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PubMedDate not supplied

Curcumin and curcumin derivatives inhibit Tat-mediated transactivation of type 1 human immunodeficiency virus long terminal repeat.

The transcription of HIV1 provirus is regulated by both cellular and viral factors. Various evidence suggests that Tat protein secreted by HIV1-infected cells may have additional action in the pathogenesis of AIDS because of its ability to also be taken up by non-infected cells. Curcumin [diferuloylmethane or 1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is the yellow pigment in turmeric Curcuma longa (Linn). It exhibits a variety of pharmacological effects including antiinflammatory and antiretroviral activities. Here, we demonstrated that curcumin used at 10 to 100 nM inhibited Tat transactivation of HIV1-LTR lacZ by 70 to 80% in HeLa cells. In order to develop more efficient curcumin derivatives, we synthesized and tested in the same experimental system the inhibitory activity of reduced curcumin (C1), which lacks the spatial structure of curcumin; allyl-curcumin (C2), which possesses a condensed allyl derivative on curcumin that plays the role of metal chelator; and tocopheryl-curcumin (C3), which enhances the antioxidant activity of the molecule. Results obtained with C1, C2 and C3 curcumin derivatives showed a significant inhibition (70 to 85%) of Tat transactivation. Despite the fact that tocopheryl-curcumin (C3) failed to scavenge O2.-, this curcumin derivative exhibited the most activity; 70% inhibition was obtained at 1 nM, while only 35% inhibition was obtained with the curcumin.

Curcumin↗
PubMed1998

Mechanisms of anticarcinogenic properties of curcumin: the effect of curcumin on glutathione linked detoxification enzymes in rat liver.

Curcumin, an antioxidant isolated from turmeric (curcuma longa), has been shown to attenuate chemical carcinogenesis in rodents. Previous studies have shown that curcumin causes an increase in glutathione S-transferase (GST) activity in rodent liver which may contribute to its anti-cancer and anti-inflammatory activities. Since the effects of curcumin on specific GST isozymes and other glutathione (GSH)-linked enzymes are incompletely defined, we have examined in the present studies the effect of curcumin on hepatic non-protein sulfhydryls and GSH-linked enzymes in male Sprague-Dawley rats. When rats were fed curcumin at doses from 1 to 500 mg kg-1 body weight daily for 14 days, the induction of hepatic GST activity towards 1-chloro-2,4-dinitrobenzene (CDNB) was found to be biphasic, with maximal induction of about 1.5 fold at the 25 to 50 mg kg-1 body weight dosage. At higher doses, a decrease was observed in the activity and in the rats treated with 500 mg kg-1 curcumin this activity was below the levels observed in controls. In contrast, GST activity towards 4-hydroxynonenal (4-HNE) increased in a saturable, dose dependent manner. Western-blot analyses of liver cytosols revealed that curcumin caused a dose dependent induction of rGST 8-8, an isozyme which is known to display the highest activity towards 4-HNE, a highly toxic product of lipid peroxidation. Glutathione peroxidase (GPx) activity towards cumene hydroperoxide in liver homogenate was also found to be increased in a saturable manner with respect to curcumin dose. Our results suggest that induction of enzymes involved in the detoxification of the electrophilic products of lipid peroxidation may contribute to the anti-inflammatory and anti-cancer activities of curcumin.

Animals↗
PubMed1993

Inhibition of the HIV-1 and HIV-2 proteases by curcumin and curcumin boron complexes.

Curcumin, a relatively non-toxic natural product isolated from Curcuma longa, is a modest inhibitor of the HIV-1 (IC50 = 100 microM) and HIV-2 (IC50 = 250 microM) proteases. Simple modifications of the curcumin structure raise the IC50 value but complexes of the central dihydroxy groups of curcumin with boron lower the IC50 to a value as low as 6 microM. The boron complexes are also time-dependent inactivators of the HIV proteases. The increased affinity of the boron complexes may reflect binding of the orthogonal domains of the inhibitor in interesecting sites within the substrate-binding cavity of the enzyme, while activation of the alpha, beta-unsaturated carbonyl group of curcumin by chelation to boron probably accounts for time-dependent inhibition of the enzyme.

