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The use of turmeric, derived from the root of the plant Curcuma longa, for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years. The active component of turmeric responsible for this activity, curcumin, was identified almost two centuries ago. Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets, including transcription factors (e.g., NF-B, AP-1, Egr-1, ␤-catenin, and PPAR-␥), enzymes (e.g., COX2, 5-LOX, iNOS, and hemeoxygenase-1), cell cycle proteins (e.g., cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6, and chemokines), receptors (e.g., EGFR and HER2), and cell surface adhesion molecules. Because it can modulate the expression of these targets, curcumin is now being used to treat cancer, arthritis, diabetes, Crohn's disease, cardiovascular diseases, osteoporosis, Alzheimer's disease, psoriasis, and other pathologies. Interestingly, 6-gingerol, a natural analog of curcumin derived from the root of ginger (Zingiber officinalis), exhibits a biologic activity profile similar to that of curcumin. The efficacy, pharmacologic safety, and cost effectiveness of curcuminoids prompt us to "get back to our roots."

Curcumin (diferuloylmethane), an anti-inflammatory agent used in traditional medicine, has been shown to suppress cellular transformation, proliferation, invasion, angiogenesis, and metastasis through a mechanism not fully understood. Because several genes that mediate these processes are regulated by nuclear factor-B (NF-B), we have postulated that curcumin mediates its activity by modulating NF-B activation. Indeed, our laboratory has shown previously that curcumin can suppress NF-B activation induced by a variety of agents (J Biol Chem 270:24995-50000, 1995) . In the present study, we investigated the mechanism by which curcumin manifests its effect on NF-B and NF-B-regulated gene expression. Screening of 20 different analogs of curcumin showed that curcumin was the most potent analog in suppressing the tumor necrosis factor (TNF)-induced NF-B activation. Curcumin inhibited TNF-induced NF-B-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF-B reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2, NF-B-inducing kinase, IB kinase complex (IKK), and the p65 subunit of NF-B. Such TNFinduced NF-B-regulated gene products involved in cellular proliferation [cyclooxygenase-2 (COX-2), cyclin D1, and c-myc], antiapoptosis [inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x L , Bfl-1/A1, TNF receptor-associated factor 1, and cellular Fas-associated death domain protein-like interleukin-1␤-converting enzyme inhibitory protein-like inhibitory protein], and metastasis (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1) were also down-regulated by curcumin. COX-2 promoter activity induced by TNF was abrogated by curcumin. We found that curcumin suppressed TNFinduced nuclear translocation of p65, which corresponded with the sequential suppression of IB␣ kinase activity, IB␣ phosphorylation, IB␣ degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Curcumin also inhibited TNF-induced Akt activation and its association with IKK. Glutathione and dithiothreitol reversed the effect of curcumin on TNF-induced NF-B activation. Overall, our results indicated that curcumin inhibits NF-B activation and NF-B-regulated gene expression through inhibition of IKK and Akt activation.It is generally assumed that traditional medicines are safe and efficacious, given that they have been used for centuries. Despite the widespread use of these medicines, however, research to definitively establish safety and efficacy of many of them is lacking. Between 1981 and 2002, almost 74% (48 of 65) of all drugs approved for cancer were either natural products or based on natural products (typically, analogs or mimics) (Newman et al., 2003). The delineation of their Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.doi:10.1124/mol.105.017400. ABBREVIATIONS:COX-2, cyclooxygenase-2; MMP, matrix metalloproteinase; TNF, tumor necro...

Currently, there is no effective therapy for metastatic breast cancer after surgery, radiation, and chemotherapy have been used against the primary tumor. Because curcumin suppresses nuclear factor-nB (NF-nB) activation and most chemotherapeutic agents activate NF-nB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis. We tested this hypothesis using paclitaxel (Taxol)-resistant breast cancer cells and a human breast cancer xenograft model. As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-nB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of InBa kinase activation and InBa phosphorylation and degradation. Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-nB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-nB and NF-nB^regulated gene products.Although early-stage breast cancer is highly treatable, no effective treatment is available for metastatic breast cancer that follows surgery, radiation, and chemotherapy for the primary tumor (1). Paclitaxel (Taxol) is currently used as the front-line chemotherapeutic agent in breast cancers (1); however, because the drug frequently induces drug resistance (2 -4), probably through the activation of nuclear factor-nB (NF-nB; ref. 5), it is not useful in treating advanced breast cancer.Curcumin (diferuloylmethane), a polyphenol (see Fig. 1A) derived from turmeric, Curcuma longa, is a pharmacologically safe and effective agent that can block NF-nB activation. Curcumin has been shown by us and others to suppress NFnB activation induced by various inflammatory stimuli (6) through inhibition of the activation of InBa kinase (IKK) activity needed for NF-nB activation (7,8). Based on the paclitaxel and curcumin data, we hypothesized that curcumin would improve the therapeutic outcome of paclitaxel treatment for breast cancer. We tested this hypothesis using breast cancer cells and a nude mouse xenograft model. Our goal was to determine whether curcumin can suppress paclitaxel-induced NF-nB activation and NF-nB -regulated gene products and prevent breast cancer metastasis to the lung. We found that curcumin did block paclitaxel-induced NF-nB activation and NF-nB -regulated gene expression in breast ...