Mini-reviewCurcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins
Introduction
“Smart drugs” or “magic bullets” are normally considered to be targeted therapies, whereas dirty drugs are usually regarded as multi-targeted. Most of the emphasis in the last few years have been on designing drugs that hit a single target such as coxibs, erbuitax, enbrel, herceptin, gleevec, and avastin, which inhibit cyclooxygenase (COX)-2, epidermal growth factor receptor (EGFR), tumor necrosis factor (TNF), human epidermal growth factor receptor (HER)- 2, breakpoint cluster region (bcr)-abl and vascular endothelial growth factor (VEGF), respectively (see Fig. 1). Several of these drugs (except gleevec) have been found to be ineffective, very expensive, and even unsafe. Why they have proved so ineffective is not fully understood. The new era of “OMICS”, however, has revealed that most diseases, and especially cancer, are a result of dysregulation of as many as 500 different gene products [1]. Thus inhibition of a single gene product or cell signaling pathway, is unlikely to prevent or treat cancer.
The current paradigm for most treatments is to either combine several smart drugs or design drugs that modulate multiple targets (multitargeted therapy), formally referred to as “dirty drugs”. Thus “dirty drugs” are in and “smart drugs” are out [2], [3]. The best examples of such dirty drugs are “sorafenib”, known to inhibit multiple protein kinases including vascular endothelial growth factor receptor-1 (VEGFR1), VEGFR2, platelet derived growth factor (PDGFR), and Raf kinase; imatinib, which inhibits the tyrosine kinase activity of abl (the Abelson proto-oncogene), c-kit and PDGFR; lapatinib, which inhibits EGFR and HER2 tyrosine kinase activity; suntinib inhibits tyrosine kinase activity of VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, (c-kit), fms-related tyrosine kinase (Flt)-3, and colony stimulating factor (CSF)-1R. While some of these inhibitors are currently in clinical trials [4], others have been approved for human use. Such drugs, however, already exist in “Mother nature” and are commonly referred to as natural products.
One of the most intriguing of these natural drugs is curcumin, a molecule that has been shown to suppress multiple signaling pathways and inhibit cell proliferation, invasion, metastasis, and angiogenesis (Fig. 1). Although several reviews on biological attributes of curcumin have been documented [5], this review summarizes the role of curcumin in regulating multiple cellular pathways and its clinical importance for the treatment of cancer.
Section snippets
Chemistry of curcumin and its analogues
Curcumin (diferuloylmethane), a yellow colored polyphenol, is an active principle of the perennial herb Curcuma longa (commonly known as turmeric; see Fig. 2). The yellow-pigmented fraction of Curcuma longa contains curcuminoids, which are chemically related to its principal ingredient, curcumin. It was first isolated in 1815, obtained in crystalline form in 1870 [6], [7], and identified as 1,6-heptadiene-3,5-dione-1,7-bis(4-hydroxy-3-methoxyphenyl)-(1E,6E) or diferuloylmethane. The
Molecular targets of curcumin
Accumulating evidence suggests that curcumin has a diverse range of molecular targets, supporting the concept that it acts upon numerous biochemical and molecular cascades. This polyphenol modulates various targets either through direct interaction (Fig. 3) or through modulation of gene expression (Table 1 and Fig. 1). Curcumin physically binds to as many as 33 different proteins, including thioredoxin reductase, COX2, protein kinase C (PKC), 5-lipoxygenase (5-LOX), and tubulin (Fig. 3).
Anti-cancer properties of curcumin
Curcumin exhibits anti-cancer activities both in vitro and in vivo through a variety of mechanisms. It inhibits proliferation and induces apoptosis in a wide array of cancer cell types in vitro, including cells from cancers of the bladder, breast, lung, pancreas, prostate, cervix, head and neck, ovary, kidney, brain, bone marrow, and skin [67]. It has also been shown to potentiate the effect of chemotherapeutic agents [44], [45], [68] and of γ-radiation [69] in cell culture. In vivo curcumin
Bioavailability, pharmacodyanamics, pharmacokinetics, and metabolism of curcumin
Studies over the past three decades related to absorption, distribution, metabolism and excretion of curcumin have revealed poor absorption and rapid metabolism of curcumin that severely curtails its bioavailability. For example, Wahlstrom and Blennow in 1978 reported the first study to examine the uptake, distribution, and excretion of curcumin using Sprague–Dawley rats. They found negligible amounts of curcumin in blood plasma of rats after oral administration of 1 g/kg curcumin, indicating
Clinical trials with curcumin
Clinical trials with curcumin have been reported in a few cancers including, oral, breast, vulva, skin, liver, colorectal, bladder and cervical cancer (Table 4).
Conclusion
Almost 3000 studies carried out with curcumin suggest that this natural agent affects numerous pathways linked with tumorigenesis and thus has potential both for prevention and treatment of cancer. Although pharmacologically curcumin is quite safe in humans, its limited bioavailability may be a problem. More clinical trials with curcumin either alone or in combination with existing therapies are needed to fully appreciate its potential. Reformulation of curcumin may also hold promise in the
Acknowledgements
This research was supported by The Clayton Foundation for Research (to B.B.A.). We thank Walter Pagel for a careful editing of the manuscript.
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