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PubMed2002

The molecular mechanisms for the antitumorigenic effect of curcumin.

Curcumin, an active yellow pigment of turmeric and curry, possesses anti-inflammatory, antioxidative and anticarcinogenic properties. Analysis of its structure revealed the presence of beta-diketone moiety and phenolic hydroxy groups that were believed to contribute to antioxidation. And vanillin, ferulic acid and a dimer of curcumin were identified as the curcumin-derived radical reaction products. In addition to antioxidation, curcumin could also induce apoptosis by targeting mitochondria, affecting p53-related signaling and blocking NF-kappaB activation. To further dissect its anticarcinogenic mechanisms, a number of curcumin targets were identified. These included the aryl hydrocarbon receptor, cytochrome P450, glutathione S-transferase, serine/threonine kinases, transcription factors, cyclooxygenase, ornithine decarboxylase, nitric oxide synthase, matrix metalloproteinases and tyrosine kinases. This review will summarize our current knowledge on how these important proteins are affected by curcumin, and hopefully, may provide a whole picture illustrating how the chemopreventive and antitumorigenic effect of curcumin is achieved.

Animals↗

PubMedDate not supplied

Immunomodulatory activity of curcumin.

Curcumin, an active ingredient present in Curcuma longa, was analysed for the immunomodulatory activity in Balb/c mice. Curcumin administration was found to increase the total WRC count (15,290) significantly on the 12th day Group of animals treated with vehicle alone showed results similar to that of normal animal (10,130 on 12th day). Curcumin increased the circulating antibody titre (512) against SRBC. Curcumin administration increased the plaque forming cells (PFC) in the spleen and the maximum number of PFC was observed on the 6th day (1,130 PFC/10(6) spleen cells) after immunization with SRBC. Rone marrow cellularity (16.9x10(6) cells/femur) and alpha-esterase positive cells (1,622/4000 cells) were also enhanced by Curcumin administration. A significant increase in macrophage phagocytic activity was also observed in Curcumin treated animals (P<0.001). These results indicate the immunostimulatory activity of Curcumin.

Adjuvants, Immunologic↗

PubMed2005

Preventive and therapeutic effects of NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid.

AIM: To ascertain the molecule mechanism of nuclear factor-kappaB (NF-kappaB) inhibitor curcumin preventive and therapeutic effects in rats' colitis induced by trinitrobenzene sulfonic acid (TNBS). METHODS: Sixty rats with TNBS-induced colitis were treated with 2.0% curcumin in the diet. Thirty positive control rats were treated with 0.5% sulfasalazine (SASP). Thirty negative control rats and thirty model rats were treated with general diet. Changes of body weight together with histological scores were evaluated. Survival rates were also evaluated. Cell nuclear NF-kappaB activity in colonic mucosa was evaluated by using electrophoretic mobility shift assay. Cytoplasmic IkappaB protein in colonic mucosa was detected by using Western Blot analysis. Cytokine messenger expression in colonic tissue was assessed by using semiquantitative reverse-transcription polymerase chain reaction. RESULTS: Treatment with curcumin could prevent and treat both wasting and histopathologic signs of rats with TNBS-induced intestinal inflammation. In accordance with these findings, NF-kappaB activation in colonic mucosa was suppressed in the curcumin-treated groups. Degradations of cytoplasmic IkappaB protein in colonic mucosa were blocked by curcumin treatment. Proinflammatory cytokine messenger RNA expression in colonic mucosa was also suppressed. CONCLUSION: This study shows that NF-kappaB inhibitor curcumin could prevent and improve experimental colitis in murine model with inflammatory bowel disease (IBD). The findings suggest that NF-kappaB inhibitor curcumin could be a potential target for the patients with IBD.

Animals↗

PubMed2000

Curcumin inhibits lipoxygenase by binding to its central cavity: theoretical and X-ray evidence.

Many lipoxygenase inhibitors including curcumin are currently being studied for their anti-carcinogenic properties. Curcumin is a naturally occurring polyphenolic phytochemical isolated from the powdered rhizome of the plant Curcuma longa that possesses anti-inflammatory properties and inhibits cancer formation in mice. Recently it was shown that the soybean lipoxygenase L1 catalyzed the oxygenation of curcumin and that curcumin can act as a lipoxygenase substrate. In the current study, we investigated the fate of curcumin when used as a soybean lipoxygenase L3 substrate. By use of X-ray diffraction and mass spectrometry, we found an unoccupied electron mass that appears to be an unusual degradation product of curcumin (4-hydroxyperoxy-2-methoxyphenol) located near the soybean L3 catalytic site. Understanding how curcumin inhibits lipoxygenase may help in the development of novel anti-cancer drugs used for treatment where lipoxygenases are involved.

