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PubMed2004

Curcumin inhibits mitogen stimulated lymphocyte proliferation, NFkappaB activation, and IL-2 signaling.

BACKGROUND: T cell mediated acute rejection of transplanted organ continues to be a noticeable problem in solid organ transplantation. We showed that Curcumin is a potent inhibitor of Cyclosporin A resistant T cell CD28 co-stimulation pathway. Here we report the inhibitory effects of Curcumin on mitogen-stimulated lymphocyte proliferation, IL-2 synthesis/signaling, and NFkappaB (transcription factor of IL-2 promoter) activation. MATERIALS AND METHODS: Human lymphocytes were isolated from fresh human spleen (SP-L). Mitogens [final concentrations of 2 microg/ml concanavalin A (Con A), 5 microg/ml phytohemagglutinin (PHA), and 20 ng/ml of phorbol-12-myristate-13-acetate (PMA)] were added to the designated wells in a 96-well plate with 0.2 million SP-L and cultured for 48 h and then assayed for IL-2 synthesis by ELISA and 3H-thymidine uptake. In another parallel experiment we added IL-2 (0.5 nM) to stimulate the cells to check if Curcumin's inhibition of IL-2 synthesis is the sole reason for inhibition of cell proliferation. Electrophoretic mobility shift assay (EMSA) was performed in PMA (20 ng/ml, 1 h) stimulated cells with or without Curcumin to assay NFkappaB activation. RESULTS: Curcumin at 2.5 microg/ml inhibited Con A, PHA, and PMA stimulated SP-L proliferation at 77, 23, and 48%, respectively, over controls and Curcumin at 5 microg/ml completely (nearly 100%) inhibited the mitogen stimulated proliferation. Curcumin inhibited IL-2 synthesis in Con A, PHA, and PMA stimulated SP-L in a concentration-dependent manner with an ED50 (concentration required for 50% inhibition) measured at 3.5 microg/ml. Exogenous IL-2 stimulated SP-L proliferation was also inhibited by Curcumin in a concentration-dependent manner with an ED50 of 2 microg/ml. EMSA assay indicated that PMA at 20 ng/ml stimulated NFkappaB activation 253% over control, which was inhibited by 24, 38, and 73%, respectively, with Curcumin at final concentrations of 2.5, 5, and 10 microg/ml, respectively. CONCLUSION: Curcumin has profound immunosuppressive effects mediated via inhibition of IL-2 synthesis, mitogen, and IL-2 induced activation of human lymphocytes. This effect may be mediated via NFkappaB inhibition.

Cell Division↗

PubMed2002

Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells.

Multidrug resistance (MDR) is a phenomenon that is often associated with decreased intracellular drug accumulation in the tumor cells of a patient, resulting from enhanced drug efflux. It is often related to the overexpression of P-glycoprotein (Pgp) on the surface of tumor cells, thereby reducing drug cytotoxicity. In this study, curcumin was tested for its potential ability to modulate the expression and function of Pgp in the multidrug-resistant human cervical carcinoma cell line KB-V1. Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) showed that treatment with 1, 5, and 10 microM curcumin for up to 72hr was able to significantly lower Pgp expression in KB-V1 cells. Curcumin (1-10 microM) decreased Pgp expression in a concentration-dependent manner and was also found to have the same effect on MDR1 mRNA levels. The effect of curcumin on Pgp function was demonstrated by rhodamine 123 (Rh123) accumulation and efflux in Pgp-expressing KB-V1 cells. Curcumin increased Rh123 accumulation in a concentration-dependent manner (1-55 microM) and inhibited the efflux of Rh123 from these cells, but did not affect the efflux of Rh123 from the wild-type drug-sensitive KB-3-1 cells. Treatment of drug-resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with an increased intracellular accumulation of Rh123. In addition, curcumin inhibited verapamil-stimulated ATPase activity and the photoaffinity labeling of Pgp with the prazosin analog [125I]iodoarylazidoprazosin in a concentration-dependent manner, demonstrating that curcumin interacts directly with the transporter. Thus, curcumin seems to be able to modulate the in vitro expression and function of Pgp in multidrug-resistant human KB-V1 cells. In summary, this study describes the duel modulation of MDR1 expression and Pgp function by the phytochemical curcumin, which may be an attractive new agent for the chemosensitization of cancer cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Effect of curcumin on the advanced glycation and cross-linking of collagen in diabetic rats.

