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PubMed2001

Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo.

BACKGROUND: Earlier work from our laboratory highlighted the therapeutic potential of curcumin (turmeric), used as a dietary ingredient and as a natural anti-inflammatory agent in India and other Southeast Asian countries. This agent was shown to decrease the proliferative potential and induce the apoptosis potential of both androgen-dependent and androgen-independent prostate cancer cells in vitro, largely by modulating the apoptosis suppressor proteins and by interfering with the growth factor receptor signaling pathways as exemplified by the EGF-receptor. To extend these observations made in vitro and to study the efficacy of this potential anti-cancer agent in vivo, the growth of LNCaP cells as heterotopically implanted tumors in nude mice was followed. METHODS: The androgen-dependent LNCaP prostate cancer cells were grown, mixed with Matrigel and injected subcutaneously into nude mice. Experimental group received a synthetic diet containing 2% curcumin for up to 6 weeks. At the end point, sections taken from the excised tumors were evaluated for pathology, cell proliferation, apoptosis, and vascularity. RESULTS: Curcumin causes a marked decrease in the extent of cell proliferation as measured by the BrdU incorporation assay and a significant increase in the extent of apoptosis as measured by an in situ cell death assay. Moreover, a significant decrease in the microvessel density as measured by the CD31 antigen staining was also seen. CONCLUSIONS: Curcumin could be a potentially therapeutic anti-cancer agent, as it significantly inhibits prostate cancer growth, as exemplified by LNCaP in vivo, and has the potential to prevent the progression of this cancer to its hormone refractory state.

Animals↗
PubMed2004

Complementary inhibition of synoviocyte, smooth muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex compared to curcumin alone.

A novel vanadyl curcumin complex (VO(cur)2) has been synthesized and and its physicochemical properties characterized. Biological characterization included in vitro testing for anti-rheumatic activity in synoviocytes, angiogenesis inhibition in smooth muscle cells and anti-cancer potential in mouse lymphoma cells; as well as in vivo testing for hypoglycemic activity by oral gavage in streptozotocin (STZ)-diabetic rats. VO(cur)2 was more effective as an anti-cancer agent, compared to uncomplexed curcumin or vanadyl ion alone, was more than twice as effective as curcumin alone as an anti-arthritic agent, and was more than four times as effective as curcumin alone in inhibiting smooth muscle cell proliferation. In both acute and chronic screening tests, VO(cur)2 was ineffective as an insulin mimetic agent; however, it also proved to be exceptionally non-toxic, with no evidence of negative symptomatology during a month-long treatment period, at doses up to and including 2.0 mmol kg(-1) day(-1).

Animals↗
PubMed2005

Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of phospholipid complex of curcumin.

To study pharmacokinetic properties of curcumin, a fast sensitive assay method was developed to determine curcumin and its metabolite tetrahydrocurcumin in rat plasma. The assay was based on tandem mass spectrometry detection (LC/MS/MS). Salbutamol was used as the internal standard (IS). The method had the lower limit of quantitation (LLOQ) of 0.5 ng/ml in rat plasma, which corresponds to 2.5 pg for the 5 microl injection volume. Good linearity was got to 500 ng/ml. The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Phospholipid complex of the natural compound curcumin was prepared in order to improve its bioavailability. Complex formation resulted in an obvious increase in bioavailability of curcumin in rat in vivo according to the assay by above LC/MS/MS method.

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↗
PubMed2001

Chemical studies on antioxidant mechanism of curcumin: analysis of oxidative coupling products from curcumin and linoleate.

As a part of a research project on the antioxidant mechanism of natural phenolics in food components, curcumin, a turmeric antioxidant, was investigated in the presence of ethyl linoleate as one of the polyunsaturated lipids. During the antioxidation process, curcumin reacted with four types of linoleate peroxyl radicals. Six reaction products were observed in the reaction and subsequently isolated. Their structures were determined by physical techniques, revealing that they have novel tricyclic structures, including a peroxyl linkage. On the basis of the formation pathway for their chemical structures, an antioxidant mechanism of curcumin in polyunsaturated lipids was proposed, which consisted of an oxidative coupling reaction at the 3'-position of the curcumin with the lipid and a subsequent intramolecular Diels--Alder reaction.

