Nitric oxide scavenging by curcuminoids
Sreejayan; Rao M.N.A., India
Journal of Pharmacy and Pharmacology (U. K.) , 1997, 49/1 (105-107)
Because curcumin, a compound with anti-inflammatory and anticancer activity, inhibits induction of nitric oxide synthase in activated macrophages and has been shown to be a potent scavenger of free radicals we have investigated whether it can scavenge nitric oxide directly. Curcumin reduced the amount of nitrite formed by the reaction between oxygen and nitric oxide generated from sodium nitroprusside. Other related compounds, e.g. demethoxycurcumin, bisdemethoxycurcumin and diacetylcurcumin were as active as curcumin, indicating that the methoxy and the phenolic groups are not essential for the scavenging activity. The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free-radical scavenging properties, including those toward nitric oxide.
Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells
Kuo M.-L.; Huang T.-S.; Lin J.-K.
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei Taiwan
Biochimica et Biophysica Acta-Molecular Basis of Disease (Netherlands),1996,1317/2 (95-100)
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 microg/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 microg/ml curcumin treatment. The apoptosis-inducing activity of curcumin was not affected by cycloheximide, actinomycin D, EGTA, W; (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-acetyI-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.
Antimutagenic and anticarcinogenic activity of natural and synthetic curcuminoids
Anto R.J.; George J.; Dinesh Babu K.V.; Rajasekharan K.N.; Kuttan R.
Amala Cancer Research Centre, Amala Nagar, Thrissur 680553, Kerala India
Mutation Research - Genetic Toxicology (Netherlands) , 1996, 370/2 (127-131)
Five synthetic curcuminoids and three natural curcuminoids were investigated for their antimutagenic and anti-promotional activity. The natural curcuminoids, curcumin I (diferuloylmethane), curcumin II (feruloyl-p-hydroxycinnamoylmethane) and curcumin III (bis-(p-hydroxycinnamoyl) methane) isolated from Curcuma longa were found to be potent inhibitors of mutagenesis and crotean oil-induced tumour promotion. Curcumin III produced 87.6% inhibition to 2-acetamidofluorene (2-AAF) induced mutagenesis, at a concentration of 100 microg/plate, curcumin II and curcumin I produced 70.5% and 68.3% inhibition at the same concentration. All the synthetic curcuminoids were found to inhibit 2-AAF-induced mutagenicity among which salicyl- and anisylcurcuminoids were the most active. Curcumin III was the most effective anti-promotor among natural curcuminoids. While 90% of the control animals were having papillomas on the 10th week of tumour initiation, only 10% of the curcumin III-treated animals, 20% of the curcumin II-treated animals, and 40% of the curcumin I-treated animals were having papillomas. Salicylcurcuminoid, which was causing no papillomas by the 10th week, was the most potent anti-carcinogen among the synthetic curcuminoids. Piperonal curcuminoid also exhibited anti-promotional activity.
Antioxidant Curcuma extracts decrease the blood lipid peroxide levels of human subjects
Age (USA), 1995, 18/4 (167-169)
Extracts of the rhyzome of Curcuma longa are widely used as food additives in India and other Asiatic and Central American countries. Moreover, it has been recently shown that these extracts ('turmeric'), as well as 'curcumin' and related phenolic compounds isolated from Curcuma, have a powerful lipid antioxidant action, when tested in in vitro systems. This justifies the present attempt to find out whether hydroalcoholic extracts of Curcum longa also exert an antioxidant effect in human subjects. Our data show that a 45- day intake (by healthy individuals ranging in age from 27 to 67 years) of Curcuma hydroalcoholic extract (at a daily dose equivalent to 20 mg of curcumine) results in a significant decrease in the levels of serum lipid peroxides. These peroxides probably play an important pathogenic role in normal senescence and age-related diseases such as atherosclerosis. Therefore, hydroalcoholic extracts of Curcuma longa (that have very low toxicity and have been cleared as food additives in the above countries) may find use in future preventive geriatrics after further clinical studies.
Inhibition of tumor necrosis factor by curcumin, a phytochemical
Biochemical Pharmacology (United Kingdom), 1995, 49/11 (1551-1556)
Curcumin, contained in the rhizome of the plant Curcuma longa Linn, is a naturally occurring phytochemical that has been used widely in India and Indonesia for the treatment of inflammation. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) induces the production of interleukin-1beta (IL-1), and, together, they play significant roles in many acute and chronic inflammatory diseases. They have been implicated in the pathogenesis of intracellular parasitic infections, atherosclerosis, AIDS and autoimmune disorders. This report shows that, in vitro, curcumin, at 5 microM, inhibited lipopolysaccharide (LPS)-induced production of TNF and IL-1 by a human monocytic macrophage cell line, Mono Mac 6. In addition, it demonstrates that curcumin, at the corresponding concentration, inhibited LPS-induced activation of nuclear factor kappa B and reduced the biological activity of TNF in L929 fibroblast lytic assay.