A close association between increased oxidative stress and hyperglycemia has been postulated to contribute significantly to the accelerated accumulation of advanced glycation end products (AGEs) and the cross-linking of collagen in diabetes mellitus. In the present work, we report the influence of curcumin, an efficient antioxidant, on the level of AGEs and the cross-linking of collagen in diabetic rats. Diabetic rats were given curcumin (200 mg/kg body wt) orally for a duration of 8 weeks. The antioxidant status in serum and the level of AGEs, cross-linking and browning of collagen in tail tendons and skin were investigated. The oxidative stress observed in diabetic rats was reduced significantly by curcumin administration. Nonenzymic antioxidants such as vitamin C, vitamin E, and glutathione were maintained at near normal values in curcumin-treated diabetic animals. Similarly, the accumulation of lipid peroxidation products in diabetic serum was reduced significantly by curcumin. Accelerated accumulation of AGE-collagen in diabetic animals, as detected by ELISA, was prevented by curcumin. Extensive cross-linking of collagen in the tail tendon and skin of diabetic animals was also prevented to a greater extent by curcumin treatment. A correlation between the level of AGEs and collagen cross-linking was noted, suggesting the involvement of advanced glycation in cross-linking. It was also noted that the preventive effect of curcumin on the advanced glycation and cross-linking of collagen was more pronounced than its therapeutic effect. However, the Maillard reaction fluorescence in both tail and skin collagen remained unaltered by curcumin. This study confirms the significance of free radicals in the accumulation of AGEs and cross-linking of collagen in diabetes. It supports curcumin administration for the prevention of AGE-induced complications of diabetes mellitus.

Animals↗

PubMed1999

Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling.

Curcumin, a dietary spice from turmeric, is known to be anti-inflammatory, anticarcinogenic, and antithrombotic. Here, we studied the mechanism of the antiplatelet action of curcumin. We show that curcumin inhibited platelet aggregation mediated by the platelet agonists epinephrine (200 microM), ADP (4 microM), platelet-activating factor (PAF; 800 nM), collagen (20 microg/mL), and arachidonic acid (AA: 0.75 mM). Curcumin preferentially inhibited PAF- and AA-induced aggregation (IC50; 25-20 microM), whereas much higher concentrations of curcumin were required to inhibit aggregation induced by other platelet agonists. Pretreatment of platelets with curcumin resulted in inhibition of platelet aggregation induced by calcium ionophore A-23187 (IC50; 100 microM), but curcumin up to 250 microM had no inhibitory effect on aggregation induced by the protein kinase C (PKC) activator phorbol myrsitate acetate (1 microM). Curcumin (100 microM) inhibited the A-23187-induced mobilization of intracellular Ca2+ as determined by using fura-2 acetoxymethyl ester. Curcumin also inhibited the formation of thromboxane A2 (TXA2) by platelets (IC50; 70 microM). These results suggest that the curcumin-mediated preferential inhibition of PAF- and AA-induced platelet aggregation involves inhibitory effects on TXA2 synthesis and Ca2+ signaling, but without the involvement of PKC.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

Effects of curcumin on P-glycoprotein in primary cultures of rat hepatocytes.

Curcumin is a natural phenolic compound found in the rhizomes of Curcuma longa and endowed with beneficial biological activities including antioxidant, anticarcinogenic and hepatoprotective effects. In this study curcumin was tested for its potential ability to interact in vitro with hepatic P-glycoprotein (Pgp), in a model system represented by primary cultures of rat hepatocytes, in which spontaneous overexpression of multidrug resistance (mdr) genes occurs. In both freshly-plated hepatocytes, containing low levels of Pgp, and 72 hour-cultured hepatocytes, containing high levels of Pgp, the Rhodamine-123 (R-123) efflux, which represents a specific functional test for Pgp-mediated transport, was inhibited by curcumin in a dose-dependent manner. Western blot analysis showed that 25microM curcumin, when included in the culture medium throughout the experimental observation (72 hours), was able to significantly lower the increase of mAb C219-immunoreactive protein spontaneously occurring in the cells during culture. Curcumin, at doses ranging from 50 to 150microM was cytotoxic for freshly-plated hepatocytes, as shown by the strong decrease in the cell ability to exclude trypan blue 24 hours later, but it was significantly less cytotoxic when added to 24 or 48 hour-cultured cells. The resistance to curcumin, progressively acquired by cells during culture, was significantly reduced by high concentrations of dexamethasone (DEX) or dimethyl-sulfoxide (DMSO), culture conditions known to inhibit the spontaneous overexpression of Pgp. In addition, in a concentration-dependent manner, verapamil reverted curcumin resistance in Pgp overexpressing hepatocytes. In photoaffinity labeling studies, curcumin competed with azidopine for binding to Pgp, suggesting a direct interaction with glycoprotein. These results suggest that curcumin is able to modulate in vitro both expression and function of hepatic Pgp and support the hypothesis that curcumin, a chemopreventive phytochemical, could reveal itself also as a compound endowed with chemosensitizing properties on mdr phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3.

