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PubMed2004

Suppression of protein kinase C and nuclear oncogene expression as possible action mechanisms of cancer chemoprevention by Curcumin.

Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)kappaB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans.

Animals↗

PubMed2005

Inhibition of cellular proliferation and induction of apoptosis by curcumin in human malignant astrocytoma cell lines.

Nuclear factor (NF)-kappaB is known to control cellular proliferation and apoptosis. In malignant astrocytoma cells, it was reported that NF-kappaB was activated aberrantly and promoted their proliferation. Thus, inhibition of NF-kappaB activity is considered to be a promising therapeutic strategy for malignant astrocytoma. Recently, curcumin, the major constituent of turmeric, was reported to inhibit NF-kappaB activity. In this study, we investigated inhibitory effects of curcumin on NF-kappaB activity and cellular proliferation, and induction of apoptosis by curcumin in human malignant astrocytoma cell lines. Alteration of NF-kappaB activity in NP-2 human malignant astrocytoma cell line after treatment with curcumin was examined using electrophoretic mobility shift assay. Alterations of DNA synthesis and cellular growth in five human malignant astrocytoma cell lines after treatment with curcumin were examined using [(3)H]thymidine incorporation assay and the trypan blue dye exclusion method, respectively. Induction of apoptosis by curcumin in NP-2 and NP-3 human malignant astrocytoma cell lines was examined by DNA-fragmentation analysis and morphological observation. We found that the NF-kappaB activity in NP-2 was significantly reduced by curcumin. The DNA synthesis and the cellular growth were inhibited by curcumin in dose-dependent manner in all the five malignant astrocytoma cell lines. Nuclear condensation and fragmentation, and DNA fragmentation were observed in both NP-2 and NP-3 after the treatment with curcumin. These results indicate that curcumin inhibits the cellular proliferation and induces apoptosis in human malignant astrocytoma cell lines. These results are considered to be resulted from the inhibition of NF-kappaB activity by curcumin.

Antineoplastic Agents↗

PubMed1996

Effects of curcumin on cytochrome P450 and glutathione S-transferase activities in rat liver.

The stability of curcumin, as well as the interactions between curcumin and cytochrome P450s (P450s) and glutathione S-transferases (GSTs) in rat liver, were studied. Curcumin is relatively unstable in phosphate buffer at pH 7.4. The stability of curcumin was strongly improved by lowering the pH or by adding glutathione (GSH), N-acetyl L-cysteine (NAC), ascorbic acid, rat liver microsomes, or rat liver cytosol. Curcumin was found to be a potent inhibitor of rat liver P450 1A1/1A2 measured as ethoxyresorufin deethylation (EROD) activity in beta-naphthoflavone (beta NF)-induced microsomes, a less potent inhibitor of P450 2B1/2B2, measured as pentoxyresorufin depentylation (PROD) activity in phenobarbital (PB)-induced microsomes and a weak inhibitor of P450 2E1, measured as p-nitrophenol (PNP) hydroxylation activity in pyrazole-induced microsomes. Ki values were 0.14 and 76.02 microM for the EROD- and PROD-activities, respectively, and 30 microM of curcumin inhibited only 9% of PNP-hydroxylation activity. In ethoxyresorufin deethylation (EROD) and pentoxyresorufin depentylation (PROD) experiments, curcumin showed a competitive type of inhibition. Curcumin was also a potent inhibitor of glutathione S-transferase (GST) activity in cytosol from liver of rats treated with phenobarbital (PB), beta-naphthoflavone (beta NF) and pyrazole (Pyr), when measured towards 1-chloro-2,4-dinitrobenzene (CDNB) as substrate. In liver cytosol from rats treated with phenobarbital (PB), curcumin inhibited GST activity in a mixed-type manner with a Ki of 5.75 microM and Ki of 12.5 microM. In liver cytosol from rats treated with pyrazole (Pyr) or beta-naphthoflavone (beta NF), curcumin demonstrated a competitive type of inhibition with Ki values of 1.79 microM and 2.29 microM, respectively. It is concluded that these strong inhibitory properties of curcumin towards P450s and GSTs, in addition to its well-known antioxidant activity, may help explain the previously observed anticarcinogenic, antimutagenic, and cytoprotective effects of this important natural compound and food constituent.