Antioxidants↗
PubMed2002

Solubility, chemical and photochemical stability of curcumin in surfactant solutions. Studies of curcumin and curcuminoids, XXVIII.

The natural compound curcumin was incorporated into various micellar systems in order to improve the water solubility and the hydrolytic and photochemical stability. The presence of micellar structures resulted in an increase in water solubility at pH 5 by a factor of at least 10(5). The hydrolytic stability of curcumin under alkaline conditions was strongly improved by incorporation into micelles while the photodecomposition rate was increased compared to curcumin in hydrogen bonding organic solvents or aqueous solutions. The ability of curcumin to act as a photosensitizer was dependent on the type of micelles and pH of the medium.

Cetylpyridinium↗
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↗
PubMed2006

Solubility and stability of curcumin in solutions containing alginate and other viscosity modifying macromolecules. Studies of curcumin and curcuminoids. XXX.

The solubility, chemical- and photochemical stability of curcumin in aqueous solutions containing alginate, gelatin or other viscosity modifying macromolecules have been investigated in order to obtain an alternative to the use of surfactants or cyclodextrins. The solubility of curcumin in aqueous solution at pH 5 increased by a factor > or = 10(4) in the presence of 0.5% (w/v) alginate (various qualities) or gelatin compared to plain buffer, while propylene glycol alginate ester, cesapectin and sodium carboxymethyl cellulose did not have a similar solubilizing effect. The solubilization was slightly influenced by pH, ionic strength and type and concentration of buffer salts. The macromolecules do, however, not stabilize towards hydrolytic- or photolytic degradation of curcumin.

Alginates↗
PubMed2000

Therapeutic potential of curcumin in human prostate cancer-I. curcumin induces apoptosis in both androgen-dependent and androgen-independent prostate cancer cells.

In an effort to find an alternative nontoxic means of inducing the apoptosis potential in both androgen-dependent and hormone refractory prostate cancer cells, attention was focused on curcumin (turmeric), traditionally used in medicine and cuisine in India and other south-east Asian countries. The results indicate that curcumin is a novel and potent inducer of apoptosis in both androgen-dependent and androgen-independent prostate cancer cells. This was accomplished by down-regulating apoptosis suppressor proteins and other crucial proteins such as the androgen receptor. It is concluded that curcumin may provide an alternative, nontoxic modality by which the clinician may prevent the progression of prostate cancer to its hormone refractory state or to treat advanced prostate cancer by forcing them to undergo apoptosis. Prostate Cancer and Prostatic Diseases (2000) 3, 84-93

Journal Article↗
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↗
PubMedDate not supplied

Anti- and pro-oxidant effects of oxidized quercetin, curcumin or curcumin-related compounds with thiols or ascorbate as measured by the induction period method.