Curcumin (Diferuloylmethane) is a major chemical component of turmeric (curcuma longa) and is used as a spice to give a specific flavor and yellow color in Asian food. Curcumin exhibits growth inhibitory effects in a broad range of tumors as well as in TPA-induced skin tumors in mice. This study was undertaken to investigate the radiosensitizing effects of curcumin in p53 mutant prostate cancer cell line PC-3. Compared to cells that were irradiated alone (SF(2)=0.635; D(0)=231 cGy), curcumin at 2 and 4 microM concentrations in combination with radiation showed significant enhancement to radiation-induced clonogenic inhibition (SF(2)=0.224: D(0)=97 cGy and SF(2)=0.080: D(0)=38 cGy) and apoptosis. It has been reported that curcumin inhibits TNF-alpha-induced NFkappaB activity that is essential for Bcl-2 protein induction. In PC-3 cells, radiation upregulated TNF-alpha protein leading to an increase in NFkappaB activity resulting in the induction of Bcl-2 protein. However, curcumin in combination with radiation treated showed inhibition of TNF-alpha-mediated NFkappaB activity resulting in bcl-2 protein downregulation. Bax protein levels remained constant in these cells after radiation or curcumin plus radiation treatments. However, the downregulation of Bcl-2 and no changes in Bax protein levels in curcumin plus radiation-treated PC-3 cells, together, altered the Bcl2 : Bax ratio and this caused the enhanced radiosensitization effect. In addition, significant activation of cytochrome c and caspase-9 and -3 were observed in curcumin plus radiation treatments. Together, these mechanisms strongly suggest that the natural compound curcumin is a potent radiosesitizer, and it acts by overcoming the effects of radiation-induced prosurvival gene expression in prostate cancer.

Apoptosis↗

PubMed2006

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.

High expression of epidermal growth factor receptor (EGFR) is found in a variety of solid tumors, including colorectal cancer. EGFR has been identified as a rational target for anticancer therapy. Curcumin, the yellow pigment of turmeric in curry, has received attention as a promising dietary supplement for cancer prevention and treatment. We recently reported that curcumin inhibited the growth of human colon cancer-derived Moser cells by suppressing gene expression of cyclinD1 and EGFR. The aim of the present study was to explore the molecular mechanisms underlying curcumin inhibition of gene expression of EGFR in colon cancer cells. The generality of the inhibitory effect of curcumin on gene expression of EGFR was verified in other human colon cancer-derived cell lines, including Caco-2 and HT-29 cells. Promoter deletion assays and site-directed mutageneses identified a binding site for the transcription factor early growth response-1 (Egr-1) in egfr promoter as a putative curcumin response element in regulating the promoter activity of the gene in Moser cells. Electrophoretic mobility shift assays demonstrated that curcumin significantly reduced the DNA-binding activity of the transcription factor Egr-1 to the curcumin response element. In addition, curcumin reduced the trans-activation activity of Egr-1 by suppressing egr-1 gene expression, which required interruption of the ERK signal pathway and reduction of the level of phosphorylation of Elk-1 and its activity. Taken together, our results demonstrated that curcumin inhibited human colon cancer cell growth by suppressing gene expression of EGFR through reducing the trans-activation activity of Egr-1. These results provided novel insights into the mechanisms of curcumin inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.

Antineoplastic Agents↗

PubMed2004

Activation of PPARgamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro.