Animals↗

PubMed2006

Curcumin enhances Apo2L/TRAIL-induced apoptosis in chemoresistant ovarian cancer cells.

OBJECTIVE: Curcumin, the active component of turmeric (Curcuma longa), exhibits growth inhibitory activity against prostate, colon, and breast cancer; however, the effect of curcumin on ovarian cancer cells is not known. We hypothesized that curcumin could induce cell death in ovarian cancer cells, and enhance apoptosis induced by tumor necrosis factor-related apoptosis inducing Apo2 ligand/TRAIL. METHODS: Chemoresistant ovarian cancer cell lines SKOV3 and ES-2 were used. The cytotoxic effect of curcumin, Apo2L/TRAIL, and curcumin+Apo2L/TRAIL in combination was determined by sulforhodamine assay. Apoptotic fraction was determined by staining cells with propidium iodide followed by analysis of the sub-G0 DNA content of cells by flow cytometry. Caspase activation was determined by immunoblotting. RESULTS: Curcumin alone had a cytotoxic effect in cisplatin-resistant cells at 25 microM. Curcumin at low doses (5-15 microM) or Apo2L/TRAIL alone was not significantly cytotoxic to the cell lines tested. Preincubating cells with curcumin at low doses prior to treating with Apo2L/TRAIL resulted in markedly enhanced cell death. The combined treatment of curcumin and Apo2L/TRAIL resulted in activation of both the extrinsic, receptor-mediated apoptotic pathway (cleavage of caspase-8) and the intrinsic, mitochondria-mediated apoptotic pathway (cleavage of caspase-9). CONCLUSIONS: Combined curcumin and Apo2L/TRAIL treatment results in enhanced induction of apoptotic cell death. Because curcumin and Apo2L/TRAIL together can activate both the extrinsic and intrinsic pathways of apoptosis, they may circumvent chemoresistance to conventional chemotherapeutic agents.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells.

Curcumin, widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anti-tumor promoting activities. In the present study, curcumin was found to induce apoptotic cell death in promyelocytic leukemia HL-60 cells at concentrations as low as 3.5 micrograms/ml. The apoptosis-inducing activity of curcumin appeared in a dose- and time-dependent manner. Flow cytometric analysis showed that the hypodiploid DNA peak of propidium iodide-stained nuclei appeared at 4 h after 7 micrograms/ml curcumin treatment. The apoptosis-inducing activity of curcumin was not affected by cycloheximide, actinomycin D, EGTA, W7 (calmodulin inhibitor), sodium orthovanadate, or genistein. By contrast, an endonuclease inhibitor ZnSO4 and proteinase inhibitor N-tosyl-L-lysine chloro-methyl ketone (TLCK) could markedly abrogate apoptosis induced by curcumin, whereas 12-O-tetradecanoylphorbol-13-acetate (TPA) had a partial effect. The antioxidants, N-acetyl-L-cysteine (NAC), L-ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase, all effectively prevented curcumin-induced apoptosis. This result suggested that curcumin-induced cell death was mediated by reactive oxygen species. Immunoblot analysis showed that the level of the antiapoptotic protein Bcl-2 was decreased to 30% after 6 h treatment with curcumin, and was subsequently reduced to 20% by a further 6 h treatment. Furthermore, overexpression of bcl-2 in HL-60 cells resulted in a delay of curcumin-treated cells entering into apoptosis, suggesting that bcl-2 plays a crucial role in the early stage of curcumin-triggered apoptotic cell death.