Inhibitory effect of curcumin, an anti-inflammatory agent, on vascular smooth muscle cell proliferation
EUR. J. PHARMACOL. (Netherlands), 1992, 221/2-3 (381-384)
The effects of curcumin, an anti-inflammatory agent from Curcuma longa, on the proliferation of blood mononuclear cells and vascular smooth muscle cells were studied. Proliferative responses were determined from the uptake of tritiated thymidine. In human peripheral blood mononuclear cells, curcumin dose dependently inhibited the responses to phytohemagglutinin and mixed lymphocyte reaction at the dose ranges of 10-6 to 3 x 10-5 and 3 x 10-6 to 3 x 10-5 M, respectively. Curcumin (10-6 to 10-4 M) dose dependently inhibited the proliferation of rabbit vascular smooth muscle cells stimulated by fetal calf serum. Curcumin had a greater inhibitory effect on platelet-derived growth factor-stimulated proliferation than on serum-stimulated proliferation. Cinnamic acid, coumaric acid and ferulic acid were much less effective than curcumin as inhibitors of serum-induced smooth muscle cell proliferation, suggesting that the cinnamic acid and ferulic acid moieties alone are not sufficient for activity, and that the characteristics of the diferuloylmethane molecule itself are necessary for activity. Curcumin may be useful as a new template for the development of better remedies for the prevention of the pathological changes of atherosclerosis and restenosis.
Curcumin protects against 4-hydroxy-2-trans-nonenal-induced cataract formation in rat lenses
Awasthi S; Srivatava SK; Piper JT; Singhal SS; Chaubey M; Awasthi YC
Department of Internal Medicine, University of Texas Medical Branch Galveston 77555-1067, USA.
Am J Clin Nutr (UNITED STATES) Nov 1996, 64 (5) p761-6
Age-related cataractogenesis is a significant health problem worldwide. Oxidative stress has been suggested to be a common underlying mechanism of cataractogenesis, and augmentation of the antioxidant defenses of the ocular lens has been shown to prevent or delay cataractogenesis. The present studies were designed to test the efficacy of curcumin, an antioxidant present in the commonly used spice turmeric, in preventing cataractogenesis in an in vitro rat model. Rats were maintained on an AIN-76 diet (ICN Pharmaceuticals Inc, Cleveland) for 2 wk, after which they were given a daily dose of corn oil alone or 75 mg curcumin/kg in corn oil for 14 d. Their lenses were removed and cultured for 72 h in vitro in the presence or absence of 100 mumol 4-hydroxy-2-nonenal (4-HNE)/L, a highly electrophilic product of lipid peroxidation. The results of these studies showed that 4-HNE caused opacifications of cultured lenses as indicated by the measurements of transmitted light intensity using digital image analysis. However, the lenses from curcumin-treated rats were much more resistant to 4-HNE-induced opacification than were lenses from control animals. Curcumin treatment caused a significant induction of the glutathione S-transferase (GST) isozyme rGST8-8 in rat lens epithelium. Because rGST8-8 utilizes 4-HNE as a preferred substrate, we suggest that the protective effect of curcumin may be mediated through the induction of this GST isozyme. These studies suggest thaumin may be an effective protective agent against cataractogenesis induced by lipid peroxidation.
Action of curcumin on the cytochrome P450-system catalyzing the activation of aflatoxin B1
Chem Biol Interact (IRELAND) Mar 8 1996, 100 (1) p41-51
Curcumin, in a dose-dependent manner, inhibited the formation of covalent adduct between aflatoxin B1 and DNA, as catalyzed by microsomes or a reconstituted microsomal monooxygenase system. Its effect on the cytochrome P450-system was investigated in the latter system. The inhibition (50%) of aflatoxin B1-DNA adduct formation by curcumin in this system could be reversed by increasing the amount of cytochrome P450 but not by that of NADPH-cytochrome P450 reductase. Curcumin inhibited the reductase activity when measured by the reduction of cytochrome C but not when measured by the reduction of dichlorophenolindophenol, an artificial electron acceptor. These results, as well as the reversal of curcumin-induced inhibition of P450 reductase activity by higher amounts of cytochrome C, indicated a strong affinity of curcumin towards cytochromes. This was further substantiated from the observation that curcumin-pretreated cytochrome P450 had reduced ability to catalyze aflatoxin B1-DNA adduct formation in the reconstituted system. Curcumin, thus, may inhibit chemical carcinogenesis by modulating cytochrome P450 function.
Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin
Indian J Physiol Pharmacol (INDIA) Oct 1992, 36 (4) p239-43
Effect of oral administration of curcumin (diferuloyl methane) on lipid peroxidation in various organs of mice like liver, lung, kidney and brain was studied in control animals as well as those given carbon tetrachloride, paraquat and cyclophosphamide. Oral administration of curcumin significantly lowered the increased peroxidation of lipids in these tissues produced by these chemicals. Administration of curcumin was also found to lower significantly the serum and tissue cholesterol levels in these animals, indicating that the use of curcumin helps in conditions associated with peroxide induced injury such as liver damage and arterial diseases.
Induction of glutathione S-transferase activity by curcumin in mice
Arzneimittelforschung (GERMANY) Jul 1992, 42 (7) p962-4
Curcumin, a natural constituent of Curcuma longa (turmeric, CAS 458-37-7), has been studied for its induction of glutathione S-transferase activity in mice. At a dose of 250 mg/kg orally for 15 days, the enzyme activity in liver was increased by 1.8 fold. Its effect on other tissues like stomach, small intestine, lungs, kidney was not significant. Curcumin also depleted sulfhydryl levels in tissues, especially in stomach where 45% depletion was observed.
Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells
Biochim Biophys Acta (NETHERLANDS) Nov 15 1996, 1317 (2) p95-100
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.
Hypolipidemic action of curcumin, the active principle of turmeric (Curcuma longa) in streptozotocin induced diabetic rats
Molecular and Cellular Biochemistry (Netherlands)), 1997, 166/1-2 (169-175)
Streptozotocin-induced diabetic rats were maintained on 0.5% curcumin containing diet for 8 weeks. Blood cholesterol was lowered significantly by dietary curcumin in these diabetic animals. Cholesterol decrease was exclusively from LDL-VLDL fraction. Significant decrease in blood triglyceride and phospholipids was also brought about by dietary curcumin in diabetic rats. In a parallel study, wherein diabetic animals were maintained on a high cholesterol diet, the extents of hypercholesterolemia and phospholipidemia were still higher compared to those maintained on control diet. Curcumin exhibited lowering of cholesterol and phospholipid in these animals also. Liver cholesterol, triglyceride and phospholipid contents were emin showed a distinct tendency to counter these changes in lipid fractions of liver. This effect of curcumin was also seen in diabetic animals maintained on high cholesterol diet. Dietary curcumin also showed significant countering of renal cholesterol and triglycerides elevated in diabetic rats. In order to understand the mechanism of hypocholesterolemic action of dietary curcumin, activities of hepatic cholesterol-7a-hydroxylase and HMG CoA reductase were measured. Hepatic cholesterol-7a-hydroxylase activity was markedly higher in curcumin fed diabetic animals suggesting a higher rate of cholesterol catabolism.
Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets
Prostaglandins Leukotrienes and Essential Fatty Acids (United Kingdom), 1995, 52/4 (223-227)
In traditional medicine, Ayurveda, several spices and herbs are held to possess medicinal properties. Earlier we have reported that extracts from several spices, including turmeric, inhibit platelet aggregation and modulate eicosanoid biosynthesis. Due to their eicosanoid-modulating property, it was suggested that the spices may serve to provide clues to drugs directed to arachidonic acid (AA) pathway enzymes as pharmacological targets. Curcumin, a major component of turmeric, inhibited platelet aggregation induced by arachidonate, adrenaline and collagen. This compound inhibited thromboxane B2 (TXB2) production from exogenous (14C) arachidonate in washed platelets with a concomitant increase in the formation of 12-lipoxygenase products. Moreover, curcumin inhibited the incorporation of (14C)AA into platelet phospholipids and inhibited the deacylation of AA-labelled phospholipids (liberation of free AA) on stimulation with calcium ionophore A23187. Curcumin's anti-inflammatory property may, in part, be explained by its effects on eicosanoid biosynthesis.
