CommentaryCurcumin as “Curecumin”: From kitchen to clinic
Introduction
Natural plant products have been used throughout human history for various purposes. Having coevolved with life, these natural products are billions of years old. Tens of thousands of them are produced as secondary metabolites by the higher plants as a natural defense against disease and infection. Medicines derived from plants have played a pivotal role in the health care of many cultures, both ancient and modern [1], [2], [3], [4], [5]. The Indian system of holistic medicine known as Ayurveda uses mainly plant-based drugs or formulations to treat various ailments including cancer. Of the approximately 877 small-molecule drugs introduced worldwide between 1981 and 2002, most (61%) can be traced back to their origins in natural products [1]. This is not surprising since plant-based drugs may be more suitable – at least in biochemical terms – for medicinal human use than the many exotic synthetic drugs produced through combinatorial chemistry. Nonetheless, modern medicine has neither held in very high esteem nor encouraged the medicinal use of natural products.
Over the last two decades, however, successful attempts to better understand molecular mechanisms of action of some natural products have kindled interest in their therapeutic use in modern medical settings. Remarkably, most of the natural products experimentally evaluated so far have been found to be nontoxic or to have effective doses far below their toxic doses. The role of natural products in human healthcare cannot be underestimated. An estimated 80% of individuals in developing countries depend primarily on natural products to meet their healthcare needs [6]. Recent surveys suggest that one in three Americans uses medicinal natural products daily and that possibly one in two cancer patients (i.e., up to 50% of patients treated in cancer centers) uses them as well. The current review is limited to curcumin, a natural product in use for thousands of years
Curcumin (diferuloylmethane), a polyphenol, is an active principle of the perennial herb Curcuma longa (commonly known as turmeric) (Fig. 1). The yellow-pigmented fraction of turmeric contains curcuminoids, which are chemically related to its principal ingredient, curcumin. The major curcuminoids present in turmeric are demethoxycurcumin (curcumin II), bisdemethoxycurcumin (curcumin III), and the recently identified cyclocurcumin [7]. The major components of commercial curcumin are curcumin I (∼77%), curcumin II (∼17%), and curcumin III (∼3%). The curcuminoid complex is also referred to as Indian saffron, yellow ginger, yellow root, kacha haldi, ukon, or natural yellow 3. Curcuminoids are present in 3–5% of turmeric. Though principally cultivated in India, Southeast Asia, China, and other Asian and tropical countries and regions, turmeric is also common in other parts of the world and is recognized by different names in different languages worldwide (Table 1). [8]
Curcumin was first isolated in 1815, obtained in crystalline form in 1870 [9], [10], and ultimately identified as 1,6-heptadiene-3,5-dione-1,7-bis(4-hydroxy-3-methoxyphenyl)-(1E,6E) or diferuloylmethane. In 1910, the feruloylmethane skeleton of curcumin was confirmed and synthesized by Lampe [11]. Curcumin is a yellow-orange powder that is insoluble in water and ether but soluble in ethanol, dimethylsulfoxide, and acetone. Curcumin has a melting point of 183 °C, a molecular formula of C21H20O6, and a molecular weight of 368.37 g/mol. Spectrophotometrically, the maximum absorption (λmax) of curcumin in methanol occurs at 430 nm and in acetone at 415–420 nm [12]. A 1% solution of curcumin contains 1650 absorbance units. Curcumin appears brilliant yellow hue at pH 2.5–7 and red at pH > 7. Curcumin exists in enolic and β-diketonic forms. The fact that curcumin in solution exists primarily in its enolic form [13] has an important bearing on the radical-scavenging ability of curcumin.
The stability of curcumin in aqueous media improves at high pH (>11.7) [14], [15]. Although quite soluble in organic solvents such as DMSO, ethanol, methanol, or acetone, it is poorly soluble in aqueous solvents [16]. Curcumin is stable at acidic pH but unstable at neutral and basic pH, under which conditions it is degraded to ferulic acid and feruloylmethane [15], [16], [17]. Most curcumin (>90%) is rapidly degraded within 30 min of placement in phosphate buffer systems of pH 7.2 [15], [17]. The ability of antioxidants such as ascorbic acid, N-acetylcysteine (NAC), and glutathione to prevent this degradation suggests that an oxidative mechanism is at work. Degradation of curcumin is extremely slow at pH 1–6 [15], as normally encountered in the stomach. In contrast, one of curcumin's major metabolites (tetrahydrocurcumin, or THC) is quite stable at neutral or basic pH [18] and still possesses antioxidant activities [19], [20], [21]. Curcumin is soluble in 0.1 M sodium hydroxide, although it remains stable for only 1–2 h. In comparison, curcumin is more stable in cell culture medium containing 10% fetal calf serum and in human blood, <20% of curcumin being degraded within 1 h and approximately 50% by 8 h [15]. trans-6-(4′-Hydroxy-3′-methoxyphenyl)-2,4-dioxo-5-hexenal is a major degradation product; vanillin, ferulic acid, feruloylmethane are minor degradation products. The amount of vanillin increases with incubation time. In addition, curcumin appears to be stabilized by forming complexes with cyclodextrin [22].