Antineoplastic Agents↗

PubMed1998

Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin.

Curcumin, a dietary pigment in curry, suppresses tumor initiation and tumor promotion. Curcumin is also a potent inhibitor for AP-1 and NF-kappaB activation. In this report, we show that curcumin inhibits JNK activation by various agonists including PMA plus ionomycin, anisomycin, UV-C, gamma radiation, TNF-alpha, and sodium orthovanadate. Although both JNK and ERK activation by phorbol 12-myristate 13-acetate (PMA) plus ionomycin were suppressed by curcumin, the JNK pathway was more sensitive. The IC50 (50% inhibition concentration) of curcumin was between 5-10 microM for JNK activation and was 20 microM for ERK activation. In transfection assays, curcumin moderately suppressed MEKK1-induced JNK activation; however, it effectively blocked JNK activation caused by co-transfection of TAK1, GCK, or HPK1. Curcumin did not directly inhibit JNK, SEK1, MEKK1 or HPK1 activity. Although curcumin suppressed TAK1 and GCK activities at high concentrations, this inhibition cannot fully account for the JNK inhibition by curcumin in vivo. Our data suggest that curcumin may affect the JNK pathway by interfering with the signaling molecule(s) at the same level or proximally upstream of the MAPKKK level. Taken together, the inhibition of the MEKK1-JNK pathway reveals a possible mechanism of suppression of AP-1 and NF-kappaB signaling by curcumin, and may explain the potent anti-inflammatory and anti-carcinogenic effects of this chemical.

Antineoplastic Agents↗

PubMed2002

Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation.

Cyclin D1 is a proto-oncogene that is overexpressed in many cancers including breast and prostate. It plays a role in cell proliferation through activation of cyclin-dependent kinases. Curcumin, a diferuloylmethane, is a chemopreventive agent known to inhibit the proliferation of several breast and prostate cancer cell lines. It is possible that the effect of curcumin is mediated through the regulation of cyclin D1. In the present report we show that inhibition of the proliferation of various prostate, breast and squamous cell carcinoma cell lines by curcumin correlated with the down-regulation of the expression of cyclin D1 protein. In comparison, the down-regulation by curcumin of cyclin D2 and cyclin D3 was found only in selective cell lines. The suppression of cyclin D1 by curcumin led to inhibition of CDK4-mediated phosphorylation of retinoblastoma protein. We found that curcumin-induced down-regulation of cyclin D1 was inhibited by lactacystin, an inhibitor of 26S proteosome, suggesting that curcumin represses cyclin D1 expression by promoting proteolysis. We found that curcumin also down-regulated mRNA expression, thus suggesting transcriptional regulation. Curcumin also inhibited the activity of the cyclin D1 promoter-dependent reporter gene expression. Overall our results suggest that curcumin down-regulates cyclin D1 expression through activation of both transcriptional and post-transcriptional mechanisms, and this may contribute to the antiproliferative effects of curcumin against various cell types.

Acetylcysteine↗

PubMed1998

Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells.

