A. Disease-specific studies
Curcumin useful in multiple sclerosis?
Curcumin is reported to be immunologically effective in experimental allergic encephalopathy, an experimental animal model of multiple sclerosis. The authors of a recent study on mice postulate that the mechanism of action is by blocking IL-12 (interleukin-12) signaling in T cells, suggesting potential applications in the management of multiple sclerosis and related disorders IL-12 is an inflammatory cytokine that plays a crucial role in the cell-mediated demyelinating autoimmune disorders.
Natarajan C, Bright JJ (2002) Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes IL-12. J Immunol 168(12):6506-13
Curcumin and colon cancer:
The efficacy of curcumin in inhibiting the development of adenomas of the intestinal tract has been confirmed in earlier studies. A recent study explored the chemopreventive efficacy and pharmacokinetics of curcumin in the Min/+ Mouse, a model of familial adenomatous polyposis.
The authors concluded from this study that the comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. The authors also mention that a clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.
Perkins, S. et al. (2002) Chemopreventive Efficacy and Pharmacokinetics of Curcumin in the Min/+ Mouse, a Model of Familial Adenomatous Polyposis. Cancer Epidemiol Biomarkers Prev 11(6):535-540.
Curcumin and prostate cancer:
Curcumin was shown to enhance cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21 (WAF1/C1P1) and C/EPBbeta, in two androgen-independent prostate cancer cell lines. Curcumin was also able to inhibit both the constitutional and time-dependent NF-kappa activation in a time-dependent manner. Synergistic effects were observed when curcumin was combined with standard chemotherapeutic agents. The authors of this study concluded that curcumin may be incorporated into cytotoxic therapies in the treatment of androgen-independent prostate cancer, to provide synergistic effects.
Hour, T.C. et al. (2002) Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NF-kappaB activation. Prostate 51(3):211-8
Curcumin and skin cancer:
The increased incidence of non-melanoma skin cancer, consisting of basal and squamous cell carcinoma, is a major health concern in recent years and is attributed to the action of solar (UV) B radiation as a result of atmospheric ozone layer depletion. Several compounds have been evaluated as photochemoprotective agents that provide protection against UV B radiation induced oxidative stress. The authors of this study propose that botanical antioxidants such as curcumin, by virtue of their free radical quenching action are an effective strategy to inhibit UV B radiation induced damage and thereby reduce the incidence of skin cancer.
Afaq, F. et al. (2002) Botanical antioxidants for chemoprevention of carcinogenesis. Plant Biosci. 7:d784-92.
Curcumin was found to cause cell death in eight melanoma cell lines, four with wild-type and four with mutant p53 (resistant to standard chemotherapy). The molecular pathways targeted by curcumin during apoptosis of human melanoma cells were investigated in a recent study. The authors report that apoptosis occurs through a membrane-mediated reaction, in a dose-dependent manner. Curcumin blocks the NF-kappa B cell survival pathway and suppresses the apoptopic inhibitor X1AP, thereby facilitating apoptosis in melanoma cell lines that are resistant to conventional chemotherapy.
Bush, J.A. et al. (2001) Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp Cell Res 271(2):305-1.
Curcumin and mammary cancer:
Curcumin was found to inhibit the proliferation of human breast cancer cells in vitro. The antiproliferative effects were found to be estrogen-dependent in estrogen receptor (ER) positive MCF-7 cells. Strong anti-invasive effects were also observed in ER negative cells through down regulation of matrix metalloproteinase and upregulation of tissue inhibitor metalloproteinase. Curcumin was also found to inhibit angiogenesis factors.
Shao. Z.M. et al. (2002) Curcumin exerts multiple suppressive effects on human breast carcinoma cells. Int. J. Cancer. 98(2):234-240.
Curcumin was found to prevent the development of radiation-induced mammary tumors in rats. Radiation induced nitric oxide is believed to be responsible for tumors developed due to irradiation. The administration of curcumin during irradiation was found to reduce the incidence of tumors in the presence of tumor promoter.
Inano, H. and Onoda, M. (2002) Prevention of radiation-induced mammary tumors. Int. J. Radiat. Oncol. Biol. Phys. 52(1):212-223.