During liver fibrogenesis, quiescent HSC (hepatic stellate cells) become active, a transformation that is associated with enhanced cell proliferation and overproduction of ECM (extracellular matrix). Inhibition of cell proliferation and induction of apoptosis are potential strategies to block the activation of HSC for the prevention and treatment of liver fibrosis. Levels of PPARgamma (peroxisome proliferator-activated receptor gamma) are dramatically diminished in parallel with HSC activation. Stimulation of PPARgamma by its agonists inhibits HSC activation in vitro and in vivo. We demonstrated recently that curcumin, the yellow pigment in curry, inhibited HSC activation in vitro, reducing cell proliferation, inducing apoptosis and inhibiting ECM gene expression. Further studies indicated that curcumin induced the gene expression of PPARgamma and stimulated its activity in activated HSC in vitro, which was required for curcumin to inhibit HSC proliferation. The aims of the present study were to evaluate the roles of PPARgamma activation in the induction of apoptosis and suppression of ECM gene expression by curcumin in activated HSC, and to elucidate the underlying mechanisms. Our results demonstrated that blocking PPARgamma activation abrogated the effects of curcumin on the induction of apoptosis and inhibition of the expression of ECM genes in activated HSC in vitro. Further experiments demonstrated that curcumin suppressed the gene expression of TGF-beta (transforming growth factor-beta) receptors and interrupted the TGF-beta signalling pathway in activated HSC, which was mediated by PPARgamma activation. Taken together, our results demonstrate that curcumin stimulated PPARgamma activity in activated HSC in vitro, which was required for curcumin to reduce cell proliferation, induce apoptosis and suppress ECM gene expression. These results provide novel insight into the mechanisms responsible for the inhibition of HSC activation by curcumin. The characteristics of curcumin, which has no adverse health effects, make it a potential candidate for prevention and treatment of hepatic fibrosis.

Animals↗

PubMed2005

Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner.

Curcumin (diferuloylmethane) is known to induce apoptosis in tumor cells. In asynchronous cultures, with time-lapse video-micrography in combination with quantitative fluorescence microscopy, we have demonstrated that curcumin induces apoptosis at G(2) phase of cell cycle in deregulated cyclin D1-expressed mammary epithelial carcinoma cells, leaving its normal counterpart unaffected. In our search toward delineating the molecular mechanisms behind such differential activities of curcumin, we found that it selectively increases p53 expression at G(2) phase of carcinoma cells and releases cytochrome c from mitochondria, which is an essential requirement for apoptosis. Further experiments using p53-null as well as dominant-negative and wild-type p53-transfected cells have established that curcumin induces apoptosis in carcinoma cells via a p53-dependent pathway. On the other hand, curcumin reversibly inhibits normal mammary epithelial cell cycle progression by down-regulating cyclin D1 expression and blocking its association with Cdk4/Cdk6 as well as by inhibiting phosphorylation and inactivation of retinoblastoma protein. In addition, curcumin significantly up-regulates cell cycle inhibitory protein (p21Waf-1) in normal cells and arrests them in G(0) phase of cell cycle. Therefore, these cells escape from curcumin-induced apoptosis at G(2) phase. Interestingly, these processes remain unaffected by curcumin in carcinoma cells where cyclin D1 expression is high. Similarly, in ectopically overexpressed system, curcumin cannot down-regulate cyclin D1 and thus block cell cycle progression. Hence, these cells progress into G(2) phase and undergo apoptosis. These observations together suggest that curcumin may have a possible therapeutic potential in breast cancer patients.

Animals↗

PubMed2007

Effect of azoxymethane and curcumin on transcriptional levels of cyclooxygenase-1 and -2 during initiation of colon carcinogenesis.