Phenolic antioxidants, such as quercetin (QUE), curcumin (CUR) and the CUR-related compounds eugenol (EUG) and isoeugenol (IsoEUG), do not act in isolation in vivo but form an intricate antioxidant network together with ascorbate or glutathione (GSH). To clarify the antioxidant/prooxidant activity of these compounds in their interplay with ascorbate or GSH, the induction period (IP) and propagation rate (Rp) for mixtures of 2-mercapto-1-methylimidazole (MMI, a thiol) or L-ascorbyl-2,6-dibutyrate (ASDB, an ascorbate derivative) with QUE, CUR, EUG or IsoEUG were determined from differential scanning calorimetry (DSC) monitoring of the polymerization of methyl methacrylate (MMA), initiated by thermal decomposition of 1.0 mol% benzoyl peroxide (BPO, a PhCOO* radical) under nearly anaerobic conditions. The IP (min) for 0.01 mol% test compounds declined in the order CUR (28.31) > IsoEUG (19.47) > EUG (16.83) > QUE (10.17) > MMI (2.06) > ASDB (0.16). The inhibition rate constant (kin(inh), M(-1)s(-1)) declined in the order ASDB (7.85 x 10(5)) > MMI (5.99 x 10(4)) > QUE (1.21 x 10(4)) > EUG (7.93 x 10(3)) > IsoEUG (7.04 x 10(3)) > CUR (4.50 x 10(3)). The observed IP for MMI/QUE mixtures, particularly at molar ratios of 2:1 and 5:1, was significantly less than that for QUE alone as well as that calculated for MMI/QUE. The decrease in IP was similar to the observed IP in the control, suggesting the occurrence of oxygen uptake, possibly due to the formation of thiol RS radicals which, together with oxygen, produce oxo- and peroxo-sulphur radicals. The observed IPs for MMI/CUR or the MMI/IsoEUG mixtures, particularly the former, were less than the corresponding calculated IPs, suggesting co-oxidation of the MMI without oxygen uptake. In contrast, the observed IP of MMI/EUG mixtures was much greater than the corresponding calculated IP, suggesting the formation of an new antioxidative adduct between EUG-quinonemethide and MMI. The observed IP for the ASDBI/QUE mixtures was greater than the corresponding calculated IP, suggesting the effectiveness of QUE as a co-antioxidant for ascorbate. In contrast, the observed IP for the ASDB/CUR mixtures was significantly less than the corresponding calculated IP, suggesting the catalytic effectiveness of CUR for ascorbate co-oxidation. Cancer cells are anaerobic in their metabolism and they selectively absorb more ascorbate than normal cells do. Thus, the present findings for the ASDB/CUR mixtures could help explain the effectiveness of CUR in chemoprevention by inducing cancer cell apoptosis. In addition, the findings for the MMI/QUE mixtures suggest the production of toxic oxo- and peroxo-sulphur radicals from thiols.

Antioxidants↗
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↗
PubMed2001

Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production.

Curcumin, the yellow pigment in turmeric, has been shown to prevent malignancies in a variety of tissues in rodents, especially in the intestinal tract. Pharmacological activities of curcumin in cells in situ germane to chemoprevention, such as inhibition of expression of cyclooxygenase-2 (COX-2), require drug concentrations in the 10(-5) - 10(-4) M range. The systemic bioavailability of curcumin is low, so that its pharmacological activity may be mediated, in part, by curcumin metabolites. To investigate this possibility, we compared curcumin metabolism in human and rat hepatocytes in suspension with that in rats in vivo. Analysis by high-performance liquid chromatography with detection at 420 and 280 nm permitted characterization of metabolites with both intact diferoylmethane structure and increased saturation of the heptatrienone chain. Chromatographic inferences were corroborated by mass spectrometry. The major metabolites in suspensions of human or rat hepatocytes were identified as hexahydrocurcumin and hexahydrocurcuminol. In rats, in vivo, curcumin administered i.v. (40 mg/kg) disappeared from the plasma within 1 h of dosing. After p.o. administration (500 mg/kg), parent drug was present in plasma at levels near the detection limit. The major products of curcumin biotransformation identified in rat plasma were curcumin glucuronide and curcumin sulfate whereas hexahydrocurcumin, hexahydrocurcuminol, and hexahydrocurcumin glucuronide were present in small amounts. To test the hypothesis that curcumin metabolites resemble their progenitor in that they can inhibit COX-2 expression, curcumin and four of its metabolites at a concentration of 20 microM were compared in terms of their ability to inhibit phorbol ester-induced prostaglandin E2 (PGE2) production in human colonic epithelial cells. Curcumin reduced PGE2 levels to preinduction levels, whereas tetrahydrocurcumin, previously shown to be a murine metabolite of curcumin, hexahydrocurcumin, and curcumin sulfate, had only weak PGE2 inhibitory activity, and hexahydrocurcuminol was inactive. The results suggest that (a) the major products of curcumin biotransformation by hepatocytes occur only at low abundance in rat plasma after curcumin administration; and (b) metabolism of curcumin by reduction or conjugation generates species with reduced ability to inhibit COX-2 expression. Because the gastrointestinal tract seems to be exposed more prominently to unmetabolized curcumin than any other tissue, the results support the clinical evaluation of curcumin as a colorectal cancer chemopreventive agent.

Adult↗
PubMed2002

Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine.