Curcumin, a potent antioxidant and chemopreventive agent, has recently been found to be capable of inducing apoptosis in human hepatoma and leukemia cells by way of an elusive mechanism. Here, we demonstrate that curcumin also induces apoptosis in human basal cell carcinoma cells in a dose- and time-dependent manner, as evidenced by internucleosomal DNA fragmentation and morphologic change. In our study, consistent with the occurrence of DNA fragmentation, nuclear p53 protein initially increased at 12 h and peaked at 48 h after curcumin treatment. Prior treatment of cells with cycloheximide or actinomycin D abolished the p53 increase and apoptosis induced by curcumin, suggesting that either de novo p53 protein synthesis or some proteins synthesis for stabilization of p53 is required for apoptosis. In electrophoretic mobility gel-shift assays, nuclear extracts of cells treated with curcumin displayed distinct patterns of binding between p53 and its consensus binding site. Supportive of these findings, p53 downstream targets, including p21(CIP1/WAF1) and Gadd45, could be induced to localize on the nucleus by curcumin with similar p53 kinetics. Moreover, we immunoprecipitated extracts from basal cell carcinoma cells with different anti-p53 antibodies, which are known to be specific for wild-type or mutant p53 protein. The results reveal that basal cell carcinoma cells contain exclusively wild-type p53; however, curcumin treatment did not interfere with cell cycling. Similarly, the apoptosis suppressor Bcl-2 and promoter Bax were not changed with the curcumin treatment. Finally, treatment of cells with p53 antisense oligonucleotide could effectively prevent curcumin-induced intracellular p53 protein increase and apoptosis, but sense p53 oligonucleotide could not. Thus, our data suggest that the p53-associated signaling pathway is critically involved in curcumin-mediated apoptotic cell death. This evidence also suggests that curcumin may be a potent agent for skin cancer prevention or therapy.

Apoptosis↗

PubMed1999

Chemoprevention by curcumin during the promotion stage of tumorigenesis of mammary gland in rats irradiated with gamma-rays.

We have evaluated the chemopreventive effects of curcumin on diethylstilbestrol (DES)-induced tumor promotion of rat mammary glands initiated with radiation. Sixty-four pregnant rats received whole body irradiation with 2.6 Gy gamma-rays from a 60Co source at day 20 of pregnancy and were divided into two groups after weaning. In the control group of 39 rats fed a basal diet and then implanted with a DES pellet for 1 year, 33 (84.6%) developed mammary tumors. Twenty-five rats were fed diet containing 1% curcumin immediately after weaning and received a DES pellet, as for the control. The administration of dietary curcumin significantly reduced the incidence (28.0%) of mammary tumors. Multiplicity and Iball's index of mammary tumors were also decreased by curcumin. Rats fed the curcumin diet showed a reduced incidence of the development of both mammary adenocarcinoma and ER(+)PgR(+) tumors in comparison with the control group. On long-term treatment with curcumin, body weight and ovarian weight were reduced, but liver weight was increased. Compared with the control rats, the curcumin-fed rats showed a significant reduction in serum prolactin, whereas estradiol-17beta and progesterone concentrations were not significantly different between the two groups. Curcumin did not have any effect on the concentration of free cholesterol, cholesterol ester and triglyceride. Feeding of the curcumin diet caused a significant increase in the concentrations of tetrahydrocurcumin, arachidonic acid and eicosapentaenoic acid and a significant decrease in thiobarbituric acid-reactive substance concentration in serum. Whole mounts of the mammary glands showed that curcumin yielded morphologically indistinguishable proliferation and differentiation from the glands of the control rats. These findings suggest that curcumin has a potent preventive activity during the DES-dependent promotion stage of radiation-induced mammary tumorigenesis.

Animals↗

PubMed2000

Potent preventive action of curcumin on radiation-induced initiation of mammary tumorigenesis in rats.

This investigation evaluated the preventive effect of curcumin on radiation-induced tumor initiation in rat mammary glands. Fifty-four female rats were mated and then divided into two groups at day 11 of pregnancy. As the control group, 27 rats were fed a basal diet during the experimental period. As the experimental group, 27 rats were fed a diet containing 1% curcumin between day 11 of pregnancy and parturition (day 23 of pregnancy). All rats of both groups received whole body irradiation with 1.5 Gy gamma-rays from a (60)Co source at day 20 of pregnancy and were then implanted with a diethylstilbestrol pellet 1 month after weaning. A high incidence (70.3%) of mammary tumorigenesis was observed in the control group. The tumor incidence (18.5%) was significantly reduced in the rats fed curcumin during the initiation stage. The appearance of the first palpable tumor was delayed by 6 months in the curcumin-fed group and the average latent period until the appearance of mammary tumors was 2.5 months longer in the curcumin-fed group than in the control group. By histological examination, the proportion of adenocarcinoma (16.7%) in total tumors in the curcumin-fed rats was found to be decreased to half that (32.1%) in the control group. Compared with the control rats, the body weight of rats in the experimental group was decreased slightly by administration of the curcumin diet from day 11 of pregnancy, in spite of a similar intake of diet, but had recovered to the level of the control by the end of the experiment. At the time of irradiation, curcumin did not have any effect on organ weight or on the development and differentiation of mammary glands of pregnant rats. In addition, the serum concentrations of fatty acids, thiobarbituric acid-reactive substances and ovarian and pituitary hormones, except LH, remained at the control level. Also, no change in litter size and body weight of pups born from curcumin-fed rats indicated no toxicity of curcumin. These results suggest that curcumin does not have any side-effects and is an effective agent for chemoprevention acting at the radiation-induced initiation stage of mammary tumorigenesis.