Influence of capsaicin, eugenol, curcumin and ferulic acid on sucrose-induced hypertriglyceridemia in rats
NUTR. REP. INT. (USA), 1988, 38/3 (571-581)
The spice active principles, capsaicin, eugenol curcumin and 'ferulic acid' a common plant constituent were found to counter many of the metabolic changes caused by a high sucrose diet fed to rats. The compounds tested at high and low levels were mostly found to lower or tend to lower liver weight, liver triglycerides, free fatty acids, phospholipids, serum total, VLDL+LDL and HDL triglycerides, VLDL+LDL cholesterol, free fatty acids and also elevate serum total and HDL cholesterol.
Anti-tumour and antioxidant activity of natural curcuminoids
Cancer Lett (IRELAND) Jul 20 1995, 94 (1) p79-83
Matural curcuminoids, curcumin, I, II and III isolated from turmeric (Curcuma longa) were compared for their cytotoxic, tumour reducing and antioxidant activities. Curcumin III was found to be more active than the other two as a cytotoxic agent and in the inhibition of Ehrlich ascites tumour in mice (ILS 74.1%). These compounds were also checked for their antioxidant activity which possibly indicates their potential use as anti-promoters. The amount of curcuminoids (I, II and III) needed for 50% inhibition of lipid peroxidation was 20, 14 and 11 g/m. Concentrations needed for 50% inhibition of superoxides were 6.25, 4.25 and 1.9 micrograms/ml and those for hydroxyl radical were 2.3, 1.8 and 1.8 micrograms/ml, respectively. The ability of these compounds to suppress the superoxide production by macrophages activated with phorbol-12-myristate-13-acetate (PMA) indicated that all the three curcuminoids inhibited superoxide production and curcumin III produced maximum effect. These results indicate that curcumin III is the most active of the curcuminoids present in turmeric. Synthetic curcumin I and III had similar activity to natural curcumins.
The effect of spices on cholesterol 7 alpha-hydroxylase activity and on serum and hepatic cholesterol levels in the rat
Int J Vitam Nutr Res (SWITZERLAND) 1991, 61 (4) p364-9
The effect of feeding curcumin, capsaicin, ginger, mustard, black pepper and cumin on cholesterol and bile acid metabolism was studied in rats. The activity of hepatic cholesterol-7 alpha-hydroxylase, the rate-limiting enzyme of bile acid biosynthesis, was significantly elevated in curcumin (turmeric), capsaicin (red pepper), ginger and mustard treated animals. The enzyme activity was comparable to controls in black pepper and cumin fed rats. Serum and liver microsomal cholesterol contents were significantly higher in the curcumin and capsaicin treated animals. Thus, this study has suggested that the spices--turmeric, red pepper, ginger and mustard can stimulate the conversion of cholesterol to bile acids, an important pathway of elimination of cholesterol from the body. However, simultaneous stimulation of cholesterol synthesis by the spice principles--curcumin and capsaicin suggests that there may not be any significant contribution of stimulation of bile acid biosynthesis to the hypocholesterolemic action of these spices, and the latter action may solely be due to interference with exogenous cholesterol absorption.
Influence of dietary curcumin and cholesterol on the progression of experimentally induced diabetes in albino rat
Molecular and Cellular Biochemistry (USA), 1995, 152/1 (13-21)
Effect of feeding 0.5% curcumin diet or 1% cholesterol diet was examined in albino rats rendered diabetic with streptozotocin injection. Diabetic rats maintained on curcumin diet for 8 weeks excreted Comparatively less amounts of albumin, urea, creatinine and inorganic phosphorus. Urinary excretion of the electrolytes sodium and potassium were also significantly lowered under curcumin treatment. Dietary curcumin also partially reversed the abnormities in plasma albumin, urea, creatinine and inorganic phosphorus in diabetic animals. On the other hand, glucose excretion or the fasting sugar level was unaffected by dietary curcumin and so also the body weights were not improved to any significant extent. Diabetic rats fed curcumin diet had a lowered relative liver weight at the end of the study compared to other diabetic rat groups. Diabetic rats fed a curcumin diet also showed lowered lipid peroxidation in plasma and urine when compared to other diabetic groups. The extent of lipid peroxidation on the other hand, was still higher in cholesterol fed diabetic groups compared to diabetic rats fed with control diet. Thus, the study reveals that curcumin feeding improves the metabolic status in diabetic condition, despite no effect on hyperglycemic status or the body weights. The mechanism by which curcumin improves this situation is probably by virtue of its hypocholesterolemic influence, antioxidant nature and free radical scavenging property.