BACKGROUND: Curcumin is well documented as an effective colonic chemopreventive agent in preclinical studies. Inhibition of arachidonic acid metabolism has been considered one of anticarcinogenic mechanisms of curcumin. We recently reported resistance of middle-aged F344 male rats to inhibition of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) by curcumin (Nutr Cancer, 48, 37-43). It was important to confirm this finding and to find potential mechanisms responsible, as loss of preventive activity of curcumin due to aging was a novel finding, with important implications for human intervention trials. METHODS: To confirm our previous findings, and investigate arachidonic acid metabolism as a potential mechanism of age-related differences in response to curcumin, middle-aged F344 male rats were given AOM injections after being fed their experimental diets, 0.6% curcumin or control diet. Colonic ACF were evaluated and colonic levels of cyclooxygenase (COX)-1 and 2 mRNA and prostaglandin E2 (PGE2) were measured. Next, we investigated the short-term effect of AOM and curcumin on arachidonic acid metabolism in young rats. Six week-old rats were given injections of either AOM or untreated following their experimental diets. Colonic COX-1 and COX-2 mRNA as well as PGE2 levels were measured shortly after AOM treatment. Lastly, three different ages of F344 rats were treated with either AOM or saline, and colonic COX-1 and COX-2 mRNA levels were measured shortly after the injections to find if aging alters the effect of AOM on COX mRNA expression. RESULTS: In middle-aged rats, dietary curcumin did not reduce the number of ACF and surprisingly increased colonic levels of COX-2 mRNA. Colonic COX-2 and PGE2 levels were also significantly increased in young rats fed curcumin after AOM injections. Interestingly, AOM did not affect COX-2 but decreased COX-1 expression in all ages. CONCLUSIONS: Our study suggests that during initiation, AOM inhibits colonic COX-1 expression without affecting COX-2 and dietary curcumin may increase COX-2 expression to compensate AOM-induced reduction of COX-1 expression.

Aging↗

PubMed2004

Reactions of superoxide radicals with curcumin: probable mechanisms by optical spectroscopy and EPR.

Reactions of superoxide-crown ether complex with curcumin have been studied in acetonitrile. Optical absorption spectra showed that curcumin on reaction with superoxide forms a blue color intermediate absorbing at 560 nm, which subsequently decayed in a few hours with the development of the absorption band corresponding to the parent curcumin. The regeneration was 100% at low superoxide concentrations (1:1, or 1:2 or 1:3 of curcumin:superoxide) but reduced to 60% at high superoxide concentration (>1:5). The regeneration of curcumin is confirmed by HPLC analysis. Stopped-flow studies in acetonitrile following either the decay of parent curcumin at 420 nm or formation of 560 nm absorption have been used to determine the rate constant for the reaction of superoxide with curcumin. EPR studies confirmed the disappearance of characteristic superoxide signal in presence of curcumin with the formation of new featureless signal with g = 2.0067. Based on these studies it is concluded that at low superoxide concentrations curcumin effectively causes superoxide dismutation without itself undergoing any chemical change. At higher concentrations of superoxide, curcumin inhibits superoxide activity by reacting with it.

Acetonitriles↗

PubMed2003

Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa).

INTRODUCTION: Tumeric is a spice that comes from the root Curcuma longa, a member of the ginger family, Zingaberaceae. In Ayurveda (Indian traditional medicine), tumeric has been used for its medicinal properties for various indications and through different routes of administration, including topically, orally, and by inhalation. Curcuminoids are components of tumeric, which include mainly curcumin (diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcmin. OBJECTIVES: The goal of this systematic review of the literature was to summarize the literature on the safety and anti-inflammatory activity of curcumin. METHODS: A search of the computerized database MEDLINE (1966 to January 2002), a manual search of bibliographies of papers identified through MEDLINE, and an Internet search using multiple search engines for references on this topic was conducted. The PDR for Herbal Medicines, and four textbooks on herbal medicine and their bibliographies were also searched. RESULTS: A large number of studies on curcumin were identified. These included studies on the antioxidant, anti-inflammatory, antiviral, and antifungal properties of curcuminoids. Studies on the toxicity and anti-inflammatory properties of curcumin have included in vitro, animal, and human studies. A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for 3 months found no toxicity from curcumin. Five other human trials using 1125-2500 mg of curcumin per day have also found it to be safe. These human studies have found some evidence of anti-inflammatory activity of curcumin. The laboratory studies have identified a number of different molecules involved in inflammation that are inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12). CONCLUSIONS: Curcumin has been demonstrated to be safe in six human trials and has demonstrated anti-inflammatory activity. It may exert its anti-inflammatory activity by inhibition of a number of different molecules that play a role in inflammation.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis.