Animals↗

PubMed2003

Ectopic expression of Hsp70 confers resistance and silencing its expression sensitizes human colon cancer cells to curcumin-induced apoptosis.

We have shown earlier that heat shock renders human colon cancer cells resistant to curcumin-induced apoptosis, but the contribution of individual heat shock proteins (hsps) to this resistance has not been tested. High expression of hsp27 and hsp70 in breast, endometrial and gastric cancers has been associated with metastasis, poor prognosis and resistance to chemo- or radiotherapy. In this study, SW480 cells were transfected with hsp70 cDNA in either the sense or antisense orientation and stable clones were selected and tested for their sensitivity to curcumin. The cells were protected from curcumin-induced cell death by hsp70 while cells harboring antisense hsp70 (Ashsp70) were highly sensitive to curcumin. Curcumin-induced nuclear condensation was less in hsp70 but more in Ashsp70 cells when compared with control vector-transfected cells. Loss of mitochondrial transmembrane potential induced by curcumin was further accelerated by antisense hsp70 expression and hsp70 restored it partly. Ashsp70 cells released more cytochrome c, AIF and Smac from mitochondria upon curcumin treatment than control cells. hsp70 partly prevented the release of AIF but not the other proteins. Activation of caspases 3 and 9 induced by curcumin was also inhibited by hsp70, whereas more activation could be seen in Ashsp70 cells, although caspase 8 activation was unaffected by changes in hsp70 expression. Curcumin-induced cleavage of PARP and DFF45 was inhibited by hsp70 but enhanced in Ashsp70 cells. The present study demonstrates the potential of hsp70 in protecting SW480 cells from curcumin-induced apoptosis and highlights that silencing the expression of hsp70 is an effective approach to augment curcumin-based therapy in cancers that are resistant due to hsp70 expression.

Antineoplastic Agents↗

PubMed2005

Human colon cancer cells lacking Bax resist curcumin-induced apoptosis and Bax requirement is dispensable with ectopic expression of Smac or downregulation of Bcl-XL.

Multiple apoptotic stimuli induce conformational changes in Bax, a proapoptotic protein from the Bcl-2 family and its deficiency is a frequent cause of chemoresistance in colon adenocarcinomas. Curcumin, a dietary compound from turmeric, is known to induce apoptosis in a variety of cancer cells. To understand the role of Bax in curcumin-induced apoptosis we used HCT116 human colon cancer cells with one allele of Bax gene (Bax+/-) and Bax knockout HCT116 (Bax-/-) cells in which Bax gene is inactivated by homologous recombination. Cell viability decreased in a concentration-dependent manner in Bax+/- cells treated with curcumin (0-50 microM) whereas only minimal changes in viability were observed in Bax-/- cells upon curcumin treatment. In Bax-/- cells curcumin-induced activation of caspases 9 and 3 was blocked and that of caspase 8 remained unaltered. Curcumin-induced release of cytochrome c, Second mitochondria derived activator of caspase (Smac) and apoptosis inducing factor (AIF) was also blocked in Bax-/- cells and reintroduction of Bax, downregulation of the antiapoptotic protein Bcl-XL by antisense DNA as well as the overexpression of Smac, highly sensitized the Bax-/- cells toward curcumin-induced apoptosis. There was no considerable difference in the percentage of apoptotic cells in Bak RNAi transfected Bax+/- or Bax-/- cells treated with curcumin when compared with their corresponding vector transfected cells treated with curcumin. The present study demonstrates the role of Bax but not Bak as a critical regulator of curcumin-induced apoptosis and implies the potential of targeting antiapoptotic proteins like Bcl-XL or overexpression of proapoptotic proteins like Smac as interventional approaches to deal with Bax-deficient chemo-resistant cancers for curcumin-based therapy.

