Curcumin: The story so far
Introduction
Phytochemicals are naturally occurring substances found in plants. There has been considerable public and scientific interest in the use of phytochemicals derived from dietary components to combat human diseases, especially the two commonest killers in the developed world, cardiovascular disease and cancer. The dried ground rhizome of the perennial herb Curcuma longa Linn., called turmeric in English, haldi in Hindi and ukon in Japanese, has been used in Asian medicine since the second millenium BC [1]. Its utility is referred to in the ancient Hindu scripture, the Ayurveda. In addition to its aromatic, stimulant and colouring properties in the diet, turmeric is mixed with other natural compounds such as slaked lime and has been used topically as a treatment for wounds, inflammation and tumours. In contrast to the maximum dietary consumption of 1.5 g per person per day in certain South East Asian communities, smaller quantities of turmeric tend to be used for medicinal purposes [2]. The appeal of turmeric as a colouring, food preservative and flavouring is global – according to the Food and Agriculture Organization of the United Nations, over 2400 metric tons of turmeric are imported annually into the USA for consumer use.
Curcuma spp. contain turmerin (a water-soluble peptide), essential oils (such as turmerones, atlantones and zingiberene) and curcuminoids including curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione]. Curcuminoids can be defined as phenolic compounds derived from the roots of Curcuma spp. (Zingiberaceae). Curcumin (diferuloylmethane) is a low molecular weight polyphenol, first chemically characterised in 1910, that is generally regarded as the most active constituent of and comprises 2–8% of most turmeric preparations 3, 4. Curcumin has been the subject of hundreds of published papers over the past three decades, studying its antioxidant, anti-inflammatory, cancer chemopreventive and potentially chemotherapeutic properties. The pharmacology and putative anti-cancer properties of curcumin have been the subject of several review articles published since 1991 5, 6, 7, which pre-date a number of clinical studies of curcumin which have been completed and published within the last 2 years. The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer, particularly of the gastrointestinal tract, via an understanding of its pharmacology at preclinical and clinical levels. It will be argued on the basis of the data presented that the current state of knowledge on this phytochemical is sufficient to advocate its advancement into phase II clinical studies.
Section snippets
Chemical properties
Curcumin is a bis-α,β-unsaturated β-diketone. As such, curcumin exists in equilibrium with its enol tautomer. The bis-keto form predominates in acidic and neutral aqueous solutions and in the cell membrane [8]. At pH 3–7, curcumin acts as an extraordinarily potent H-atom donor [9]. This is because, in the keto form of curcumin, the heptadienone linkage between the two methoxyphenol rings contains a highly activated carbon atom, and the C–H carbon bonds on this carbon are very weak due to
Preclinical pharmacokinetics
The absorption, metabolism and tissue distribution of curcumin has been studied in at least 10 studies performed in rodents over the past three decades. In an early study, a dose of 1 g/kg was administered to rats in the diet [16]. About 75% of the dose was excreted in the faeces and negligible amounts appeared in the urine. A few years later, a study of oral curcumin administered to rats demonstrated 60% absorption of curcumin and presented evidence for the presence of glucuronide and sulphate
Safety
Recent concerns regarding the safety of selective enzyme inhibitors in large-scale chemoprevention trials emphasise the importance of carefully evaluating any potential toxicity of agents at the preclinical and early clinical trial levels. It cannot be assumed that diet-derived agents will be innocuous when administered as pharmaceutical formulations at doses likely to exceed those consumed in the dietary matrix. Anecdotal reports suggest that dietary consumption of turmeric up to 1.5 g per
Biological activity in preclinical models
Curcumin is notable for the diversity of its biological actions in preclinical models of carcinogenesis at a very wide range of physiologically attainable and supra-physiological doses (see Fig. 4). Indeed, some studies have suggested that curcumin elicits systemic effects relevant to the chemoprevention of cancer in hepatic and mammary tissues of animals following attainment of levels of curcumin in these tissues that are only in the 10−9–10−8 M range 36, 37.
Dose–effect relationships
Although any substantial data in favour of a dose–response relationship for any biomarker of curcumin’s activity is currently lacking, several observations in human volunteers and patients suggest that curcumin may possess systemic biological activity at low oral doses. In a small study performed in Taiwan, a single oral dose of 20 mg curcumin appeared to induce contraction of the gall bladder assessed by ultrasound scanning in human volunteers, compared to amylum placebo [117].
In a pilot study
Conclusions
Curcumin possesses wide-ranging anti-inflammatory and anti-cancer properties. Many of these activities can be attributed to its potent antioxidant capacity at neutral and acidic pH, its inhibition of cell signalling pathways at multiple levels, its diverse effects on cellular enzymes and its effects on angiogenesis and cell adhesion. In particular, curcumin’s ability to affect gene transcription and induce apoptosis in preclinical models advocates its potential utility in cancer chemoprevention
Conflict of interest statement
None declared.
Acknowledgements
We thank the patients who have participated in the clinical trials reviewed in this article, our many postdoctoral and student collaborators who have conducted laboratory work on curcumin over the past decade, and Jo Arden, Sue Spriggs and Sara Jones for help with the manuscript.
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