Catalytic Domain↗

PubMed2001

Curcumin inhibits activation of Vgamma9Vdelta2 T cells by phosphoantigens and induces apoptosis involving apoptosis-inducing factor and large scale DNA fragmentation.

Curcumin, in addition to its role as a spice, has been used for centuries to treat inflammatory disorders. Although the mechanism of action remains unclear, it has been shown to inhibit the activation of NF-kappaB and AP-1, transcription factors required for induction of many proinflammatory mediators. Due to its low toxicity it is currently under consideration as a broad anti-inflammatory, anti-tumor cell agent. In this study we investigated whether curcumin inhibited the response of gammadelta T cells to protease-resistant phosphorylated derivatives found in the cell wall of many pathogens. The results showed that curcumin levels > or =30 microM profoundly inhibited isopentenyl pyrophosphate-induced release of the chemokines macrophage inflammatory protein-1alpha and -1beta and RANTES. Curcumin also blocked isopentenyl pyrophosphate-induced activation of NF-kappaB and AP-1. Commencing around 16 h, treatment with curcumin lead to the induction of cell death that could not be reversed by APC, IL-15, or IL-2. This cytotoxicity was associated with increased annexin V reactivity, nuclear expression of active caspase-3, cleavage of poly(ADP-ribose) polymerase, translocation of apoptosis-inducing factor to the nucleus, and morphological evidence of nuclear disintegration. However, curcumin led to only large scale DNA chromatolysis, as determined by a combination of TUNEL staining and pulse-field and agarose gel electrophoresis, suggesting a predominantly apoptosis-inducing factor-mediated cell death process. We conclude that gammadelta T cells activated by these ubiquitous Ags are highly sensitive to curcumin, and that this effect may contribute to the anti-inflammatory properties of this compound.

Adult↗

PubMed2002

Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes.

Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE. Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.

Adoptive Transfer↗

PubMed2004

Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis.

Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with cancers and other diseases. Gene deletion studies have shown that receptor activator of NF-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. How RANKL mediates osteoclastogenesis is not fully understood, but an agent that suppresses RANKL signaling has potential to inhibit osteoclastogenesis. In this report, we examine the ability of curcumin (diferuloylmethane), a pigment derived from turmeric, to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and preexposure of the cells to curcumin completely suppressed RANKL-induced NF-kappaB activation. Curcumin inhibited the pathway leading from activation of IkappaBalpha kinase and IkappaBalpha phosphorylation to IkappaBalpha degradation. RANKL induced osteoclastogenesis in these monocytic cells, and curcumin inhibited both RANKL- and TNF-induced osteoclastogenesis and pit formation. Curcumin suppressed osteoclastogenesis maximally when added together with RANKL and minimally when it was added 2 days after RANKL. Whether curcumin inhibits RANKL-induced osteoclastogenesis through suppression of NF-kappaB was also confirmed independently, as RANKL failed to activate NF-kappaB in cells stably transfected with a dominant-negative form of IkappaBalpha and concurrently failed to induce osteoclastogenesis. Thus overall these results indicate that RANKL induces osteoclastogenesis through the activation of NF-kappaB, and treatment with curcumin inhibits both the NF-kappaB activation and osteoclastogenesis induced by RANKL.

Animals↗

PubMed2007

Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK.

Curcumin, a major active component of turmeric, is known to induce apoptosis in several types of cancer cells, but little is known about its activity in chemoresistant cells. Hence, the aim of the present study was to investigate the anticancer properties of curcumin in cisplatin-resistant human ovarian cancer cells in vitro. The results indicated that curcumin inhibited the proliferation of both cisplatin-resistant (CR) and sensitive (CS) human ovarian cancer cells almost equally. Enhanced superoxide generation was observed in both CR and CS cells treated with curcumin. Curcumin induced G(2)/M phase cell-cycle arrest in CR cells by enhancing the p53 phosphorylation and apoptosis through the activation of caspase-3 followed by PARP degradation. Curcumin also inhibited the phosphorylation of Akt while the phosphorylation of p38 MAPK was enhanced. In summary, our results showed that curcumin inhibits the proliferation of cisplatin-resistant ovarian cancer cells through the induction of superoxide generation, G(2)/M arrest, and apoptosis.