Aspartic Acid Endopeptidases↗
PubMed1987

Studies on curcumin and curcuminoids. IX: Investigation of the photobiological activity of curcumin using bacterial indicator systems.

The dye curcumin is a natural, nontoxic food constituent. On irradiation with visible light, curcumin proves to be phototoxic for Salmonella typhimurium and Escherichia coli, even at very low concentrations. The observed phototoxicity makes curcumin a potential photosensitizing drug which might find application in the phototherapy of, for example, psoriasis, cancer, and bacterial and viral diseases.

Catechols↗
PubMedDate not supplied

Metabolism of curcumin--studies with [3H]curcumin.

Radioactivity was detectable in blood, liver and kidney following dosage with 400, 80 or 10 mg of [3H]curcumin. The major route of elimination of the label was the feces; the urinary excretion of the label was very low regardless of the dose. At the lower doses of 80 mg and 10 mg of [3H]-curcumin, most of the label was excreted within 72 h, while with 400 mg, considerable amounts of the label was present in the tissues 12 days after dosage. The percentage of curcumin absorbed (60-66% of the given dose) remained constant regardless of the dose administered.

Animals↗
PubMed1986

Studies on curcumin and curcuminoids. VIII. Photochemical stability of curcumin.

The photodecomposition of curcumin when exposed to UV/visible radiation is studied. The main degradation products are identified. The reaction mechanisms are investigated and the order of the over-all degradation reactions and the half-lives of curcumin in different solvents and in the solid state are determined.

Catechols↗
PubMed1998

Effect of curcumin on cell cycle progression and apoptosis in vascular smooth muscle cells.

1. The possible mechanisms of the antiproliferative and apoptotic effects of curcumin (diferuloylmethane), a polyphenol in the spice turmeric, on vascular smooth muscle cells were studied in rat aortic smooth muscle cell line (A7r5). 2. The proliferative response was determined from the uptake of [3H]-thymidine. Curcumin (10(-6)-10(-4) M) inhibited serum-stimulated [3H]-thymidine incorporation of both A7r5 cells and rabbit cultured vascular smooth muscle cells in a concentration-dependent manner. Cell viability, as determined by the trypan blue dye exclusion method, was unaffected by curcumin at the concentration range 10(-6) to 10(-5) M in A7r5 cells. However, the number of viable cells after 10(-4) M curcumin treatment was less than the basal value (2 x 10(5) cells). 3. To analyse the various stages of the cell cycle, [3H]-thymidine incorporation into DNA was determined every 3 h. After stimulation with foetal calf serum, quiescent A7r5 cells started DNA synthesis in 9 to 12 h (G1/S phase), then reached a maximum at 15 to 18 h (S phase). Curcumin (10(-6)-10(-4) M) added during either the G1/S phase or S phase significantly inhibited [3H]-thymidine incorporation. 4. Following curcumin (10(-6)-10(-4) M) treatment, cell cycle analysis utilizing flow cytometry of propidium iodide stained cells revealed a G0/G1 arrest and a reduction in the percentage of cells in S phase. Curcumin at 10(-4) M also induced cell apoptosis. It is suggested that curcumin arrested cell proliferation and induced cell apoptosis, and hence reduced the [3H]-thymidine incorporation. 5. The apoptotic effect of 10(-4) M curcumin was also demonstrated by haematoxylin-eosin staining, TdT-mediated dUTP nick end labelling (TUNEL), and DNA laddering. Curcumin (10(-4) M) induced cell shrinkage, chromatin condensation, and DNA fragmentation. 6. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by curcumin at the concentration range 10(-5) to 10(-4) M. On the other hand, the cytosolic protein kinase C activity stimulated by phorbol ester was reduced by 10(-4) M curcumin, but unaffected by lower concentrations (10(-6)-10(-5) M). 7. The levels of c-myc, p53 and bcl-2 mRNA were analysed using a reverse transcription-polymerase chain reaction (RT-PCR) technique. The level of c-myc mRNA was significantly reduced by curcumin (10(-5)-10(-4) M) treatment. And, the level of bcl-2 mRNA was significantly reduced by 10(-4) M curcumin. However, the alteration of the p53 mRNA level by curcumin (10(-5)-10(-4) M) treatment did not achieve significance. The effects of curcumin on the levels of c-myc and bcl-2 mRNA were then confirmed by Northern blotting. 8. Our results demonstrate that curcumin inhibited cell proliferation, arrested the cell cycle progression and induced cell apoptosis in vascular smooth muscle cells. Curcumin may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis. Our results suggest that the antiproliferative effect of curcumin may partly be mediated through inhibition of protein tyrosine kinase activity and c-myc mRNA expression. And, the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase activity, protein kinase C activity, c-myc mRNA expression and bcl-2 mRNA expression.