Effect of retinol deficiency and curcumin or turmeric feeding on brain Na+-K+ adenosine triphosphatase activity
MOL. CELL. BIOCHEM. (USA), 1994, 137/2 (101-107)
The effect of retinol deficiency and curcumin and turmeric feeding on brain microsomal Na+-K+ ATPase activity was investigated. The brain Na+- K+ ATPase activity registered an increase of 148.5% as compared to the control group. Upon treating retinol deficient rats with curcumin or turmeric, the abnormally elevated activity showed a decrease of 36.9 and 47.1%, respectively, when compared to the retinol deficient group. An increase in V(max) by 67% and K(m) by 66% for ATP was observed in the retinol deficient group. Curcumin or turmeric fed retinol-deficient groups reduced the V(max) by 25 and 33%, while K(m) was reduced by 25 and 31%, respectively, compared to the retinol deficient group. Arrhenius plot of Na+-K+ ATPase showed a typical bi-phasic pattern in all the groups. Cholesterol:Phospholipid ratio showed a decrease in the retinol-deficient group by 67.8%, which showed a marked increase in curcumin or turmeric treated groups. Detergents could increase the Na+-K+ ATPase activity more in the control group than in the retinol deficient groups. Curcumin or turmeric improved the detergent action on the enzyme. Subsequent freezing and thawing over a period of 30 min decreased the enzyme activity by 22.8% in the retinol deficient group compared to 15.9% decrease in the control group. Curcumin or turmeric treated groups showed a decrease in the enzyme activity by 22.0 and 19.2%, respectively, when compared to the zero time in each group. In the presence of concanavalin-A (Con-A) there was only 52.4% stimulation in the enzyme activity in retinol deficient groups, compared to 108.0% in the control group. Curcumin or turmeric treated retinol-deficient groups showed a stimulation in the presence of con-A by 70 and 99.5%, respectively.
Mechanism of antiinflammatory actions of curcumine and boswellic acids
J. ETHNOPHARMACOL. (Ireland), 1993, 38/2-3 (113-119)
Curcumine from Curcuma longa and the gum resin of Boswellia serrata, which were demonstrated to act as antiinflammatories in in vivo animal models, were studied in a set of in vitro experiments in order to elucidate the mechanism of their beneficial effects. Curcumine inhibited the 5-lipoxygenase activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets. In a cell free peroxidation system curcumine exerted strong antioxidative activity. Thus, its effects on the dioxygenases are probably due to its reducing capacity. Boswellic acids were isolated from the gum resin of Boswellia serrata and identified as the active principles. Boswellic acids inhibited the leukotriene synthesis via 5-lipoxygenase, but did not affect the 12-lipoxygenase and the cyclooxygenase activities. Additionally, boswellic acids did not impair the peroxidation of arachidonic acid by iron and ascorbate. The data suggest that boswellic acids are specific, non-redox inhibitors of leukotriene synthesis either interacting directly with 5-lipoxygenase or blocking its translocation.
Influence of dietary spices on adrenal steroidogenesis in rats
NUTR. RES. (USA), 1993, 13/4 (435-444)
Experiments were carried on adult rats which were fed the following diets for 2 months: Control, Curcumin (0.5%), Capsaicin (15mg%), Ginger (50mg%), Black pepper (0.5%), Cumin (1.25%), Mustard (250mg%), Fenugreek (2%) and Onion (3%). Adrenal weights in the various experimental groups were comparable to controls. Adrenal cholesterol was found to be significantly lower in all the spice fed animals except mustard suggesting a higher rate of cholesterol turnover to corticosteroid hormones. Cholesterol depletion was accompanied by reduced ascorbic acid content in the adrenals of curcumin, capsaicin, fenugreek and onion fed rats. Urinary excretion of 17-oxo and 17- hydroxy steroids which are the metabolites of corticosteroids was significantly higher in these spice fed groups. These data are indicative of the stimulatory influence of dietary spices on adrenal steroidogenesis.
Differential effects of dietary lipids and curcumin on kidney microsomal fatty acids and Na+, K+ - ATPase activity in rat
NUTR. RES. (USA), 1992, 12/7 (893-904)
The effect of dietary lipids and spice principle curcumin on kidney microsomal lipids, Na+, K+ - ATPase activity and serum lipid levels were studied. Rats were fed a diet containing either coconut oil, safflower oil or menhaden oil for 8 weeks. Safflower oil and menhaden oil feeding resulted in the accumulation of n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA respectively in the kidney microsomes. The specific activity of Na+, K+ - ATPase was higher by 26% in animals fed safflower oil when compared to animals fed coconut oil or menhaden oil. Supplementation of curcumin in the diets containing different lipids did not affect either the kidney microsomal fatty acid profiles or Na+, K+ - ATPase activity. However, dietary curcumin reduced the serum triglyceride level by 44% in safflower oil fed animals and serum cholesterol levels by 24% and 31% in animals fed safflower oil and menhaden oil respectively. These studies indicated that dietary lipids and curcumin differentially affect membrane fatty acid composition, Na+, K+ - ATPase activity and serum lipids.