Antineoplastic Agents↗

PubMed2005

Proapoptotic effect of curcumin on human neutrophils: activation of the p38 mitogen-activated protein kinase pathway.

OBJECTIVE: Despite advances in the management of sepsis and acute respiratory distress syndrome, the mortality rate remains high. Delayed apoptosis of neutrophils is associated with multiple organ failure under those conditions. Thus, development of nontoxic neutrophil apoptosis regulating molecules may provide a novel therapeutic strategy. Curcumin is a promising dietary supplement for cancer prevention. However, the effect of curcumin on human neutrophil apoptosis remains unknown. We therefore hypothesized that curcumin would produce a proapoptotic effect on neutrophils. DESIGN: Prospective, controlled, and randomized in vitro study. SETTING: Research institute laboratory. SUBJECTS: Human peripheral neutrophils obtained from normal subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the presence or absence of curcumin, both spontaneous neutrophil apoptosis and apoptosis of neutrophils following transmigration across a human lung endothelium-epithelium bilayer were studied by morphology and terminal dUTP nucleotide end labeling analyses, respectively. Myeloperoxidase activity and migration assays were performed to determine the impact of curcumin on neutrophil function. To elucidate the potential mechanism, the p38 mitogen-activated protein kinase pathway and caspase-3 activity were examined by Western blotting and enzymatic analyses. The data demonstrate that curcumin increased constitutive neutrophil apoptosis and abrogated the transbilayer migration-induced delay in neutrophil apoptosis. Neutrophil activation was reduced by curcumin treatment as evidenced by a decrease in migration and myeloperoxidase release. A marked increase in p38 phosphorylation and caspase-3 activity was observed following curcumin exposure. In addition, inhibition of p38 mitogen-activated protein kinase with SB203580 suppressed apoptosis and caspase-3 activation induced by curcumin. Thus, activation of p38 mitogen-activated protein kinase or an increase in caspase-3 activity appears to contribute to the proapoptotic effect of human neutrophil apoptosis by curcumin. CONCLUSION: The characteristics of curcumin, including its proapoptotic effect and antidegranulation effect, make it a potential candidate for the therapy of neutrophil-induced lung injury and sepsis.

Antineoplastic Agents↗

PubMed2005

Curcumin blocks fibrosis in anti-Thy 1 glomerulonephritis through up-regulation of heme oxygenase 1.