Curcumin has been widely used as a spice and coloring agent in foods. Recently, curcumin was found to possess chemopreventive effects against skin cancer, forestomach cancer, colon cancer and oral cancer in mice. Clinical trials of curcumin for prevention of human cancers are currently ongoing. In this study, we examine the chemopreventive effect of curcumin on murine hepatocarcinogenesis. C3H/HeN mice were injected i.p. with N-diethylnitrosamine (DEN) at the age of 5 weeks. The curcumin group started eating 0.2% curcumin-containing diet 4 days before DEN injection until death. The mice were then serially killed at the scheduled times to examine the development of hepatocellular carcinoma (HCC) and changes in intermediate biological markers. At the age of 42 weeks, the curcumin group, as compared with the control group (DEN alone), had an 81% reduction in multiplicity (0.5 versus 2.57) and a 62% reduction in incidence (38 versus 100%) of development of HCC. A series of intermediate biological markers were examined by western blot. While hepatic tissues obtained from the DEN-treated mice showed a remarkable increase in the levels of p21(ras), PCNA and CDC2 proteins, eating a curcumin-containing diet reversed the levels to normal values. These results indicate that curcumin effectively inhibits DEN-induced hepatocarcinogenesis in the mouse. The underlying mechanisms of the phenomenon and the feasibility of using curcumin in the chemoprevention of human HCC should be further explored.

Animals↗

PubMed2004

Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR.

Colorectal cancer is a leading cause of cancer-related morbidity and mortality in the United States. Curcumin, the yellow pigment in turmeric, possesses inhibitory effects on growth of a variety of tumor cells by reducing cell proliferation and inducing apoptosis. Effects of the peroxisome proliferator-activated receptor-gamma (PPARgamma) on stimulating cell differentiation and on inducing cell cycle arrest have attracted attention from the perspective of treatment and prevention of cancer. The aim of this study was to elucidate the mechanisms by which curcumin inhibits colon cancer cell growth. In the present report, we observed that curcumin, in a dose-dependent manner, inhibited the growth of Moser cells, a human colon cancer-derived cell line, and stimulated the trans-activating activity of PPARgamma. Further studies demonstrated that activation of PPARgamma was required for curcumin to inhibit Moser cell growth. Activation of PPARgamma mediated curcumin suppression of the expression of cyclin D1, a critical protein in the cell cycle, in Moser cells. In addition, curcumin blocked EGF signaling by inhibiting EGF receptor (EGFR) tyrosine phosphorylation and suppressing the gene expression of EGFR mediated by activation of PPARgamma. In addition to curcumin reduction of the level of phosphorylated PPARgamma, inhibition of cyclin D1 expression played a major and significant role in curcumin stimulation of PPARgamma activity in Moser cells. Taken together, our results demonstrated for the first time that curcumin activation of PPARgamma inhibited Moser cell growth and mediated the suppression of the gene expression of cyclin D1 and EGFR. These results provided a novel insight into the roles and mechanisms of curcumin in inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.

Antineoplastic Agents↗

PubMed2006

Effect of curcumin on proliferation of human retinal endothelial cells under in vitro conditions.

PURPOSE: To investigate the effect of high glucose on the proliferation of human retinal endothelial cells (HRECs) and to elucidate the possible mechanisms of antiangiogenic activity of curcumin, a diferuloylmethane. METHODS: Human retinal endothelial cells were isolated from the retinal tissue obtained from human donors and the culture system was established. The effect of curcumin on the proliferation of primary HRECs in the presence of low and high glucose was measured by MTT and thymidine uptake assays. Apoptosis was assessed by TUNEL assay and other adjuvant tools. Effect of curcumin on phorbol ester stimulated intracellular reactive oxygen species (ROS) generation in high glucose conditions was assessed by fluorescence assay. Finally, semiquantitative RT-PCR and Western blot analysis was performed to measure VEGF mRNA production and VEGF induced PKC-betaII translocation, respectively in the presence and absence of curcumin. RESULTS: HREC culture was established successfully at passages 3 and 4 at 80% confluence. Curcumin effectively inhibited endothelial cell proliferation in a dose-dependent manner. At a concentration of 10 microM, curcumin significantly inhibited HREC proliferation in high-glucose-treated cells, as verified by both MTT and thymidine uptake assay. Curcumin also showed a significant (P = 0.03) reduction of intracellular ROS generation in HRECs. RNA expression studies showed that curcumin had an inhibitory effect on the glucose-induced VEGF mRNA expression. In addition, VEGF-mediated, membrane-associated changes in the PKC-betaII translocation in HRECs was inhibited by 31% on treatment with 10 microM curcumin. CONCLUSIONS: These data suggest an underlying mechanism whereby curcumin induces the apoptosis in HRECs by the regulation of intracellular ROS generation, VEGF expression and release, and VEGF-mediated PKC-betaII translocation.

