and toxicity testing is essential to fully determine the therapeutic utility of BDMC33.