Animals↗
PubMed1994

Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice.

Curcumin (diferuloylmethane), a yellow pigment that is obtained from the rhizomes of Curcuma longa Linn., is a major component of turmeric and is commonly used as a spice and food-coloring agent. The inhibitory effects of feeding commercial grade curcumin (77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin) in AIN 76A diet on carcinogen-induced tumorigenesis in the forestomach, duodenum, and colon of mice were evaluated. Administration p.o. of commercial grade curcumin in the diet inhibited benzo(a)pyrene-induced forestomach tumorigenesis in A/J mice, N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumorigenesis in C57BL/6 mice, and azoxymethane (AOM)-induced colon tumorigenesis in CF-1 mice. Dietary commercial grade curcumin was given to mice at: (a) 2 weeks before, during, and for 1 week after carcinogen administration (during the initiation period); (b) 1 week after carcinogen treatment until the end of the experiment (during the postinitiation period); or (c) during both the initiation and postinitiation periods. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of benzo(a)pyrene-induced forestomach tumors per mouse by 51-53% when administered during the initiation period and 47-67% when administered during the postinitiation period. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumors per mouse by 47-77% when administered during the postinitiation period. Administration of 0.5-4.0% commercial grade curcumin in the diet both during the initiation and postinitation periods decreased the number of AOM-induced colon tumors per mouse by 51-62%. Administration of 2% commercial grade curcumin in the diet inhibited the number of AOM-induced colon tumors per mouse by 66% when fed during the initiation period and 25% when fed during the postinitiation period. The ability of commercial grade curcumin to inhibit AOM-induced colon tumorigenesis is comparable to that of pure curcumin (purity greater than 98%). Administration of pure or commercial grade curcumin in the diet to AOM-treated mice resulted in development of colon tumors which were generally smaller in number and size as compared to the control group of AOM-treated mice. These results indicate that not only did curcumin inhibit the number of tumors per mouse and the percentage of mice with tumors but it also reduced tumor size. Histopathological examination of the tumors showed that dietary curcumin inhibited the number of papillomas and squamous cell carcinomas of the forestomach as well as the number of adenomas and adenocarcinomas of the duodenum and colon.

Adenocarcinoma↗
PubMed1994

Spectral and photochemical properties of curcumin.