Curcumin and genistein, plant natural products, show synergistic inhibitory effects on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides
Biochemical and Biophysical Research Communications (USA), 1997, 233/3 (692-696)
Curcumin and genistein are two natural products of plants obtained from Curcuma longa Linn (turmeric) and soybeans, respectively. Both compounds when present at micromolar concentrations are able to inhibit the growth of estrogen-posthe pesticides endosulfane, DDT and chlordane or 17-beta estradiol. When curcumin and genistein were added together to MCF-7 cells, a synergistic effect resulting in a total inhibition of the induction of MCF-7 cells by the highly estrogenic activity of endosulfane/chlordane/DDT mixtures was noted. These data suggest that the combination of curcumin and genistein in the diet have the potential to reduce the proliferation of estrogen-positive cells by mixtures of pesticides or 17-beta estradiol. Since it is difficult to remove pesticides completely from the environment or the diet and since both turmeric and soybeans are not toxic to humans, their inclusion in the diet in order to prevent hormone related cancers deserves consideration.
Curcumin inhibits the proliferation and cell cycle progression of human umbilical vein endothelial cell
Cancer Letters (Ireland), 1996, 107/1 (109-115)
We have studied the effect of curcumin (diferuloylmethane), a major component of the food flavor turmeric, on the proliferation and cell cycle progression of human umbilical vein endothelial cells (HUVEC). Curcumin inhibited the DNA synthesis of HUVEC as revealed by (3H)thymidine incorporation in a dose-dependent manner without significantly affecting the viability of the cells. The growth of HUVEC stimulated with fibroblast growth factor (FGF) and endothelial growth supplement (EGGS) was also inhibited by curcumin. Addition of curcumin to HUVEC resulted in an accumulation of > 46% of the cells in early S-phase, as determined by the FAGS analysis. Pulse labeling studies with (3H)thymidine demonstrated that curcumin affected cells that were actively undergoing DNA synthesis. The de-novo synthesis of thymidine depends on thymidine kinase (TK) enzyme.Curcumin caused a significant loss of TK activity, which may be one of the possible mechanism(s) for the inhibition of DNA synthesis activity of HUVEC by curcumin. These studies have revealed a unique mode of action of curcumin S-phase by inhibiting the activity of TK enzyme. The migration, proliferation and differentiation of HUVEC leads to angiogenesis, which facilitates the tumor initiation and promotion. Since curcumin inhibited the proliferation of HUVEC, it could turn out to be a very useful compound for the development of novel anti-cancer therapy.
Natural products and their derivatives as cancer chemopreventive agents
Progress in Drug Research (Switzerland), 1997, 48/- (147-171) :
This review summarizes currently available data on the chemopreventive efficacies, proposed mechanisms of action and relationships between activities and structures of natural products like vitamin D, calcium, dehydroepidandrosterone, coenzyme Q10, celery seed oil, parsley leaf oil, sulforaphane, isoflavonoids, lignans, protease inhibitors, tea polyphenols, curcumin, and polysaccharides from Acanthopanax genus.
New agents for cancer chemoprevention
Nation996, 63/SUPPL. 26 (1-28)
Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids (e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid), calcium, betacarotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylomithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3- carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs.Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.