Section snippets
Traditional uses of curcumin
Traditionally, turmeric has been put to use as a foodstuff, cosmetic, and medicine. As a spice, it is used to provide curry with its distinctive yellow color and flavor. It is used a coloring agent in cheese, butter, and other foods [23], [24]. In folk medicine, turmeric and natural curcuminoids have been applied as therapeutic preparations over the centuries in different parts of the world. In Ayurvedic medicine, curcumin is a well-documented treatment for various respiratory conditions (e.g.,
Molecular targets of curcumin
Accumulating evidence suggests that curcumin has a diverse range of molecular targets, which supports the notion that curcumin influences numerous biochemical and molecular cascades (Table 2). Among its molecular targets are transcription factors, growth factors and their receptors, cytokines, enzymes, and genes regulating cell proliferation and apoptosis.
Curcumin is a potent chemopreventive agent
Numerous studies in rodent models argue for curcumin's chemopreventive potential in cancer (Table 4). Curcumin can reportedly suppress the tumorigenic activity of a wide variety of carcinogens in cancers of the colon, duodenum, esophagus, forestomach, stomach, liver, breast, leukemia, oral cavity, and prostate. In studies in mice, curcumin was able to inhibit 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation [31], [120],
Pharmacokinetic and pharmacodynamic studies of curcumin in animals and humans
The pharmacokinetics and pharmacodynamics of curcumin have been widely investigated. Perhaps the first study to examine the uptake, distribution, and excretion of curcumin was conducted in 1978 by Wahlstrom and Blennow in Sprague-Dawley rats [150]. When administered orally at a dose of 1 g/kg, approximately 75% of the ingested curcumin was excreted in the feces and only negligible amounts in the urine. As indicated by blood plasma levels and biliary excretion, curcumin was poorly absorbed from
Clinical studies of curcumin
In response to the growing mass of in vitro and in vivo evidence for curcumin's chemopreventive and therapeutic efficacy, a number of clinical trials over the past two and a half decades have addressed the pharmacokinetics, safety, and efficacy of curcumin in humans (Table 6). Although these trials have concerned numerous inflammatory diseases including cancer, our focus in the sections to come will be on those dealing with cancers.
Ongoing clinical trials of curcumin
Enthusiasm for further studies of curcumin's chemopreventive and therapeutic effects continues to grow. Three trials of curcumiun have recently concluded, although their results have yet to be published. At least 12 active clinical trials of curcumin are ongoing in the United States, Israel, and Hong Kong (Table 7). Curcumin is being used alone in most of these trials and in combination with quercetin or sulindac in one. Meanwhile, chemoprevention trials of curcumin in hepatocellular carcinoma,
Adverse effects of curcumin
Though curcumin is demonstrably bioactive and nontoxic, there are rare anecdotal reports of its deleterious side effects under certain conditions. Frank et al. [197] reported that copper-bound curcumin loses its ability to inhibit liver and kidney tumors in Cinnamon rats. Others have noted that curcumin can exhibit some blood-thinning properties such as suppression of platelet aggregation, although it remains to be established whether curcumin interacts in any way with blood-thinning drugs.
Conclusions
Extensive research over the last half century has made clear that most chronic illnesses can only be cured by multi-targeted, as opposed to mono-targeted, therapy [204], [205], [206] and that promiscuous targeting of a disease cell's multiple bypass mechanisms is a therapeutic virtue [207]. Consequently, agents that can modulate multiple cellular targets are now attractive objects of research. As this review has shown, curcumin is one such agent and has the potential to treat a variety of
Acknowledgements
We would like to thank Jude Richard, ELS, for carefully editing the manuscript and providing valuable comments. Dr. Aggarwal is the Ransom Horne, Jr, Professor of Cancer Research. This work was supported by grants from the Clayton Foundation for Research and from cancer center support grant 5P30 CA016672-32 from National Institute of Health.
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