Curcumin, bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is a natural yellow-orange dye derived from the rhizome of Curcuma longa, an East Indian plant. In order to understand the photobiology of curcumin better we have studied the spectral and photochemical properties of both curcumin and 4-(4-hydroxy-3-methoxy-phenyl)-3-buten-2-one (hC, half curcumin) in different solvents. In toluene, the absorption spectrum of curcumin contains some structure, which disappears in more polar solvents, e.g. ethanol, acetonitrile. Curcumin fluorescence is a broad band in acetonitrile (lambda max = 524 nm), ethanol (lambda max = 549 nm) or micellar solution (lambda max = 557 nm) but has some structure in toluene (lambda max = 460, 488 nm). The fluorescence quantum yield of curcumin is low in sodium dodecyl sulfate (SDS) solution (phi = 0.011) but higher in acetonitrile (phi = 0.104). Curcumin produced singlet oxygen upon irradiation (lambda > 400 nm) in toluene or acetonitrile (phi = 0.11 for 50 microM curcumin); in acetonitrile curcumin also quenched 1O2 (kq = 7 x 10(6) M-1 s-1). Singlet oxygen production was about 10 times lower in alcohols and was hardly detectable when curcumin was solubilized in a D2O micellar solution of Triton X-100. In SDS micelles containing curcumin no singlet oxygen phosphorescence could be observed. Curcumin photogenerates superoxide in toluene and ethanol, which was detected using the electron paramagnetic resonance/spin-trapping technique with 5,5-dimethyl-pyrroline-N-oxide as a trapping agent. Unidentified carbon-centered radicals were also detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Inhibitory effects of curcumin on tumorigenesis in mice.

Curcumin (diferuloylmethane), the naturally occurring yellow pigment in turmeric and curry, is isolated from the rhizomes of the plant Curcuma longa Linn. Curcumin inhibits tumorigenesis during both initiation and promotion (post-initiation) periods in several experimental animal models. Topical application of curcumin inhibits benzo[a]pyrene (B[a]P)-mediated formation of DNA-B[a]P adducts in the epidermis. It also reduces 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in skin inflammation, epidermal DNA synthesis, ornithine decarboxylase (ODC) mRNA level, ODC activity, hyperplasia, formation of c-Fos, and c-Jun proteins, hydrogen peroxide, and the oxidized DNA base 5-hydroxymethyl-2'-deoxyuridine (HmdU). Topical application of curcumin inhibits TPA-induced increases in the percent of epidermal cells in synthetic (S) phase of the cell cycle. Curcumin is a strong inhibitor of arachidonic acid-induced edema of mouse ears in vivo and epidermal cyclooxygenase and lipoxygenase activities in vitro. Commercial curcumin isolated from the rhizome of the plant Curcuma longa Linn contains 3 major curcuminoids (approximately 77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin). Commercial curcumin, pure curcumin, and demethoxycurcumin are about equipotent as inhibitors of TPA-induced tumor promotion in mouse skin, whereas bisdemethoxycurcumin is somewhat less active. Topical application of curcumin inhibits tumor initiation by B[a]P and tumor promotion by TPA in mouse skin. Dietary curcumin (commercial grade) inhibits B[a]P-induced forestomach carcinogenesis, N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)-induced duodenal carcinogenesis, and azoxymethane (AOM)-induced colon carcinogenesis. Dietary curcumin had little or no effect on 4-(methylnitosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis and 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast carcinogenesis in mice. Poor circulating bioavailability of curcumin may account for the lack of lung and breast carcinogenesis inhibition.

Administration, Oral↗
PubMed1995

Effects of curcumin on the formation of benzo[a]pyrene derived DNA adducts in vitro.

The effects of turmeric (T), curcumins (Cs), aqueous turmeric extract (ATE) and curcumin-free aqueous turmeric extract (CFATE) on the formation of [3H]benzo[a]pyrene ([3H]B(a)P)-derived DNA adducts was studied in vitro employing mouse liver S9. A dose-dependent decrease in binding of [3H]B(a)P metabolites to calf thymus DNA was observed in the presence of T, Cs and ATE but not in the presence of CFATE, suggesting curcumins to be active principles. Further studies employing mouse liver microsomes and individual components of curcumins, i.e. curcumin (C), demethoxycurcumin (dmC) and bisdemethoxycurcumin (bdmC) showed that all the three components brought about dose-dependent; inhibition of [3H]B(a)P-DNA adduct formation and inhibitory activity was in the order C > dmC > bdmC. Investigations on the inhibitory effect of curcumin showed a dose-dependent decrease in cytochrome P450 and aryl hydrocarbon hydroxylase (AHH) activity resulting in relatively larger amounts of unmetabolized B(a)P in the presence of curcumin. Comparison of structures of curcumins with their activity profile suggested the importance of both parahydroxy (p-OH) and methoxy groups (-OCH3) in the structure activity relationship. Experiments to study the mechanism of action of curcumin indicated that the presence of curcumin was essential for the inhibitory effect, as removal of curcumin resulted in restoration of cytochrome P450 activity and the levels of [3H]-B(a)P-DNA adducts to control values. The present studies demonstrate that curcumin is effective in inhibiting [3H]B(a)P derived DNA adducts by interfering with the metabolic enzymes and its physical presence is essential for this effect.

