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[Inhibitory effects of curcumin on apoptosis of human ovary cancer cell line A2780 and its molecular mechanism].

BACKGROUND & OBJECTIVE: Curcumin is the major effective component of curcuma, which is a kind of traditional Chinese medicine. It has been paid more attention to curcumin recently for its specific proliferation inhibition and apoptosis inducing effects on tumor cells; however, the involved mechanisms were not clear. This study was designed to explore the apoptosis inducing effects of curcumin on human ovary A2780 cell line and its related molecular mechanisms. METHODS: A2780 cancer cells were treated with 10-50 mumol/L curcumin for 6-24 h and the growth inhibition rates of A2780 cancer cells were measured by MTT method. Cell apoptosis was inspected by flow cytometry (FCM) and acridine orange-ethidium bromide fluorescent staining method. The protein levels of NF-kappa B (P65) and Caspase-3 in cancer cells were observed by SP immunohistochemistry. RESULTS: The growth inhibition rates of the cancer cells reached 62.05%-89.24%, with the peak of sub G1 appeared on DNA histogram in FCM. Partial cells presented the characteristic morphological changes of apoptosis under the fluorescent microscope; the apoptosis rates were 21.5%-33.5%. The NF-kappa B (p65) expression was decreased while Caspase-3 expression was increased, which depended on the action time. CONCLUSIONS: Curcumin could significantly inhibit the growth of ovary cancer cells; inducing apoptosis through up-regulating Caspase-3 and down-regulating expression of NF-kappa B was probably one of its molecular mechanisms.

Antineoplastic Agents↗

Inhibitory effect of curcumin on proliferation of K562 cells involves down-regulation of p210(bcr/abl) initiated Ras signal transduction pathway.

AIM: To investigate the effects of curcumin (Cur) on proliferation of K562 cells and the relationship between these effects and Ras signal transduction pathway activated by p210bcr/abl. METHODS: K562 cell line was used as a p210bcr/abl-positive cell system and HL-60 cell line as a p210bcr/abl-negative control; etoposide (VP-16), which has no influence on p210bcr/abl and has resistance to K562 cells[1], was used as an anticancer drug control to compare with curcumin. MTT was used to determine the proliferative effects of drugs on K562 and HL-60 cells. Western blot and flow cytometry were used to examine the abundance of signal protein molecules expressed in tumor cells. RESULTS: An exposure of K562 cells or HL-60 cells to Cur produced both concentration- and time-dependent increase in the anti-proliferative rate. Moreover, both cell lines had the same sensitivity to Cur (P>0.05). In contrast, HL-60 cells had more sensitivity to VP-16 than K562 cells in anti-proliferative effect (P<0.01). The abundance of p210bcr/abl as well as MEK-1 and c-JUN proteins were strongly down-regulated in curcumin-treated p210bcr/abl-positive K562 cells while c-JUN and MEK-1 proteins were only slightly down-regulated in p210bcr/abl-negative HL-60 cells. CONCLUSION: Curcumin inhibited the proliferation of K562 cells and the inhibitory effect was correlated with down-regulation of the abundance of p210bcr/abl, which may ultimately lead to retard the Ras signal transduction pathway. Curcumin might be worthy of being evaluated as a potential chemotherapeutic agent to CML.

Antineoplastic Agents, Phytogenic↗

[Protective effect and mechanism of pretreatment with curcumin on infectious brain edema in rats].

UNLABELLED: Curcumin is a natural compound extracted from the spice tumeric, possessing both anti-inflammatory antioxidant, and anti-carcinogenic effect, is a potent stimulator of the stress-induced expression of heat shock protein 70 kd (HSP70). OBJECTIVES: To study the protective effect of pretreatment with curcumin against infectious brain edema in rats, and investigate its mechanism by assessing the free radical, cytokine and HSP70 expression of the brain. METHODS: An animal model of infectious brain edema induced by injecting pertussis bacilli (PB) through carotid artery was used. SD rats were randomly divided into five groups: (1) Normal control group (NS group, n = 9); (2) Infectious brain edema group (PB group, n = 12); (3) DMSO control group (DMSO group, n = 9); (4) HS pretreatment group (HS group, n = 9); (5) Curcumin pretreatment group (CUR group, n = 13). The water content (WC), Na(+) and K(+) content in brain tissue were measured. The content of malondialdehyde (MDA) and super oxide dismitase (SOD) were assessed by chemical colorimetry. The levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were detected by ELISA. The HSP70 expression was examined by Western blot analysis. RESULTS: (1) The WC and Na(+), MDA, TNF-alpha and IL-1beta were increased in PB group compared with NS group (P < 0.01); they were decreased in HS and CUR groups compared with PB group (P < 0.01 or P < 0.05). (2) The content of SOD was decreased in PB group than in NS group (P < 0.05), and was increased in HS and CUR group Compared with PB group, (P < 0.05). (3) Western blot analysis showed that the band density areas of HS, CUR and PB groups were higher than those in NS and DMSO groups, especially in CUR group (P < 0.01). CONCLUSION: Pretreatment with curcumin showed a protective effect against infectious brain edema in rats. The effect might be associated with antioxidant, inhibition of the activity of cytokines and inducing expression of HSP70 by curcumin.