Antineoplastic Agents↗

PubMed2001

Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin.

BACKGROUND: We investigated the chemopreventive action of dietary curcumin on 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12,0-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in Swiss albino mice. Curcumin, a yellow coloring matter isolated from roots of Curcuma longa Linn, is a phenolic compound possessing antioxidant, free radical scavenger, and antiinflammatory properties. It has been shown by previously reported work that TPA-induced skin tumors were inhibited by topical application of curcumin, and curcumin has been shown to inhibit a variety of biological activities of TPA. Topical application of curcumin was reported to inhibit TPA-induced c-fos, c-jun and c-myc gene expression in mouse skin. This paper reports the effects of orally administered curcumin, which was consumed as a dietary component at concentrations of 0.2 % or 1 %, in ad libitum feeding. RESULTS: Animals in which tumors had been initiated with DMBA and promoted with TPA experienced significantly fewer tumors and less tumor volume if they ingested either 0.2% or 1% curcumin diets. Also, the dietary consumption of curcumin resulted in a significantly decreased expression of ras and fos proto-oncogenes in the tumorous skin, as measured by enhanced chemiluminesence Western blotting detection system (Amersham). CONCLUSIONS: Whereas earlier work demonstrated that topical application of curcumin to mouse skin inhibited TPA-induced expression of c-fos, c-jun and c-myc oncogenes, our results are the first to show that orally consumed curcumin significantly inhibited DMBA- and TPA-induced ras and fos gene expression in mouse skin.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Dietary curcumin enhances antibody response in rats.

The effects of dietary curcumin on three major types of immune function were examined in rats. Antibody (IgG) production, delayed-type hypersensitivity and natural killer cell activity were evaluated after 5 weeks of dietary exposure to 1, 20 or 40 mg/kg curcumin. The highest dose of curcumin significantly enhanced IgG levels. Rats receiving lower dietary concentrations (1 or 20 mg/kg) of curcumin were not different in IgG production from rats receiving no curcumin in their diet. Neither delayed-type hypersensitivity nor natural killer cell activity was different from control values at any dietary concentration of curcumin. In vitro incubation of YAC-1 and EL4 tumor cells and normal splenocytes in varying concentrations of curcumin for varying times revealed differences between cell types in curcumin's effects on cell proliferation and viability. No cytotoxic effect was seen in EL4 cells at 125 micrograms/ml curcumin at 4, 24 and 48 hrs incubations, however, cell proliferation was reduced by almost 50% at 24 hrs. YAC-1 cell viability and cell numbers were diminished at longer incubations. A lower curcumin concentration (1.25 micrograms/ml) enhanced cell growth in the YAC-1 cells at 24 and 48 hr. This enhancement was not seen in spleen or EL4 cells.

Administration, Oral↗

PubMed2005

Curcumin derivatives inhibit the formation of Jun-Fos-DNA complex independently of their conserved cysteine residues.

Curcumin, a major active component of turmeric, has been identified as an inhibitor of the transcriptional activity of activator protein-1 (AP-1). Recently, it was also found that curcumin and synthetic curcumin derivatives can inhibit the binding of Jun-Fos, which are the members of the AP-1 family, to DNA. However, the mechanism of this inhibition by curcumin and its derivatives was not disclosed. Since the binding of Jun-Fos dimer to DNA can be modulated by redox control involving conserved cysteine residues, we studied whether curcumin and its derivatives inhibit Jun-Fos DNA binding activity via these residues. However, the inhibitory mechanism of curcumin and its derivatives, unlike that of other Jun-Fos inhibitors, was found to be independent of these conserved cysteine residues. In addition, we investigated whether curcumin derivatives can inhibit AP-1 transcriptional activity in vivo using a luciferase assay. We found that, among the curcumin derivatives examined, only inhibitors shown to inhibit the binding of Jun-Fos to DNA by Electrophoretic Mobility Shift Assay (EMSA) inhibited AP-1 transcriptional activity in vivo. Moreover, RT-PCR revealed that curcumin derivatives, like curcumin, downregulated c-jun mRNA in JB6 cells. These results suggest that the suppression of the formation of DNA-Jun-Fos complex is the main cause of reduced AP-1 transcriptional activity by curcuminoids, and that EMSA is a suitable tool for identifying inhibitors of transcriptional activation.

Animals↗