Therapeutic potential of curcumin and curcumin analogues in rheumatology

The use of alternative medicine is on the rise across nations. Americans alone spent about $34 billion out of pocket on complementary and alternative medicine in 2007.1 Patients with autoimmune disorders have increasingly sought alternative medicines as a complementary as well as 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 commonly 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 also been used as a coloring agent in several food items.3 Even though curcumin has been studied extensively in a variety of disorders, this 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., in 20015 discovered that doses under 4 g were barely measurable. Lao et al., in 20066 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 study7 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 clinical 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: (i) new methods to solubilize commercial curcumin; (ii) new methods to improve drug delivery systems; and (iii) methods to synthesize novel synthetic analogs of curcumin. Work has shown increased solubility (12-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 mice8, 9 as 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): (i) stabilized curcumin micelles by using surfactants such as Tween 80, Triton-X100 and so on; (ii) formulations of stable nanosuspensions of curcumin using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS); (iii) polyethylene glycosylated (PEGylated) curcumin analogs with increased solubility; and (iv) liposomal formulations of curcumin, namely curcumin encapsulated in dextransulfate–chitosan nanoparticles or complexing curcumin with β-cyclodextrin or its derivatives.11 Curcumin analogs have been prepared by altering the structural motif of curcumin. Such structural modifications help slow down its metabolism while increasing potency. Changes made include modification of: (i) aryl side chain; (ii) diketo functionality; (iii) double bond; (iv) active methylene functionality; and (v) metal complexation property of curcumin. Curcumin mimics with various chromophores, capable of targeting proteins important for tumor survival, have also been synthesized. Analogs 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 analog (without the active methylene group and β-diketone moiety of curcumin) to overcome the poor pharmacokinetic properties of curcumin.12 BDMC33 has previously 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 enzymes 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 interleukin-6 and cyclooxygenase-2 partially through disruption of the nuclear factor-κB (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 its real therapeutic utility can be ascertained.12 While curcumin analogs 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 NF-κB and signal transducer and activator of transcription 3 (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 analogs stem from their ability to modulate cell signaling pathways. The activation of MyD88-dependent signaling pathway by toll-like receptor (TLR) 3 and 4 leads to activation of NF-κB, thereby inducing secretion of inflammatory molecules like pro-inflammatory cytokines and cyclooxygenase-2. Curcumin modulates this inflammatory response by inhibiting NF-κB, via inhibition of IKKβ kinase in the MyD88 pathway, as well as by 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 also binds directly to different pro-inflammatory molecules like tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-1, COX-2, human α1-acid glycoprotein and myeloid differentiation protein 2, thereby bringing about anti-inflammatory effects.19 Curcumin has been shown to be beneficial in human rheumatoid arthritis, while curcumin analogs have been investigated in in vitro studies. It would be of interest to investigate the in vitro use of BDMC33 alongside curcumin solubilized by different methods, including heat/pressure8 to compare the efficacies of different forms of curcumin.