BACKGROUND: Induction of heme oxygenase 1 (HO-1) has been shown to be beneficial in a variety of pathologic settings. Curcumin, a polyphenolic compound, has antifibrotic effects in lung models of fibrosis, and is known to induce HO-1 in renal tubular cells. In this study, we determined whether curcumin has antifibrotic properties in glomerular fibrosis and if these effects are mediated by induction of HO-1. METHODS: Curcumin effects on HO-1 expression in cultured mesangial cells and in glomeruli in vivo were analyzed by Northern and Western blotting. The dose-dependent effect of curcumin on glomerular fibrosis was tested in the anti-Thy 1 glomerulonephritis model. Curcumin was applied at doses of 10 to 200 mg/kg body weight by intraperitoneal injection from days 3 to 5 after induction of disease. On day 6, glomeruli were harvested and markers of fibrosis [plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-beta (TGF-beta), fibronectin, periodic acid-Schiff (PAS) staining] were analyzed. The effect of HO-1 inhibition was tested in a second experiment were nephritic rats were treated with curcumin (100 mg/kg body weight) or the combination of curcumin and the HO-1 inhibitor zinc protoporphyrin (100 microg/kg). RESULTS: Curcumin potently induced mesangial cell HO-1 expression in vitro and up-regulated glomerular HO-1 expression in nephritic animals in vivo. Curcumin treatment led to a significant, dose-dependent reduction of markers of fibrosis and proteinuria, with maximal inhibition at doses of 50 to 100 mg/kg. Beneficial effects of curcumin on markers of fibrosis and proteinuria were lost after HO-1 inhibition. CONCLUSION: Curcumin has antifibrotic effects in glomerular disease, which are mediated through an induction of HO-1.

Animals↗

PubMed2006

Dietary antioxidant curcumin inhibits microtubule assembly through tubulin binding.

Curcumin, a component of turmeric, has potent antitumor activity against several tumor types. However, its molecular target and mechanism of antiproliferative activity are not clear. Here, we identified curcumin as a novel antimicrotubule agent. We have examined the effects of curcumin on cellular microtubules and on reconstituted microtubules in vitro. Curcumin inhibited HeLa and MCF-7 cell proliferation in a concentration-dependent manner with IC(50) of 13.8 +/- 0.7 microm and 12 +/- 0.6 microm, respectively. At higher inhibitory concentrations (> 10 microm), curcumin induced significant depolymerization of interphase microtubules and mitotic spindle microtubules of HeLa and MCF-7 cells. However, at low inhibitory concentrations there were minimal effects on cellular microtubules. It disrupted microtubule assembly in vitro, reduced GTPase activity, and induced tubulin aggregation. Curcumin bound to tubulin at a single site with a dissociation constant of 2.4 +/- 0.4 microm and the binding of curcumin to tubulin induced conformational changes in tubulin. Colchicine and podophyllotoxin partly inhibited the binding of curcumin to tubulin, while vinblastine had no effect on the curcumin-tubulin interactions. The data together suggested that curcumin may inhibit cancer cells proliferation by perturbing microtubule assembly dynamics and may be used to develop efficacious curcumin analogues for cancer chemotherapy.

Antioxidants↗

PubMed2005

Curcumin suppresses interleukin 1beta-mediated microsomal prostaglandin E synthase 1 by altering early growth response gene 1 and other signaling pathways.

Curcumin (diferuloylmethane) is one of the phytophenolic compounds found in the turmeric plant with anti-inflammatory and anticarcinogenic activities. One possible mechanism for these activities is the inhibition of prostaglandin (PG) E(2) formation. In this study and other reports, curcumin suppresses interleukin-1beta-induced formation of prostaglandin E(2) in a concentration-dependent manner. Interleukin-1beta-induced microsomal prostaglandin E synthase 1 (mPGES-1) and cyclooxygenase-2 were attenuated by curcumin at the protein and mRNA levels, but a more dramatic inhibition of mPGES-1 expression was observed at lower concentrations of curcumin in A549 human lung epithelial cells. The inhibition of mPGES-1 expression by curcumin shifted the arachidonic acid profile from PGE(2) to PGF(2alpha) and 6-keto-PGF(1alpha) as major metabolites. The expression of early growth response gene 1 (EGR-1), a key transcription factor of cytokine-induced mPGES-1, was inhibited by curcumin. Incubation with siRNA for EGR-1 inhibited interleukin (IL)-1beta-induced mPGES-1, and the controlled expression of EGR-1 increased the mPGES-1 expression. Several proinflammatory signaling molecules, such as nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinases, are also known to affect curcumin-regulated gene expression. Curcumin inhibited IkappaBalpha phosphorylation and degradation and thus reduced the expression of mPGES-1. Curcumin suppressed cytokine-induced mPGES-1 by inhibiting phosphorylation of Jun N-terminal kinase (JNK)1/2. However, EGR-1 expression was suppressed by lower concentrations of curcumin, as compared with JNK1/2 and IkappaBalpha. These results indicate that curcumin inhibits IL-1beta-induced PGE(2) formation by inhibiting the expression of mPGES-1 that is mediated by suppression of EGR-1 expression as well as NF-kappaB and JNK1/2.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor.

