Cancer Letters

Cancer Letters

Volume 269, Issue 2, 8 October 2008, Pages 199-225
Cancer Letters

Mini-review
Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins

https://doi.org/10.1016/j.canlet.2008.03.009Get rights and content

Abstract

Because most cancers are caused by dysregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. Curcumin, a yellow coloring agent in turmeric, has been shown to interact with a wide variety of proteins and modify their expression and activity. These include inflammatory cytokines and enzymes, transcription factors, and gene products linked with cell survival, proliferation, invasion, and angiogenesis. Curcumin has been found to inhibit the proliferation of various tumor cells in culture, prevents carcinogen-induced cancers in rodents, and inhibits the growth of human tumors in xenotransplant or orthotransplant animal models either alone or in combination with chemotherapeutic agents or radiation. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. These aspects of curcumin are discussed further in detail in this review.

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.

References (146)

  • A. Grandjean-Laquerriere et al.

    UVB-induced IL-18 production in human keratinocyte cell line NCTC 2544 through NF-kappaB activation

    Cytokine

    (2007)
  • H.M. Woo et al.

    Active spice-derived components can inhibit inflammatory responses of adipose tissue in obesity by suppressing inflammatory actions of macrophages and release of monocyte chemoattractant protein-1 from adipocytes

    Life Sci.

    (2007)
  • Y.R. Chen et al.

    Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin

    Oncogene

    (1998)
  • A. Kumar et al.

    Human immunodeficiency virus-1-tat induces matrix metalloproteinase-9 in monocytes through protein tyrosine phosphatase-mediated activation of nuclear transcription factor NF-kappaB

    FEBS Lett.

    (1999)
  • L. Camacho-Barquero et al.

    Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis

    Int. Immunopharmacol.

    (2007)
  • R. Mohan et al.

    Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B

    J. Biol. Chem.

    (2000)
  • Y. Zhou et al.

    The interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPARgamma in rat activated hepatic stellate cell in vitro

    Lab. Invest.

    (2007)
  • J. Skommer et al.

    Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4

    Exp. Hematol.

    (2007)
  • E.J. Dean et al.

    Novel therapeutic targets in lung cancer: Inhibitor of apoptosis proteins from laboratory to clinic

    Cancer Treat Rev.

    (2007)
  • R. Kuttan et al.

    Potential anticancer activity of turmeric (Curcuma longa)

    Cancer Lett.

    (1985)
  • A.J. Ruby et al.

    Anti-tumour and antioxidant activity of natural curcuminoids

    Cancer Lett.

    (1995)
  • S. Busquets et al.

    Curcumin, a natural product present in turmeric, decreases tumor growth but does not behave as an anticachectic compound in a rat model

    Cancer Lett.

    (2001)
  • L.G. Menon et al.

    Inhibition of lung metastasis in mice induced by B16F10 melanoma cells by polyphenolic compounds

    Cancer Lett.

    (1995)
  • L.G. Menon et al.

    Anti-metastatic activity of curcumin and catechin

    Cancer Lett.

    (1999)
  • R.J. Anto et al.

    L-929 cells harboring ectopically expressed RelA resist curcumin-induced apoptosis

    J. Biol. Chem.

    (2000)
  • K. Singletary et al.

    Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis and DMBA–DNA adduct formation by curcumin

    Cancer Lett.

    (1996)
  • S.S. Deshpande et al.

    Effects of curcumin on the formation of benzo[a]pyrene derived DNA adducts in vitro

    Cancer Lett.

    (1995)
  • H. Inano et al.

    Radioprotective action of curcumin extracted from Curcuma longa LINN: inhibitory effect on formation of urinary 8-hydroxy-2′-deoxyguanosine, tumorigenesis, but not mortality, induced by gamma-ray irradiation

    Int. J. Radiat. Oncol. Biol. Phys.

    (2002)
  • B. Vogelstein et al.

    Cancer genes and the pathways they control

    Nat. Med.

    (2004)
  • S. Radulovic et al.

    Sunitinib, sorafenib and mTOR inhibitors in renal cancer

    J. Buon.

    (2007)
  • B.B. Aggarwal et al.

    The molecular targets and therapeutics of curcumin in health and disease

  • Vogel, Pelletier, J. Pharm. 2 (1818)...
  • F.V. Daybe

    Uber Curcumin

    den Farbstoff der Curcumawurzzel Ber.

    (1870)
  • V. Lampe

    Milobedzka

    J. Ver. Dtsch. Chem. Ges.

    (1913)
  • K. Prasad et al.

    Prevention of hypercholesterolemic atherosclerosis by garlic, an antixoidant

    J. Cardiovasc. Pharmacol. Ther.

    (1997)
  • M.H. Pan et al.

    Biotransformation of curcumin through reduction and glucuronidation in mice

    Drug Metab. Dispos.

    (1999)
  • S.K. Sandur et al.

    Curcumin, demethoxycurcumin, bisdemothoxycurcumin, tetrahydrocurcumin, and turmerones differentially regulate anti-inflammatory and antiproliferative responses through a ROS-independent mechanism

    Carcinogenesis

    (2007)
  • V.S. Vadhan et al.

    Curcumin downregulates NF-κB and related genes in patients with multiple myeloma: results of a phase1/2 study

    Am. Soc. Hematol.

    (2007)
  • N. Dhillon et al.

    Phase II trial of curcumin (diferuloyl methane), an NF-κB inhibitor, in patients with advanced pancreatic cancer

    J. Clin. Oncol.

    (2006)
  • A.C. Bharti et al.

    Curcumin diferuloylmethane inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells

    J. Immunol.

    (2003)
  • B.B. Aggarwal et al.

    Curcumin-Biological and Medicinal Properties

    (2006)
  • Z. Wang et al.

    Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells

    Cancer

    (2006)
  • A.S. Jaiswal et al.

    Beta-catenin-mediated transactivation and cell–cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells

    Oncogene

    (2002)
  • M.G. Marcu et al.

    Curcumin is an inhibitor of p300 histone acetylatransferase

    Med. Chem.

    (2006)
  • A. Chen et al.

    Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1

    Oncogene

    (2006)
  • B.B. Aggarwal et al.

    TNF blockade: an inflammatory issue

    Ernst Schering Res. Found Workshop

    (2006)
  • Y. Fu et al.

    Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation

    Mol. Pharmacol.

    (2008)
  • A. Gulcubuk et al.

    Effects of curcumin on tumour necrosis factor-alpha and interleukin-6 in the late phase of experimental acute pancreatitis

    J. Vet. Med. A. Physiol. Pathol. Clin. Med.

    (2006)
  • C.A. Dinarello

    The paradox of pro-inflammatory cytokines in cancer

    Cancer Metastasis Rev.

    (2006)
  • J.W. Cho et al.

    Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets

    Int. J. Mol. Med.

    (2007)
  • Cited by (0)

    View full text