Animals↗
PubMed1997

Curcumin, a compound with anti-inflammatory and anti-oxidant properties, down-regulates chemokine expression in bone marrow stromal cells.

Chemotactic cytokines or chemokines play an important role in the regulation of myelopoiesis. Since the production of chemokines and colony stimulating factors (CSFs) by bone marrow stromal cells requires inflammatory conditions, we investigated the effect of curcumin, an agent with anti-inflammatory and anti-oxidant activities, on the expression of monocyte chemoattractant protein-1 (MCP-1 or MCP-1/JE) and interferon inducible protein-10kD (IP-10) in mouse bone marrow stromal cell line +/+-1.LDA11. Both chemokines are readily expressed in stromal cells after stimulation with pro-inflammatory interleukin-1alpha (IL-1alpha), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and endotoxin lipopolysaccharide (LPS). Curcumin attenuates the levels of MCP-1/JE and IP-10 mRNA expression by all of these stimulatory agents. A detailed analysis of the regulatory effects of curcumin on chemokine expression by IL-1alpha was performed. Curcumin inhibits both chemokine mRNAs in a dose- and time-dependent manner. The suppressive effect of curcumin on both mRNAs is reversible with complete recovery from suppression within 24 hours after removal of curcumin. The suppression of mRNA by curcumin is dependent on de novo synthesis of an intermediary protein(s), since suppression is abrogated by concomitant treatment with cycloheximide (CHX). Destabilization of mRNA transcripts is not the mechanism by which curcumin lowers the levels of mRNA; however, transcripts formed in the presence of curcumin are more stable, as indicated by their slower degradation kinetics. Run-on transcriptional assays demonstrate that curcumin inhibits the transcriptional activity of both genes. Finally, the attenuation of chemokine gene expression is associated with decreased production of chemotactic activity. Together, these findings indicate that while curcumin may post-transcriptionally stabilize mRNA transcripts formed in its presence, the overall reduction in mRNA levels by curcumin is mediated by inhibition of the transcription of chemokine genes.

Animals↗
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↗
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↗
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↗
PubMed1998

Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin.

Angiogenesis is a crucial step in the growth and metastasis of cancers. Curcumin inhibits tumor initiation and growth. We analyzed the effect of curcumin on endothelial cell migration, attachment, and tube formation on Matrigel. Curcumin had no effect on endothelial cell migration or attachment to either plastic or Matrigel. Curcumin treatment resulted in a dose-dependent inhibition of tube formation when the cells were treated before plating or at the time of plating on Matrigel. Curcumin treatment also caused the preformed tubes to break down. Curcumin inhibited angiogenesis in a s.c. Matrigel plug model in mice. The role of metalloproteinases has been shown to be important in angiogenesis; therefore, zymography was performed to determine whether curcumin affected protease activity. Zymographs of curcumin-treated culture supernatants showed a decrease in the gelatinolytic activities of secreted 53- and 72-kDa metalloproteinases. Western and Northern analysis showed a dose-dependent decrease in the protein expression and transcript of 72 kDa, indicating that curcumin may be exerting its inhibitory effect at both the transcriptional and posttranscriptional level. These findings suggest that curcumin acts as an angiogenesis inhibitor by modulating protease activity during endothelial morphogenesis. Curcumin could be developed as an antiangiogenic drug.

Animals↗