Antineoplastic Agents↗

PubMed1999

Curcumin inhibits tyrosine kinase activity of p185neu and also depletes p185neu.

Curcumin, a natural compound present in turmeric, possessing both anti-inflammatory and antioxidant effects, has been studied vigorously as a chemopreventative in several cancer models. The erbB2/neu gene-encoded p185neu tyrosine kinase is a potent oncoprotein. Overexpression of p185neu in breast cancer is known to be a poor prognostic factor. We investigated the effect of curcumin on p185neu tyrosine kinase and on the growth of breast cancer cell lines. Curcumin dose-dependently inhibited p185neu autophosphorylation and transphosphorylation in vitro and depleted p185neu protein in vivo. It dissociated the binding of p185neu with GRP94 (glucose-regulated protein), a molecular chaperone, and enhanced the depletion of p185neu. The amount of p185neu protein on the cell membrane was drastically decreased after curcumin treatment. These data demonstrated a new mechanism of the anti-tyrosine kinase activity of curcumin. The growth of several breast cancer cell lines was inhibited; the IC50 ranged from 7 to 18 microM, which, however, did not correlate with the expression level of p185neu. Colony formation in the soft agar assay, a hallmark of the transformation phenotype, was preferentially suppressed in p185neu-overexpressing cell lines by 5 microM curcumin (% of control, basal level versus overexpression: 59.3 versus 16.7%; P < 0.001 by Student's t test). Because curcumin effectively inhibited p185neu tyrosine kinase activity by depleting p185neu and potently suppressed the growth of multiple breast cancer cell lines, its therapeutic potential in advanced breast cancer is worthy of further investigation.

Antineoplastic Agents↗

PubMedDate not supplied

Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells.

We have investigated the chemopreventive role of curcumin in gastrointestinal cancers by studying the regulation of proliferation and apoptosis in gastric (KATO-III) and colon (HCT-116) cancer cells. Curcumin inhibited cell proliferation and induced G2/M arrest in HCT-116 cells. Investigation of the levels of cyclins E, D and B by immunoblot analysis showed cyclin B level was unaffected, whereas cyclin D and E levels declined with curcumin in both cell lines. Investigation of cyclin-dependent kinases, Cdk2 and Cdc2, showed activity of Cdc2, but not Cdk2, increased markedly in response to curcumin. In both cell lines, immunoblot analysis indicated that curcumin caused induction of apoptosis as evidenced by cleavage of PARP, caspase-3, and reduction in Bcl-XL levels. Curcumin also stimulated the activity of caspase-8, which initiates Fas signalling pathway of apoptosis. Curcumin therefore appears to exert its anticarcinogenic properties by inhibiting proliferation and inducing apoptosis in certain gastric and colon cancer cells.

Antineoplastic Agents↗

PubMed2004

Effect of curcumin on normal and tumor cells: role of glutathione and bcl-2.

Curcumin, a well-known dietary pigment derived from Curcuma longa, inhibited growth of several types of malignant cells both in vivo and in vitro. However, its mechanism of action still remains unclear. In this study, we have focused primarily on the cytotoxic effects of curcumin on three human tumor cell lines and rat primary hepatocytes. Curcumin induced apoptosis in MCF-7, MDAMB, and HepG2 cells in a dose-dependent and time-dependent manner. Apoptosis was mediated through the generation of reactive oxygen species. Attempts were made to establish the role played by endogenous glutathione on the apoptotic activity of curcumin. Depletion of glutathione by buthionine sulfoximine resulted in the increased generation of reactive oxygen species, thereby further sensitizing the cells to curcumin. Interestingly, curcumin had no effect on normal rat hepatocytes, which showed no superoxide generation and therefore no cell death. These observations suggest that curcumin, a molecule with varied actions, could be developed into an effective chemopreventive and chemotherapeutic agent.

Antineoplastic Agents↗

PubMed2004

[Experimental study on anticancer effect of curcumin on Raji cells in vitro].

OBJECTIVE: To study the anticancer effect and mechanism of curcumin on Raji cells in vitro and compared the cytotoxicities of curcumin on Raji cells and normal human peripheral blood mononuclear cell (PBMC). METHODS: The effects of curcumin on proliferation of Raji cells and human PBMC were tested by MTT assay, its effects on apoptosis of them were determined by Annexin-V/PI double-labeled cytometry and TUNEL, and its effects on DNA distribution in Raji cells was studied by PI single labeled cytometry. RESULTS: Curcumin showed marked inhibition on proliferation of Raji cell, could induce Raji cell apoptosis in time- and dose-dependent manner. After curcumin treatment, the cell cycle of Raji cells was blocked in G0/G1 and G2/M phase and those in the S phase decreased proportionally. But curcumin showed no significant effect on inhibiting proliferation or inducing apoptosis on human PBMC. CONCLUSION: Curcumin could regulate the cell cycle of Raji cells and induce its apoptosis, so as to inhibit its proliferation, but with no significant cytotoxicity on human PBMC. It selectively affects the tumor cell.

