Shishir Shishodia

CURCUMIN: GETTING BACK TO THE ROOTS

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‐κB, AP‐1, Egr‐1, β‐catenin, and PPAR‐γ), 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, Crohns disease, cardiovascular diseases, osteoporosis, Alzheimers 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 Suppresses the Paclitaxel-Induced Nuclear Factor-κB Pathway in Breast Cancer Cells and Inhibits Lung Metastasis of Human Breast Cancer in Nude Mice

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-κB (NF-κB) activation and most chemotherapeutic agents activate NF-κB 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-κB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IκBα kinase activation and IκBα 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-κB, 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-κB and NF-κB–regulated gene products.

Suppression of the Nuclear Factor‐κB Activation Pathway by Spice‐Derived Phytochemicals: Reasoning for Seasoning

Abstract: The activation of nuclear transcription factor κB has now been linked with a variety of inflammatory diseases, including cancer, atherosclerosis, myocardial infarction, diabetes, allergy, asthma, arthritis, Crohns disease, multiple sclerosis, Alzheimers disease, osteoporosis, psoriasis, septic shock, and AIDS. Extensive research in the last few years has shown that the pathway that activates this transcription factor can be interrupted by phytochemicals derived from spices such as turmeric (curcumin), red pepper (capsaicin), cloves (eugenol), ginger (gingerol), cumin, anise, and fennel (anethol), basil and rosemary (ursolic acid), garlic (diallyl sulfide, S‐allylmercaptocysteine, ajoene), and pomegranate (ellagic acid). For the first time, therefore, research provides “reasoning for seasoning.”

Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis.

Pancreatic carcinoma is a lethal malignancy, with the best available therapeutic option—gemcitabine—yielding response rates of < 10%. Because nuclear factor‐κB (NF‐κB) has been determined to play a role in cell survival/proliferation in human pancreatic carcinoma, this transcription factor is a potential therapeutic target.

Piceatannol Inhibits TNF-Induced NF-κB Activation and NF-κB-Mediated Gene Expression Through Suppression of IκBα Kinase and p65 Phosphorylation

Piceatannol is an anti-inflammatory, immunomodulatory, and anti-proliferative stilbene that has been shown to interfere with the cytokine signaling pathway. Previously, we have shown that resveratrol suppresses the activation of the nuclear transcription factor NF-κB. Piceatannol, previously reported as a selective inhibitor of protein tyrosine kinase Syk, is structurally homologous to resveratrol. Whether piceatannol can also suppress NF-κB activation was investigated. The treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-κB. In contrast, stilbene or rhaponticin (another analog of piceatannol) had no effect, suggesting the critical role of hydroxyl groups. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF-κB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-κB activated by H2O2, PMA, LPS, okadaic acid, and ceramide. Piceatannol abrogated the expression of TNF-induced NF-κB-dependent reporter gene and of matrix metalloprotease-9, cyclooxygenase-2, and cyclin D1. When examined for the mechanism, we found that piceatannol inhibited TNF-induced IκBα phosphorylation, p65 phosphorylation, p65 nuclear translocation, and IκBα kinase activation, but had no significant effect on IκBα degradation. Piceatannol inhibited NF-κB in cells with deleted Syk, indicating the lack of involvement of this kinase. Overall, our results clearly demonstrate that hydroxyl groups of stilbenes are critical and that piceatannol, a tetrahydroxystilbene, suppresses NF-κB activation induced by various inflammatory agents through inhibition of IκBα kinase and p65 phosphorylation.

Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway.

Nuclear factor‐κB (NF‐κB) plays a central role in cell survival and proliferation in human melanoma; therefore, the authors explored the possibility of exploiting NF‐κB for melanoma treatment by using curcumin, an agent with known, potent, NF‐κB‐inhibitory activity and little toxicity in humans.