Upon liver injury, quiescent hepatic stellate cells (HSCs), the most relevant cell type for hepatic fibrogenesis, become active and overproduce extracellular matrix (ECM). Connective tissue growth factor (CTGF) promotes ECM production. Overexpression of CTGF during hepatic fibrogenesis is induced by transforming growth factor (TGF)-beta. We recently demonstrated that curcumin reduced cell growth and inhibited ECM gene expression in activated HSCs. Curcumin induced gene expression of peroxisome proliferator-activated receptor (PPAR)-gamma and stimulated its activity in activated HSCs, which was required for curcumin to suppress ECM gene expression, including alphaI(I)-collagen. The underlying mechanisms remain largely unknown. The aim of this study was to elucidate the mechanisms by which curcumin suppresses alphaI(I)-collagen gene expression in activated HSCs. We hypothesize that inhibition of alphaI(I)-collagen gene expression in HSCs by curcumin is mediated by suppressing CTGF gene expression through attenuating oxidative stress and interrupting TGF-beta signaling. The present report demonstrated that curcumin significantly reduced the abundance of CTGF in passaged HSCs and suppressed its gene expression. Exogenous CTGF dose dependently abrogated the inhibitory effect of curcumin. Activation of PPAR-gamma by curcumin resulted in the interruption of TGF-beta signaling by suppressing gene expression of TGF-beta receptors, leading to inhibition of CTGF gene expression. The phytochemical showed its potent antioxidant property by significantly increasing the level of total glutathione (GSH) and the ratio of GSH to GSSG in activated HSCs. De novo synthesis of cellular GSH was a prerequisite for curcumin to interrupt TGF-beta signaling and inhibited gene expression of CTGF and alphaI(I)-collagen in activated HSCs. Taken together, our results demonstrate that inhibition of alphaI(I)-collagen gene expression by curcumin in activated HSCs results from suppression of CTGF gene expression through increasing cellular GSH contents and interruption of TGF-beta signaling. These results provide novel insights into the mechanisms underlying inhibition of HSC activation by curcumin.

Animals↗

PubMed2003

Photophysical studies on binding of curcumin to bovine serum albumins.

The excited-state photophysical properties of curcumin in the presence of bovine serum albumin (BSA) have been studied. The absorption and fluorescence changes in curcumin on binding to BSA have been followed at varying concentrations of either curcumin or BSA to determine the binding constant, which has been found to be approximately 10(4) to 10(5) M(-1). Stopped-flow kinetics studies suggested at least two distinct kinetic steps for the binding of curcumin to BSA. The photophysical properties of the singlet-excited state of the curcumin-BSA complex have also been studied. Whereas the absorption spectrum of curcumin is redshifted, the fluorescence spectrum of curcumin was blueshifted in the presence of BSA. The fluorescence quantum yield of curcumin on complexing with BSA was approximately 0.05. Steady-state fluorescence anisotropy studies showed a significant increase in the anisotropy value of 0.37 in BSA-bound curcumin. The fluorescence decay of the curcumin-BSA complex followed a biexponential decay with fluorescence lifetimes of 413 ps (33%) and 120 ps (67%). On the basis of these complementary results, it has been concluded that curcumin shows very high binding to BSA, probably at the hydrophobic cavities inside the protein.

Animals↗