Modulation of apoptosis by sulindac, curcumin, phenylethyl-3- methylcaffeate, and 6-phenylhexyl isothiocyanate: Apoptotic index as a biomarker in colon cancer chemoprevention and promotion
Cancer Research (USA), 1997, 57/7 (1301-1305)
Recent evidence supports the theory that tumor growth in vivo depends on evasion of normal homeostatic control mechanisms that operate through induction of cell death by apoptosis. This study tested the hypothesis that several potential chemopreventive agents share the ability to induce apoptosis and that inhibition of apoptosis is a mechanism of tumor promoters. The present study was designed to investigate whether the chemopreventive properties of sulindac, curcumin, and phenylethyl-3-methylcaffeate (PEMC) and the tumor-promoting activity of 6-phenylhexyl isothiocyanate (PHITC) that were observed in our previous studies are associatedn azoxymethane (AOM)-induced colon tumors in male F344 rats. At 5 weeks of age, groups of rats were fed control (modified AIN- 76A) diet or diets containing 320 ppm of sulindac, 2000 ppm of curcumin, 750 ppm of PEMC, or 640 ppm of PHITC. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given AOM (15 mg/kg body weight) once weekly for 2 weeks. To study the effect of sulindac administered during promotion/progression stage, the rats were fed the control diet initially and then fed the experimental diet containing 320 ppm of sulindac 14 weeks after the second AOM treatment. The rats were sacrificed 52 weeks after carcinogen treatment, and their colonic tumors were subjected to histopathological evaluation and the appearance of apoptosis. In the current study, chronic administration of sulindac, curcumin, and PEMC or sulindac given only during promotion/progression significantly increased the apoptotic index (percentage of apoptosis) as compared to administration of the control diet; the apoptotic indices in the control, sulindac, curcumin, and PEMC diets were 8.3, 17.6, 17.7, and 18.5%, respectively, and in sulindac administered during promotion/progression stage, the apoptotic index was 19.1%. However, dietary PHITC blocked the process of apoptosis during colon carcinogenesis. The apoptotic index in PHITC diet was 7.0%. Taken together, our data show that chemopreventive properties of agents are correlated with the degree of apoptosis. Therefore apoptosis seems to be a reliable biomarker for the evaluation of potential agents for cancer prevention.
Nitric oxide scavenging by curcuminoids
Journal of Pharmacy and Pharmacology (United Kingdom), 1997, 49/1 (105-107)
Because curcumin, a compound with anti-inflammatory and anticancer activity, inhibits induction of nitric oxide synthase in activated macrophages and has been shown to be a potent scavenger of free radicals we have investigated whether it can scavenge nitric oxide directly. Curcumin reduced the amount of nitrite formed by the reaction between oxygen and nitric oxide generated from sodium nitroprusside. Other related compounds, e.g. demethoxycurcumin, bisdemethoxycurcumin and diacetylcurcumin were as active as curcumin, indicating that the methoxy and the phenolic groups are not essential for the scavenging activity. The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free-radical scavenging properties, including those toward nitric oxide.
Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines
Nutrition and Cancer (USA), 1996, 26/1 (111-120)
Curcumin, which is a widely used dietary pigment and spice, has been demonstrated to be an effective inhibitor of tumor promotion in mouse skin carcinogenesis. We report that curcumin induces cell shrinkage, chromatin condensation, and DNA fragmentation, characteristics of apoptosis, in immortalized mouse embryo fibroblast NIH 3T3 erb B2 oncogene-transformed NIH 3T3, mouse sarcoma S180, human colon cancer cell HT-29, human kidney cancer cell 293, and human hepatocellular carcinoma Hep G2 cells, but not in primary culture of mouse embryonic fibroblast C3H 10T1/2, rat embryonic fibroblast, and human foreskin fibroblast cells in a concentration- and time-dependent manner. Many cellular and biochemical effects of curcumin in mouse fibroblast cells have been reported, such as inhibition of protein kinase C (PKC) activity induced by phorbol 12-myristate 13-acetate treatment, inhibition of tyrosine protein kinase activity, and inhibition of arachidonic acid (AA) metabolism. Treatment of NIH 3T3 cells with the PKC inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin A, and the AA metabolism inhibitor quinacrine induces apoptotic cell death. These results suggest that, in some immortalized and transformed cells, blocking the cellular signal transduction might trigger the induction of apoptosis.
Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz(a)anthracene-induce d mammary cancer in rats
Carcinogenesis (United Kingdom), 1996, 17/6 (1305-1311)
Curcumin and quercetin were evaluated in rats for their ability to modulate the carcinogenic activity of azoxymethane (AOM) in the colon and 7,12-dimethylbenz(a)anthracene (DMBA) in the mammary gland. In the AOM-induced colon cancer model, male Fischer 344 rats at 8 weeks receive either curcumin (8 and 16 g/kg) or quercetin (16.8 and 33.6 g/kg) in the diet and 1 week later, were administered AOM (30 mg/kg body wt.) by subcutaneous injection. The animals continued to receive the two agents in the diet until sacrificed 45 weeks later. Curcumin mediated a dose-dependent inhibition of the incidence and multiplicity of adenomas from 47% and 0.58 plus or minus 0.12 adenomas/rat in the AOM-treated control group to 19% and 0.22 plus or minus 0.08 and 0.06% and 0.08 plus or minus 0.06 adenomas/rat for the low and high dose groups, respectively. A low yield of adenocarcinomas (0.06 plus or minus 0.04 adenocarcinomas/rat) was induced by AOM which was not significantly altered by curcumin. Treatment with quercetin caused a dose-dependent increase in the yield of AOM-induced tumors in the colon from 0.06 plus or minus 0.04 adenocarcinoma/rat to 0.64 plus or minus 0.12 and 1.14 plus or minus 0.17 for the low and high dose groups, respectively. In the DMBA-induced mammary cancer model, curcumin or quercetin was administered at either 10 or 20 g/kg diet, beginning 7 days prior to DMBA and continually throughout the remainder of the experiment. Neither curcumin nor quercetin significantly altered the incidence of animals with tumors or the tumor multiplicity, while the high concentration of both agents significantly increased tumor latency. These results demonstrate different responses to these agents in the two models. While curcumin was highly effective as a chemopreventive agent in the colon model, it was only weakly effective in the mammary model. In contrast, quercetin which was also only weakly effective in the mammary model, caused a dose-dependent enhancement of tumors induced by AOM in the colon model.
Use of a microsome-mediated test system to assess efficacy and mechanisms of cancer chemopreventive agents
Carcinogenesis (United Kingdom), 1996, 17/6 (1285-1290)
There is a growing need for short-term assays which can assess the mechanisms and efficacy of cancer chemopreventive agents. In the present study we have employed a microsome-mediated test system concomitantly with DNA adduct detection to assess the efficacy of five chemopreventive agents, N-acetylcysteine, butylated hydroxytoluene (BHT), curcumin, oltipraz, and ellagic acid. 32P-Postlabeling analysis of DNA incubated with benzo(a)pyrene (BP) in the presence of Aroclor 1254-induced microsomes produced two major adducts: one derived from the interaction of benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) with deoxyguanosine (dG) and the other from further activation of 9-OH-BP (309 and 34 adducts/107 nucleotides, respectively). With the exception of N-acetylcysteine, all test agents significantly altered BP-DNA adduct levels: Intervention with ellagic acid and oltipraz substantially (64-94%) inhibited both BPDE-dG and 9-OH-BP adducts, while intervention with curcumin and BHT inhibited the BPDE-dG adduct (57% and 38%, respectively) and enhanced the 9-OH-BP adduct (230% and 650%, respectively). Furthermore, ellagic acid was the only test agent observed to inhibit the anti BPDE-dG adduct in the absence of microsomal enzymes, which is consistent with the known conjugation of ellagic acid with BPDE. These results suggest that oltipraz may be acting as an inhibitor of P4501A1, the isozyme involved in activation of BP to BPDE, or by conjugation of the electrophilic species by a metabolite of oltipraz. A plausible mechanism for inhibition of the BPDE-dG adduct and enhancement of the 9-OH-BP adduct by curcumin and BHT includes inhibition of epoxide hydrolase. Our results also indicate that N-acetylcysteine does not act as an electrophilic trapping agent of BP metabolites but may exert its protective effect in vivo by various other means, including modulation of detoxification enzymes and altering DNA repair processes. These data suggest that this cell-free system in conjunction with the sensitive 32P-postlabeling DNA adduct analysis may prove a viable test system for assessing the mechanisms and efficacy of chemopreventive agents.
Inhibition of 7,12-dimethylbenz(alpha)anthracene (DMBA)-induced mammary tumorigenesis and DMBA-DNA adduct formation by curcumin
Cancer Letters (Ireland), 1996, 103/2 (137-141)
Curcumin, a constituent of the traditional Indian spice and medicine turmeric, was evaluated for its capacity to inhibit the mammary tumor initiating activity of 7,12-dimethylbenz (alpha)anthracene (DMBA) and the in vivo formation of mammary DMBA-DNA adducts in the female rat. Administration (i.p.) of curcumin at 100 mg/kg and 200 mg/kg doses was associated with a significant decrease in the number of palpable mammary tumors and mammary adenocarcinomas. The in vivo formation of mammary DMBA-DNA adducts also was depressed for animals administered curcumin doses from 50 mg/kg to 200 mg/kg. There was, however, no significant enhancement of liver glutathione-S-transferase activity following curcumin administration. Therefore, curcumin when administered i.p. can act as an effective chemopreventative agent towards DMBA-induced rat mammary tumorigenesis and mammary adduct formation.