Curcumin and gastric cancer:
Curcumin was found to exert chemoprotective effects during the post-initiation phase of N-methyl-N'-nitro-N-nitrosoguanidine/sodium chloride induced stomach carcinogenesis in rats. Rats were fed either 0.2% or 0.05% of curcumin in the diet for 55 weeks after carcinogen exposure. The development of cancerous and precancerous lesions in the glandular stomach was decreased by exposure to pure curcumin as compared to controls that did not receive curcumin. The authors concluded that curcumin exerts chemopreventive effects when given during the post-initiation phase of glandular stomach carcinogenesis in rats.
Ikezaki, S. et al. (2001) Chemopreventive effects of curcumin on glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride in rats. Anticancer Res. 21(5):3407-11.
Curcumin and DDT toxicity and carcinogenesis:
Curcumin has anti-carcinogenic action and is reported to inhibit the estrogenic effects of DDT and is synergistic with other phytoestrogens, according to a recent review article. The authors believe that dietary modification towards a low fat diet along with the inclusion of curcumin, soy products and cruciferous vegetables would be beneficial in reducing the risk of developing cancer and probably the harmful effects of DDT, a lipid soluble organochlorine pesticide.
Jaga, K. and Duvvi, H. (2001) Risk reduction for DDT toxicity and carcinogenesis through dietary modification. J.R. Soc. Health 121(2):107-113.
Curcumin and diabetes:
The efficacy of turmeric and curcumin on blood sugar and polyol pathway in diabetic albino rats was examined. Administration of turmeric or curcumin to diabetic rats reduced the blood sugar and glycosylated hemoglobin levels significantly. Oxidative stress was also reduced by turmeric and curcumin, as determined by the standard TBARS test. The authors postulate that this could be due to decreased influx of glucose intomthe polyol pathway, leading to an increased NADPH/NADP ratio and elevated activity of the antioxidant enzyme glutathione peroxidase. The activity of sorbitol dehydrogenase, an enzyme that catalyzes the conversion of sorbitol to fructose, was also lowered significantly on treatment with turmeric or curcumin. Curcumin was found to be more effective than turmeric in all these cases.
Arun, N. and Nalini, N. (2002) Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats. Plant Foods Hum Nutr 57(1):41-52
Curumin and wound healing:
One study investigated the effects of curcumin on hydrogen peroxide and hypoxanthine-xanthine oxidase induced damage to cultured human keratinocytes and fibroblasts, in an effort to elucidate the mechanism of wound healing action of curcumin. It was observed that exposure of human keratinocytes to curcumin (10 microgram/mL) offered significant protection against hydrogen peroxide. However no protective effects were observed against hypoxanthine-xanthine oxidase injury. The authors concluded that curcumin is a powerful inhibitor of damage to human keratinocytes and fibroblasts by hydrogen peroxide.
Phan, TT et al. (2001) Protective effects of curcumin against oxidative damage on skin cells in vitro:its implication for wound healing. J Trauma 51(5):927-31
Curcumin and its derivative tetrahydrocurcumin were found to offer protection against ferric trinitrilotriacetate oxidative renal damage in male ddY mice. Intraperitoneal treatment with ferric nitrilotriacetate induces lipid peroxidation and oxidative stress in the kidney. Tetahydrocurcumin (also a metabolic product of curcumin) proved to be a better antioxidant that induced antioxidant enzymes such as glutathione peroxidase, glutathione S-transferase and NADPH. Tetrahydrocurcumin was also a better scavenger of free radicals. The authors concluded that curcumin is converted to tetrahydrocurcumin in vivo and that Tetrahydrocurcumin is a more promising chemopreventive agaent.
Okada, K. et al. (2001) Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. J. Nutr. 131(8):2090-2095.
Curcumin and Alzheimer's disease:
In light of epidemiological studies that suggest a link between long-term use of non steroidal anti-inflammatory drugs and the reduced incidence of Alzheimer's disease (AD), one group of researchers evaluated whether dietary Curcumin (at low dose 160 ppm and high dose 5000 ppm) would have a similar effect in Alzheimer transgenic APPSw mouse model.. Low and high levels of curcumin significantly lowered oxidized proteins and interleukin 1 -beta, a pro-inflammatory cytokine elevated in the brains of these mice. With low dose, but not high dose curcumin, the astrocytic marker, GFAP was reduced and insoluble beta-amyloid (Abeta), soluble Abeta and plaque burden were significantly reduced by 43-50%, although levels of the amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also inhibited in neuronal layers not adjacent to plaque.
