Mini-reviewChemopreventive and therapeutic effects of curcumin
Introduction
Chemoprevention was described as the use of natural or synthetic chemicals allowing suppression, retardation or inversion of carcinogenesis [1]. Chemopreventive products present low side effects and toxicity, neutralisation of carcinogens as well as their effects on cells.
Most chemopreventive agents known until today are plant extracts subdivided into two classes: (i) blocking agents, which inhibit the initiation step by preventing carcinogen activation and (ii) suppressing agents, which inhibit malignant cell proliferation during promotion and progression steps of carcinogenesis (Fig. 1).
Agents, such as kahweol and cafesteol (Fig. 2), two diterpens present in coffee, possess a strong chemopreventive potential and were shown to protect cells against mutagenesis and carcinogenesis in animal models [2]. Similar effects were observed with compounds from garlic like diallyl sulphide (Fig. 2), which blocks carcinogenesis in mice, presumably due to essential allyl groups and a central disulphuric chain.
Cassia siamea compound emodin (Fig. 2) presents strong anti-tumoral effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumour in mice [3] and lycopene, extracted from tomatoes, blocks dimethyl benzanthracene (DMBA)-induced carcinomas in hamster [4].
A distinct class of chemopreventive agents including curcumin and resveratrol (Fig. 2) belong to both categories as they present multiple mechanisms of action.
For this review, we summarize one of the best characterized chemopreventive agents, curcumin or diferuloylmethane extracted from the root of Curcuma longa L. (Fig. 3) which presents strong anti-oxidative, anti-inflammatory and anti-septic properties [5] and is widely used in Indian medicine and culinary traditions. However, recent data give additional evidence that curcumin could also serve in cancer therapy as a drug or as an adjuvant to traditional chemotherapy. This review will focus on both chemopreventive and chemotherapeutic effects of curcumin.
Section snippets
Anti-carcinogenic activities of curcumin
Numerous research teams provided evidence that curcumin contributes to the inhibition of tumour formation and promotion as cancer initiation, promotion or progression of tumours is decreased or blocked by this compound. Azuine et al. [6], [7] described curcumin as an inhibitor of tumour formation and promotion induced by benz(a)pyren, 7,12-dimethylbenz(a)anthracen or phorbol esters, while Ikezaki et al. [8] demonstrated that curcumin inhibits cancer development in rat stomach initiated by N
Contribution of curcumin to the induction of apoptotic mechanisms
The ability of curcumin to induce apoptosis in cancer cells without cytotoxic effects on healthy cells contributes to the understanding of the anti-cancer potential of curcumin. This spice is described to efficiently induce apoptosis in various cell lines including HL-60, K562, MCF-7 and HeLa [17]. Curcumin also leads to apoptosis in scleroderma lung fibroblasts (SLF) without affecting normal lung fibroblasts (NLF) [18]. This effect seems to be due to the weak level of protein kinase (PK) Cε in
Anti-inflammatory effects of curcumin
It was published that curcumin inhibits cyclooxygenase 2 (COX-2) as well as lipoxygenase (LOX), two enzymes involved in inflammation [30]. Indeed, cytokine-induced COX-2 transforms arachidonic acid in prostaglandins during acute inflammatory episodes. COX2 is also the prevalent isoform during chronic inflammations. Lipoxygenase transforms arachidonic acid in leukotrienes, which take part in leukocytes recruiting and play a role in inflammation [31].
Moreover, curcumin protects keratinocytes and
Inhibition of nuclear factor kappa B and activating protein-1 transcription factors
It was previously published that curcumin inhibits the activation of the two major transcription factors nuclear factor kappa B (NF-κB) and activating protein (AP)-1. Our group described this effect in K562 leukemia cells in which curcumin strongly inhibits tumor necrosis factor (TNF) α-induced NF-κB and TPA-induced AP-1 binding to the corresponding target sequences on GSTP1-1 gene promoter or consensus binding sites [36]. Bharti et al. [37] discovered that IκB kinase (IKK) complex inhibition
Effect on detoxification enzyme expression mechanisms
Cytochrome P450 (CYP) are phase I enzymes involved in activation of carcinogens whose inhibition adds a degree of cellular protection against cancer. It was previously published that curcumin inhibits alkylation reaction of ethoxyresorufin, methoxyresorufin and pentoxyresorufin catalysed by CYP 1A1, 1A2 and 2B1 in rat liver [59]. Similarly, aflatoxine-DNA adduct formation, catalysed by the CYP system, is inhibited by curcumin [60]. In DMBA-treated MCF7 cells, CYP activity is dramatically
Conclusions
The available experimental evidence suggests that it is worth testing curcumin as a cancer therapeutic agent. All published observations indicate that curcumin leads to a strong modification of cell signalling pathways including a reduction NF-κB and AP-1 transcription factors. In conclusion, cell-type specific effects of curcumin are highly significant in selected pathologies and future research will allow a better understanding of pathways targeted by curcumin as well as its chemical
Acknowledgements
The authors thank B. Aggarwal for inspiring discussions. Research of this group is supported by the ‘Fondation de Recherche Cancer et Sang’, the ‘Recherches Scientifiques Luxembourg’ association as well as by Télévie grants. AD and MS were supported by fellowships from the Government of Luxembourg. The authors thank ‘Een Häerz fir kriibskrank Kanner’ association for generous support. Print costs were paid by a FNR-Luxembourg grant.
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