Antineoplastic Agents, Phytogenic↗

PubMed2005

[Effects of combined use of curcumin and catechin on cyclooxygenase-2 mRNA expression in dimethylhydrazine-induced rat colon carcinogenesis].

OBJECTIVE: To examine the effect of combined use of curcumin and catechin on the number of aberrant crypt foci (ACF) and expression levels of cyclooxygenase-2 (COX-2) mRNA in rat colon carcinogenesis. Methods Dimethylhydrazine (DMH)-induced rats colon carcinogenesis model was used for evaluation of the synergistic inhibitory effect between curcumin and catechin in light of ACF formation and tumor incidence. COX-2 mRNA expression was also detected in rat colon carcinogenesis. RESULTS: Curcumin, catechin and their co-treatment caused significant inhibition of DMH-induced ACF and colon carcinogenesis as compared with untreated DMH-induced rat models (P<0.01). Co-treatment with curcumin and catechins caused greater inhibition of DMH-induced ACF and colon carcinogenesis than the single use of curcumin or catechin (P<0.05). A synergistic inhibitory effect between curcumin and catechin on the expression of COX-2 mRNA was observed in the early stage of rat colon carcinogenesis but not in colon tumor tissues. CONCLUSION: Curcumin and catechin have synergistic effect on ACF and COX-2 mRNA expression in rat colon carcinogenesis, suggesting their potential value in the prevention of human colon cancers.

1,2-Dimethylhydrazine↗

PubMed2005

Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin.

The antitumor effect of curcumin (diferuloylmethane) is well established. However, there have been no unbiased studies to identify novel molecular targets of this compound. We therefore undertook a gene expression profiling study to identify novel targets of curcumin. A cDNA array comprised of 12,625 probes was used to compare total RNA extracted from curcumin-treated and untreated MDA-1986 cells for differential gene expression. We identified 202 up-regulated mRNAs and 505 transcripts decreased > or =2-fold. The proapoptotic activating transcription factor 3 (ATF3) was induced >4-fold. Two negative regulators of growth control [antagonizer of myc transcriptional activity (Mad) and p27kip1] were induced 68- and 3-fold, respectively. Additionally, two dual-activity phosphatases (CL 100 and MKP-5), which inactivate the c-jun-NH2-kinases, showed augmented expression, coinciding with reduced expression of the upstream activators of c-jun-NH2-kinase (MEKK and MKK4). Of the repressed genes, the expression of Frizzled-1 (Wnt receptor) was most strongly attenuated (8-fold). Additionally, two genes implicated in growth control (K-sam, encoding the keratinocyte growth factor receptor, and HER3) as well as the E2F-5 transcription factor, which regulates genes controlling cell proliferation, also showed down-regulated expression. Considering its role in apoptosis, we determined the contribution of ATF3 to the antitumor effect of curcumin. Curcumin-treated MDA-1986 cells showed a rapid, dose-dependent increase in ATF3/mRNA protein. Moreover, expression of an exogenous ATF3 cDNA synergized with curcumin in inducing apoptosis. Thus, we have identified several putative, novel molecular targets of curcumin and showed that one, (ATF3) contributes to the proapoptotic effects of this compound.

Activating Transcription Factor 3↗

PubMed2004

[The effect of curcumin on bladder cancer cell line EJ in vitro].

OBJECTIVE: To observe the effect of curcumin on bladder cancer cell line EJ in vitro. METHODS: Cell morphology, MTT, flow cytometer, immunocytochemical method for detecting NF-KB, Cyclin D1 were used to observe the effect of 5,10,20 mg/L curcumin on bladder cancer cell line EJ in vitro. RESULTS: All concentrations curcumin resulted in the growth suppression significantly [Suppression ratio > or = (27.5 + 3.1)%, P < 0.05]. Above 10 mg/L concentrations curcumin induced apoptosis [Apoptosis ratio > or = (14.6 +/- 1.8)%, P < 0.05] and down-regulated of the expression of NF-kappaB [Expression ratio < or = (35.8 +/- 4.2)%, P < 0.05], Cyclin D1 [Expression ratio < or = (29.7 +/- 3.2)%, P < 0.05]. The cell phase arrest induced by curcumin was G1 phase arrest mainly with significant decrease of S phase. CONCLUSIONS: Curcumin can suppress the growth, induce apoptosis of bladder cancer EJ cell in vitro. Its mechanism is related with down-regulations of the expressions of NF-kappaB and Cyclin D1. Curcumin has great potential for the treatment of bladder cancer.