The authors concluded that in view of its efficacy and low toxicity, curcumin shows promise for the prevention of Alzheimer's disease.
Lim, G.P. et al (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21(21):8370-7.
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Curcumin and hyaline membrane disease:
A preliminary in vitro study explored the potential efficacy of curcumin in the regulation of pro-inflammatory cytokine expression by curcumin in hyaline membrane disease (HMD), chronic lung disease in premature infants. Curcumin significantly inhibited IL-1beta and IL-8 but produced minimal inhibition of TNFalpha expression by preterm lung inflammatory cells at 20 mM concentrations. The authors of the study concluded that Curcumin may be effective as a therapeutic agent in the attenuation of CLD.
Literat, A. et al. (2001) Regulation of pro-inflammatory cytokine expression by curcumin in hyaline membrane disease (HMD). Life Sci 70(3):253-67.
Curcumin and androgen-dependent skin disorders:
A hamster flank growth model was used to determine the efficacy of curcumin in the management of androgen-dependent skin disorders. When flank organs of a castrated hamster are treated with topical testosterone, they become larger in size and darker. 5-alpha-dihydrotestosterone (DHT) inhibitors are known to inhibit flank organ growth and curcumin an inhibitor of DHT was found to do the same. Green tea catechins (epicatechin-3-gallate and epigallocatechin-3-gallate) were shown to have the same effect, while epicatechin and epigallocatechin also inhibited growth but through a non- DHT dependent mechanism. All these natural compounds would therefore be potentially useful in androgen-mediated skin disorders, according to the authors.
Liao, S. et al. (118) Growth suppression of hamster flank organs by topical application of catechins, alizarin, curcumin and myristoleic acid. Arch. Dermatol. Res. 293(4):200-205.
B. Biological effects
Anti-inflammatory effects:
The Cyclooxygenase-2 (COX-2) enzyme plays an important role in colon carcinogenesis. One group
of researchers investigated the effect of curcumin on COX-2 expression in HT-29 human colon cancer cells. Curcumin inhibited cell growth in HT-29 cells in a concentration and time dependent manner. Curcumin inhibited mRNA and protein expression in COX-2 but not COX-1 and may have value as a specific inhibitor of COX-2 and a safe chemopreventive agent against colon cancer.
Goel, A. et al. (2001) Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer Lett. 172(2): 111-118.
Antioxidant action:
In a study that explored the role of spice principles and their active components as potential antioxidants, the inhibitory effects of curcumin, quercetin and capsaicin on the oxidation of human low density lipoprotein (LDL) were found to be comparable to that of BHA, but relatively more potent than ascorbic acid. The effects of various spice principles on copper ion-induced lipid peroxidation of LDL was determined by measuring the formation of TBARS (thiobarbituric acid reactive substances) and relative electrophoretic mobility of LDL on agarose gel. Quercetin and curcumin showed the highest inhibitory activity. The authors concluded that thesae data suggest that spice active principles offer protection against oxidation of human LDL.
Naidu KA, Thippeswamy NB.(2002) Inhibition of human low density lipoprotein oxidation by active principles from spices. Mol Cell Biochem 229(1-2):19-23
One study established the mechanism by which curcumin is synergistic with water soluble antioxidants. Two methylated curcumin derivatives were synthesized to explore the role of the phenol hydroxy and beta-diketone moieties in the free radical chemistry of curcumin. The studies showed that an initially generated beta-oxo-alkyl transforms rapidly, probably via an intramolecular H-atom shift, into the phenoxyl-type curcumin radical. This phenoxyl does not react with oxygen, and can be repaired by any water-soluble antioxidant with appropriate redox potential, for example, with ascorbic acid.
Jovanovic, S.V. et al. (2001) How curcumin works preferentially with water soluble antioxidants. J. Am. Chem. Soc. 123(13):3064-3068.
Dietary curcumin was found to prevent ocular toxicity induced by naphthalene in rats and rabbits. Naphthalene-initiated cataract is often used as a model for senile cataract in humans. The results of the study demonstrated that rats treated with naphthalene and kept on a diet supplemented with 0.005% (w/w) curcumin had significantly less opacification of lenses as compared to that observed in rats treated only with naphthalene. The authors observed that naphthalene-initiated cataract in lens is accompanied and perhaps preceded by apoptosis of lens epithelial cells and that curcumin attenuates the apoptopic effect of naphthalene.
