Most molecular targets established in modern biology were discovered within the last three decades. The effect of curcumin on most of these targets has
been examined10'12'45'50-201 (Figure 4). The results have revealed that curcumin can modulate several different transcription factors,50-96'113'114 cytokines,45'97-112 growth factors,202-215 kinases,115-128 and other enzymes.91'129-159 Although most diseases are caused by dysregulated inflammation, to find a safe and efficacious anti-inflammatory agent is a real challenge in modern medicine. Steroids are perhaps the best known anti-inflammatory agents. However, there are numerous side effects associated with them. In addition to steroids, numerous nonsteroidal antiin-flamatory drugs (NSAIDs) have been discovered within the last century, and these include salicylates, ibuprofen, sulindac, phenylbutazone, naproxen, diclofenac, indomethacin, and coxibs.216 Experience over the years has indicated that most of these NSAIDs are associated with a constellation of side effects. Perhaps the best example is the cardiovascular system-related side effects recently identified with most coxibs.217-219 Although the intake of such anti-inflammatory agents can be justified for chronic conditions, they are not appropriate as chemopreven-tive agents under normal conditions, because that purpose requires long periods of time. Thus, there is a great need for safer and efficacious anti-inflammatory agents.
Numerous lines of evidence suggest that curcumin is a potent anti-inflammatory agent (see Figure 5). First, curcumin suppresses the activation of the transcription factor NF-kB, which regulates the expression of pro-inflammatory gene products.50-81 Second, curcumin downregulates the expression of COX-2, an
Figure 4. Molecular targets of curcumin. Abbreviations used: NF-kB, nuclear factor-xB; AP-1, activating protein-1; STAT, signal transducers and activators of transcription; Nrf-2, nuclear factor erythroid 2-related factor; Egr-1, early growth response gene-1; PPAR7, peroxisome preoliferator-activated receptor-7; CBP, CREB-binding protein; EpRE, elec-trophile response element; CTGF, connective tissue growth factor; EGF, epidermal growth factor; EGFRK, EGF receptor-kinase; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; NGF, nerve growth factor; PDGF, platelet-derived growth factor; TGF-ß1, transforming growth factor-ß1; VEGF, vascular endothelial growth factor; AR, androgen receptor; Arh-R, aryl hydrocarbon receptor; DR-5, death receptor-5; EGF-R, EGF-receptor; EPC-R, endothelial protein C-receptor; ER-a, estrogen receptor-a; Fas-R, Fas receptor; H2-R, histamine (2)-receptor; InsP3-R, inositol 1,4,5-triphosphate receptor; IR, integrin receptor; IL-8-R, interleukin-8-receptor; LDL-R, low-density lipoprotein-receptor; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase-3; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; LOX, lipoxygenase; Gcl, glutamate-cysteine ligase; NAT, arylamine N-acetyltransferases; IAP, inhibitory apoptosis protein; HSP-70, heat shock protein 70; MDR, multidrug resistance; TNF-a, tumor necrosis factor-a; IL, interleukin; MCP, monocyte chemoattractant protein; MIF, migration inhibition protein; MIP, macrophage inflammatory protein; cAK, autophosphorylation-activated protein kinase; CDPK, Ca2+-dependent protein kinase; cPK, protamine kinase; ERK, extracellular receptor kinase; FAK, focal adhesion kinase; IARK, IL-1 receptor-associated kinase; JAK, janus kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PhK, phosphorylase kinase; PKA, protein kinase A; PKB, protein kinase B; PKC, protein kinase C; pp60c-src, a nonreceptor protein tyrosine kinase c-Src, cellular src kinase; TK, protein tyrosine kinase; FPTase, farnesyl protein transferase; GST, gluthathione-S-transferase; HO, hemeoxygenase; ICAM-1, intracellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; ELAM-1, endothelial leukocyte adhesion molecule-1; Bcl-2, B-cell lymphoma protein 2; SHP-2, Src homology 2 domain-containing tyrosine phosphatase 2, uPA, urokinase-type plasminogen activator, DFF40; DNA fragmentation factor, 40-kd subunit. (See also Plate 3 in the Color Plate Section.)
Acquired immune Gastric ulcer deficiency syndrome
Acquired immune Gastric ulcer deficiency syndrome
enzyme linked with most types of inflammations.75'177-181'183 Third, curcumin inhibits the expression of another pro-inflammatory enzyme, 5-LOX.177'182-184 Additionally, curcumin has been shown to bind to the active site of 5-LOX and inhibit its activity183 Fourth, curcumin downregulates the expression of various cell surface adhesion molecules that have been linked with inflammation.220-222 Fifth, curcumin downregulates the expression of various inflammatory cytokines, including TNF, IL-1, IL-6, IL-8, and chemokines.45'97-112 Sixth, curcumin has been shown to inhibit the action of TNF, one of the most pro-inflammatory cytokines.97-100 Seventh, curcumin is a potent antioxidant, which might contribute to its anti-inflammatory action.16'19'31'159'223-279 All of this recent evidence confirms the anti-inflammatory action of curcumin, known for thousands of years. Its pharmacological safety combined with its anti-inflammatory action, makes it an ideal agent to explore for preventive and therapeutic situations.
Whereas pro-oxidants are considerd mediators of numerous diseases, antioxidants are generally believed to delay or halt the disease. However, this paradigm is not always valid, as most cytokines mediate their effects through pro-oxidant mechanisms. Reactive oxygen species (ROS) also play an important role in cellmediated cytotoxicity (CMC) of the immune system. Numerous reports indicate that curcumin could mediate both pro-oxidant and antioxidant roles. First, cur-cumin could induce the expression of ROS,8'280-282 which plays an important role in the antiproliferative effects of this molecule.283 Second, curcumin binds
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