Antineoplastic Agents↗

PubMedDate not supplied

Effects of water-soluble antioxidants and MAPKK/MEK inhibitor on curcumin-induced apoptosis in HL-60 human leukemic cells.

Curcumin is the main biologically active phytochemical compound in turmeric. It has been shown to have anticarcinogenic activity. The aims of the study were to identify the mechanism of apoptosis of HL-60 human promyelocytic leukemic cells induced by curcumin and to determine the effects of water-soluble antioxidants, ascorbic acid, Trolox (a water-soluble form of vitamin E), glutathione (GSH) and N-acetylcysteine (NAC) on this process. HL-60 cells were incubated with curcumin for 24 h and apoptotic cells were quantitated by flow cytometry following staining with annexin V-FITC and propidium iodide. Curcumin-treated HL-60 cells produced reactive oxygen species as detected by the dichlorofluorescein fluorescent assay. Apoptosis occurred via the mitochondria pathway as curcumin reduced mitochondrial membrane potential in a dose-dependent manner. In the presence of 10 microM curcumin, vitamin C (56 nM-5.6 microM) inhibited apoptosis of HL-60 cells; GSH at low concentration (1 microM) reduced apoptosis but had no effect at higher concentrations (10, 100 microM); and Trolox and NAC at 10 and 100 microM, respectively, enhanced apoptosis, but this effect was abolished at higher concentration (1 mM) of NAC. MAPKK/MEK inhibitor PD98059, enhanced curcumin-induced HL-60 apoptotic cell death.

Antineoplastic Agents↗

PubMed2005

[Inhibition of the expression of prostate specific antigen by curcumin].

AIM: To study the effect of curcumin on the expression of prostate specific antigen (PSA). METHODS: AXSYM system-chemical luciferase method was used to examine the content of PSA in prostate cancer cell lines, LNCap after treated with different doses of curcumin. pGL3-PSA luciferase expression vector, containing 640 bp DNA of PSA gene 5' promoter region was constructed and transfected into LNCap cell with lipofectin. Through detecting the activity of luciferase, the effect of curcumin on the promoter of PSA was studied. Western blotting was used to detect expression of androgen receptor (AR) in LNCap cell with different concentrations of curcumin. RESULTS: The expression of PSA was inhibited and activity of luciferase was reduced by curcumin. There was also significant difference in AR expression as shown by Western blotting experiment after treatment of different doses of curcumin. CONCLUSION: Through inhibiting AR expression, curcumin reduced the function of PSA promoter and inhibited PSA protein expression.

Antineoplastic Agents↗

PubMed2005

[Apoptosis induced by curcumin and its effect on c-myc and caspase-3 expressions in human melanoma A375 cell line].

OBJECTIVE: To investigate the effect of curcumin on cell apoptosis and c-myc and caspase-3 expressions in human melanoma A375 cell line. METHODS: A375 cells were exposed to curcumin treatment and growth inhibition of the cells was examined by MTT assay. Annexin V/propidium iodide double staining and DNA fragmentation analysis were employed for assay of the cell apoptosis and morphological changes of the cells were observed with inverted microscopy and transmission electron microscopy, respectively. In situ hybridization and SABC immunohistochemistry were performed for detection of the expressions of c-Myc and caspase-3 in the A375 cells. RESULTS: Curcumin inhibited the growth of A375 cells in both time- and concentration-dependent manners. After treatment with 30 micromol/L curcumin for 48 h, apoptotic morphological changes were observed in the cells and an oligonucleosomal DNA ladder was clearly visualized in DNA fragmentation analysis. The apoptotic rates of the cells treated with curcumin at the concentration above 20 micromol/L were significantly higher than that of the control cells. c-myc expression level was decreased whereas caspase-3 expression increased with the increase in curcumin concentrations. CONCLUSION: Curcumin can inhibit the proliferation and induce apoptosis of A375 cells in vitro, and the genes encoding c-myc and caspase-3 may play a role in the process.

Antineoplastic Agents, Phytogenic↗