Pandya, U. et al. (2000) Dietary curcumin prevents ocular toxicity of naphthalene in rats. Toxicol. Lett. 115(3):195-204.
Antiparasitic action:
Curcumin was found to have leishmanicidal effects in vitro and was found to be more potent than the standard leishmaniasis drug pentamidine in in vitro studies. The LD 50 for leishmanicidal activity in vitro was found to be 37.6± 3.5 microM1. In a second study, curcumin was shown to have an IC50 of 5.3 microM against promastigotes of various leishmanial strains which is much lower as compared to pentamidine2.
1 Koide, T. et al. (2002) Leishmanicidal effects of curcumin in vitro. Biol. Pharm. Bull. 25(1):131-133.
2 Saleheen, D. et al. (2002) Latent activity of curcumin against leishmaniasis in vitro. Biol. Pharm. Bull. 25(3):386-389.
Antimutagenic potential:
The antimutagenic effects of curcumin were evaluated in vitro using chromosomal aberration assayin Wistar rats, induced by cyclophosphamide, a known carcinogen. When curcumin was given at a dose of 100 and 200 mg/kg body weight through gastric intubation for seven consecutive days before cyclophosphamide treatment, the incidence of aberrant cells was found to be reduced with both doses of curcumin when compared to a contol group treated with cyclophosphamide alone. The authors of this study concluded that curcumin has antigenotoxic potential against cyclophosphamide induced chromosomal mutations.
Shukla, Y. et al. (2002) antimutagenic potential of curcumin on chromosomal aberrations in Wistar rats. Mutat. Res . 515(1-2) 197-202.
Cytotoxic, antioxidant and anti-inflammatory activities:
One study evaluated the comparative cytotoxicity, antioxidant and anti-inflammatory activities of curcumin (Curcumin I), demethoxycurcumin (Curcumin II) and bisdemethoxycurcumin (Curcumin III).
The authors observed that:
These compounds showed activity against leukemia, colon, CNS, melanoma, renal, and breast cancer cell lines.
The inhibition of liposome peroxidation by curcumins I-III at 100 microg/ml were 58, 40 and 22%, respectively.
Curcumins I-III were active against COX-I enzyme at 125 microg/ml and showed 32, 38.5 and 39.2% inhibition of the enzyme, respectively.
Curcumins I-III also showed good inhibition of the COX-II enzyme at 125 mg/ml with 89.7, 82.5 and 58.9% inhibition of the enzyme, respectively.
Ramsewak, R.S. et al. (2000) Cytotoxicity, antioxidant and anti-inflammatory activities of curcumins I-III from Curcuma longa. Phytomedicine 7(4):303-308.
Antifibrogenic activity:
Curcumin is reported to inhibit collagen synthesis and hepatic stellate cell activation both in vivo and in vitro. The authors studied the effects of curcumin on the production of collagen and smooth muscle alpha actin proteins and of alpha(1) collagen mRNA in vivo and in vitro. Collagen synthesis was found to be lowered both in vitro and in vivo and curcumin was found to reduce DNA synthesis in vitro, and downregulated smooth muscle alpha actin and type I collagen expression, and alpha(1)collagen mRNA expression, at a concentration of 5 microg/mL. It was concluded that curcumin may therefore prove to be a valuable anti-fibrogenic agent.
Kang, H.C. et al. (2002) Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro. J. Pharm. Pharmacol. 54(1):119-26.
Metabolism of curcumin:
As the systematic bioavailability of curcumin is reported to be at least in part due to its metabolism, curcumin metabolism was explored in subcellular fractions of human and rat intestinal tissue as compared to hepatic fractions and intact intestinal sacs in rat. Curcumin glucuronide was identified in intestinal and hepatic microsomes and curcumin sulfate, tetrahydrocurcumin and hexahydrocurcumin were found in curcumin metabolites in intestinal and hepatic cytosols from humans and rats.
The extent of intestinal conjugation was greater in intestinal fractions from humans than 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 18 and 5 respectively.
Curcumin was sulfated by human sulfotransferase isoenzymes.
Equine alcohol dehydrogenase was found to catalalyze the reduction of curcumin to hexahydrocurcumin.
The authors concluded that the pharmacological implications of curcumin metabolism must be considered when formulating chemopreventive trials with curcumin.