From traditional Ayurvedic medicine to modern medicine: identification of therapeutic targets for suppression of inflammation and cancer

Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. Extensive research during the last 30 years has revealed much about the biology of cancer. Drugs used to treat most cancers are those that can block cell signalling, including growth factor signalling (e.g., epidermal growth factor); prostaglandin production (e.g., COX-2); inflammation (e.g., inflammatory cytokines: NF-κB, TNF, IL-1, IL-6, chemokines); drug resistance gene products (e.g., multi-drug resistance); cell cycle proteins (e.g., cyclin D1 and cyclin E); angiogenesis (e.g., vascular endothelial growth factor); invasion (e.g., matrix metalloproteinases); antiapoptosis (e.g., bcl-2, bcl-XL, XIAP, survivin, FLIP); and cellular proliferation (e.g., c-myc, AP-1, growth factors). Numerous reports have suggested that Ayurvedic plants and their components mediate their effects by modulating several of these recently identified therapeutic targets. However, Ayurvedic medicine requires rediscovery in light of our current knowledge of allopathic (modern) medicine. The focus of this review is to elucidate the Ayurvedic concept of cancer, including its classification, causes, pathogenesis and prevention; surgical removal of tumours; herbal remedies; dietary modifications; and spiritual treatments.

Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-κB (NF-κB) activation and NF-κB–regulated gene expression

The plant Withania somnifera Dunal (Ashwagandha), also known as Indian ginseng, is widely used in the Ayurvedic system of medicine to treat tumors, inflammation, arthritis, asthma, and hypertension. Chemical investigation of the roots and leaves of this plant has yielded bioactive withanolides. Earlier studies showed that withanolides inhibit cyclooxygenase enzymes, lipid peroxidation, and proliferation of tumor cells. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and inflammation are regulated by activation of nuclear factor-κB (NF-κB), we hypothesized that the activity of withanolides is mediated through modulation of NF-κB activation. For this report, we investigated the effect of the withanolide on NF-κB and NF-κB-regulated gene expression activated by various carcinogens. We found that withanolides suppressed NF-κB activation induced by a variety of inflammatory and carcinogenic agents, including tumor necrosis factor (TNF), interleukin-1β, doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, as both inducible and constitutive NF-κB activation was blocked by withanolides. The suppression occurred through the inhibition of inhibitory subunit of IκBα kinase activation, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. NF-κB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR-associated death domain, TNFR-associated factor 2, and IκBα kinase was also suppressed. Consequently, withanolide suppressed the expression of TNF-induced NF-κB-regulated antiapoptotic (inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like interleukin-1β-converting enzyme–inhibitory protein) and metastatic (cyclooxygenase-2 and intercellular adhesion molecule-1) gene products, enhanced the apoptosis induced by TNF and chemotherapeutic agents, and suppressed cellular TNF-induced invasion and receptor activator of NF-κB ligand-induced osteoclastogenesis. Overall, our results indicate that withanolides inhibit activation of NF-κB and NF-κB-regulated gene expression, which may explain the ability of withanolides to enhance apoptosis and inhibit invasion and osteoclastogenesis. [Mol Cancer Ther 2006;5(6):1434–45]

The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease

Curcumin: The Indian Solid Gold .- Highly Active Anti-Cancer Curcumin Analogs.- Antioxidant And Anti-Inflammatory Properties Of Curcumin.- Modulation Of Transcription Factors By Curcumin .- Cancer Chemopreventive Effects Of Curcumin.- Anti-Tumor, Anti-Invasion And Antimetastatic Effects Of Curcumin.- Curcumin As An Inhibitor Of Angiogenesis.- Neuroprotective Effects Of Curcumin.- Regulation Of Cox And Lox By Curcumin.- Molecular Targets Of Curcumin.- Cell Growth Regulation.- Curcumin As Chemosensitizer.- Radioprotection And Radiosensitization By Curcumin.- Immunomodulation By Curcumin.- Beneficial Role Of Curcumin In Skin Diseases.- Cardioprotective Effects Of Curcumin.- Protection From Acute And Chronic Lung Diseases By Curcumin.- Nephroprotective And Hepatoprotective Effects Of Curcuminoids.- Curcumin And Autoimmune Disease.- Pharmacokinetics And Pharmacodynamics Of Curcumin.- Clinical Studies With Curcumin.

Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates TNF-Induced NF-κB Activation through Inhibition of Activation of IκBα Kinase and Akt in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of COX-2 Synthesis

The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-κB plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-κB. In the present study, we investigated the effect of this drug on the activation of NF-κB by a wide variety of agents. We found that celecoxib suppressed NF-κB activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1β. Celecoxib inhibited TNF-induced IκBα kinase activation, leading to suppression of IκBα phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-κB without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-κB activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with IκBα kinase (IKK). Celecoxib abrogated the NF-κB-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-κB-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-κB, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-κB, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-κB activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.