Curcumin, the yellow pigment in turmeric, prevents malignancies in the intestinal tract of rodents. It is under clinical evaluation as a potential colon cancer chemopreventive agent. The systemic bioavailability of curcumin is low, perhaps attributable, at least in part, to metabolism. Indirect evidence suggests that curcumin is metabolized in the intestinal tract. To investigate this notion further, we explored curcumin metabolism in subcellular fractions of human and rat intestinal tissue, compared it with metabolism in the corresponding hepatic fractions, and studied curcumin metabolism in situ in intact rat intestinal sacs. Analysis by high-performance liquid chromatography, with detection at 420 or 280 nm, permitted characterization of curcumin conjugates and reduction products. Chromatographic inferences were corroborated by mass spectrometry. Curcumin glucuronide was identified in intestinal and hepatic microsomes, and curcumin sulfate, tetrahydrocurcumin, and hexahydrocurcumin were found as curcumin metabolites in intestinal and hepatic cytosol from humans and rats. The extent of curcumin conjugation was much greater in intestinal fractions from humans than in those from rats, whereas curcumin conjugation was less extensive in hepatic fractions from humans than in those from rats. The curcumin-reducing ability of cytosol from human intestinal and liver tissue exceeded that observed with the corresponding rat tissue by factors of 18 and 5, respectively. Curcumin sulfate was identified in incubations of curcumin with intact rat gut sacs. Curcumin was sulfated by human phenol sulfotransferase isoenzymes SULT1A1 and SULT1A3. Equine alcohol dehydrogenase catalyzed the reduction of curcumin to hexahydrocurcumin. The results show that curcumin undergoes extensive metabolic conjugation and reduction in the gastrointestinal tract and that there is more metabolism in human than in rat intestinal tissue. The pharmacological implications of the intestinal metabolism of curcumin should be taken into account in the design of future chemoprevention trials of this dietary constituent.

Adult↗
PubMedDate not supplied

Cytotoxicity, ROS-generation activity and radical-scavenging activity of curcumin and related compounds.

The cytotoxicity, ROS (reactive oxygen species)-generation activity and radical-scavenging activity of curcumin and related compounds such as eugenol, eugenol orthodimer (bis-eugenol; 3,3'-dimethoxy-5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) and isoeugenol were investigated. Their cytotoxicity against a human submandibular gland adenocarcinoma cell line (HSG) declined in the order curcumin > isoeugenol > bis-eugenol > eugenol. Since the hydrophobicity (log P) of curcumin, isoeugenol and eugenol is about 2.5, whereas that of bis-eugenol is 4.8, there was no relationship between cytotoxicity and log P. Generation of intracellular ROS in HSG cells was observed for curcumin alone in an assay using 5- (and -6)-carboxy-2',7'-dichlorofluorescein diacetate (CDFH-DA). The cytotoxicity of, and ROS generation by, curcumin were reduced by the addition of N-acetyl-L-cysteine (NAC) and glutathione, suggesting a possible link between cytotoxicity and ROS. The radical-scavenging (antioxidant) activity of curcumin and related compounds was determined quantitatively by the induction period method for polymerization of methyl methacrylate (MMA) initiated by peroxy radicals derived from benzoyl peroxide (BPO) under nearly anaerobic conditions. The length of the induction (inhibition) period for curcumin was significantly greater than that of the other compounds. This suggests that curcumin is an efficient scavenger of peroxy radicals. The curcumin radical possibly reacts with itself or with other radicals to yield polymeric stable products such as curcumin dimer. Such polyphenolic behavior of curcumin was considerably different from that of bis-eugenol, which, like curcumin, has two hydroxy groups, or of other compounds with one hydroxy group. The radical-scavenging activity was also investigated with 2,2-diphenyl-1-picrylhydrazyl (DPPH). Curcumin scavenged approximately one DPPH free radical, suggesting the formation of curcumin dimer. The possible formation of curcumin dimer was explored with a PM3 semiempirical molecular orbital method. A molecular mechanism of cancer prevention by curcumin is proposed, based on its high reactivity with peroxy radicals at low oxygen pressure and on ROS generation induced by curcumin radicals.

Adenocarcinoma↗