Ireson, C.R. et al. (2002) Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol. Biomarkers and Prev. 11(1):105-11.
Radioprotective effects:
Curcumin is reported to be potentially useful in preventing the development of radioresistance following radiotherapy. Phenolic compounds such as curcumin, ellagic acid and quercetin, were found to be effective in inhibiting radiation-induced protein kinase C (PKC) activity. Activation of PKC is reported to be one of the means of conferring radioresistance on a tumor cell. Therefore suppression of PKC by phenolics may be a meands of preventing the development of radioresistance following radiotherapy.
Varadkar, P. et al. (2001) Modulation of radiation-induced protein kinase C activity by phenolics. J. Radio. Prot. 21(4):361-370.
Another study on female rats exposed to gamma irradiation, revealed that curcumin can be used as an effective radioprotective agent to inhibit acute and chronic effects, but not mortality, after irradiation. The evaluation of the protective action of curcumin against the long-term effects of radiation in pregnant rats, revealed that curcumin significantly decreased the incidence of mammary and pituitary tumors. However, the experiments on revealed that curcumin was not effective in enhancing chances of survival when administered for 3 days before and/or 3 days after irradiation (9.6 Gy).
Inano H, Onoda M (2002) Radioprotective action of curcumin extracted from Curcuma longa LINN: inhibitory effect on formation of urinary 8-hydroxy-2'-deoxyguanosine, tumorigenesis, but not mortality, induced by gamma-ray irradiation. Int J Radiat Oncol Biol Phys 53(3):735-43
Cytoprotection: Induction of heat shock response:
In an effort to develop pharmacological inducers of the heat shock response, curcumin, a known inhibitor of transcription factor NF-kappa B was tested as a probable candidate.
The role of heat shock factor -1 in curcumin-mediated expression of heat shock protein 70 was tested in embryonic fibroblasts derived from heat shock factor-1 knockout mice. The authors concluded that inhibitors of the transcription factor NF kappa B for their ability to induce heat shock protein 70 may be a valid screening method in the drug discovery process for inducers of the heat shock response.
Dunsmore, K.E. et al. (2001) Curcumin, a medicinal herbal compound capable of inducing the heat shock response. Crit. Care Med. 29(11):2199-2204.
Lipid-lowering effects:
One study investigated the effects of dietary supplemented curcuminoids [commercial grade curcumin: a mixture of curcumin (73.4%), demethoxycurcumin (16.1%) and bisdemethoxycurcumin (10.5%)] on lipid metabolism in rats.
18 male Sprague-Dawley rats were assigned to three diet groups and fed a moderately high-fat diet (15 g soybean oil/100 g diet) for two weeks. One diet group did not receive supplements (CONT), while the others were supplemented with 0.2 g curcuminoids/100 g diet (CUR0.2) or 1.0 g curcuminoids/100 g diet (CUR1.0). Liver triacylglycerol and cholesterol concentrations were significantly lower in CUR1.0 rats than in CONT rats. Plasma triacylglycerols in the VLDL fraction were also lower in CUR1.0 rats than in
CONT rats (P < 0.05). Hepatic acyl-CoA oxidase activity of both the CUR0.2 and CUR1.0 rats was significantly higher than that of CONT rats.
Epididymal adipose tissue weight was found to be significantly reduced with curcuminoid intake, in a dose-dependent manner. The authors of this study concluded that these results indicate that dietary curcuminoids have lipid-lowering potency in vivo, and the mechanism of action is probably through alterations in fatty acid metabolism.
Asai, A. and Miyasawa, T. (2001) Dietary curcuminoids prevent high fat diet induced lipid accumulation in rat liver and epididymal adipose tissue. J. Nutr. 131(11):2932-2935.
Inhibition of osteoclastic bone resorption:
Curcumin is known to be a potent inhibitor of the transcriptional factors activator protein 1 and nuclear factor kappa B. These factors are known to play important functional roles in the survival of osteoclasts. Curcumin was shown to stimulate osteoclast apoptosis in a dose-dependent and time-dependent manner. Curcumin also inhibited osteoclastic bone resorption supporting the results that it stimulates osteoclast apoptosis.
Ozaki, K. et al. (2000) Stimulatory effect of curcumin on osteoclast apoptosis. Biochem. Pharmacol. 59(12):1577-81.
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