Animals↗

[Effect of curcumin on STAT5 signaling molecule in K562 cells].

OBJECTIVE: To investigate the effect of curcumin on STAT 5 signaling molecule in K562 cells and its molecular mechanism of antileukemia. METHODS: Cell proliferation was studied by tetrazolium dye assay. The expressions of STAT5 mRNA and protein were assayed by in situ hybridization, and Western blotting respectively. RESULTS: Curcumin could inhibit K562 cell proliferation in a time- and dose-dependent manner. The percentage of STAT5-positive cells was 19% in curcunin group, significantly less than 31% of that in K562 cell group (P < 0.01). The A value of the expression level of STAT5 protein in curcumin group was 15 266 +/- 769, significantly less than 25 781 +/- 1240 of that in K562 cell group (P < 0.01). CONCLUSION: The expressions of STAT5 mRNA and protein in K562 cells were inhibited by curcumin and curcumin could inhibit K562 cell proliferation.

Cell Proliferation↗

Curcumin ameliorates oxidative stress during nicotine-induced lung toxicity in Wistar rats.

Nicotine, a major toxic component of cigarette smoke has been identified as a major risk factor for lung related diseases. In the present study, we evaluated the protective effects of curcumin on lipid peroxidation and antioxidants status in bronchoalveolar lavage fluid (BALF) and bronchoalveolar lavage (BAL) of nicotine treated Wistar rats. Lung toxicity was induced by subcutaneous injection of nicotine at a dose of 2.5 mg/kg body weight (5 days a week, for 22 weeks) and curcumin (80 mg/kg body weight) was given simultaneously by intragastric intubation for 22 weeks. Measurement of biochemical marker enzymes: alkaline phosphatase, lactate dehydrogenase, lipid peroxidation and antioxidants were used to monitor the antiperoxidative effects of curcumin. The increased biochemical marker enzymes as well as lipid peroxides in BALF and BAL of nicotine treated rats was accompanied by a significant decrease in the levels of glutathione, glutathione peroxidase, superoxide dismutase and catalase. Administration of curcumin significantly lowered the biochemical marker enzymes, lipid peroxidation and enhanced the antioxidant status. The results of the present study suggest that curcumin exert its protective effect against nicotine-induced lung toxicity by modulating the biochemical marker enzymes, lipid peroxidation and augmenting antioxidant defense system.

Animals↗

[Curcumin inhibits the proliferation of cultured human fetal retinal pigment epithelium cells].

PURPOSE: To investigate the effect of curcumin on the proliferation of human fetal retinal pigment epithelium (hfRPE) cells in vitro. METHODS: Subcultured hfRPE cells were treated with different concentrations of curcumin (2.5, 5, 10, 20 microg/ml) for 24 or 48 hours. MTT assay and flow cytometry were performed to evaluate the effect of curcumin on the proliferation and cell cycle of cultured hfRPE cells. RESULTS: Curcumin was effective in inhibiting the proliferation of subcultured hfRPE, the IC50 value at 24 and 48 hours were found to be 14.27 microg/ml, 12.7 microg/ml, respectively. Cell cycle analysis indicated that CUR blocked cells in G2/M phase. CONCLUSION: Curcumin can inhibit the proliferation of hfRPE cells by cells cycle arrest.

Antineoplastic Agents↗

Curcumin as an inhibitor of cancer.

Curcumin I (Cur I) and curcumin III (Cur III) are the yellow coloring phenolic compounds isolated from the spice turmeric. The effect of curcumins on different stages of development of cancer was studied. Cur I inhibited benzopyrene- (BP) induced forestomach tumors in female Swiss mice, and Cur III inhibited dimethylbenzanthracene- (DMBA) induced skin tumors in Swiss bald mice. Cur I also inhibited DMBA-initiated, tetradeconyl phorbol acetate-promoted skin tumors in female Swiss mice. In vitro 3H-BP-DNA interaction studies, and in vivo carcinogen metabolizing enzyme studies revealed that curcumins exert anticarcinogenic activity by altering the activation and/or detoxification process of carcinogen metabolism. Cur I and Cur III also exhibit in vitro cytotoxicity against human chronic myeloid leukemia, which is dose dependent. This study shows that curcumins inhibit cancer at initiation, promotion and progression stages of development.

Administration, Oral↗

A pilot study of the antioxidant effect of curcumin in tropical pancreatitis.

BACKGROUND & OBJECTIVES: Oxidative stress occurs in association with painful exacerbations of chronic pancreatitis and antioxidant supplementation appears to benefit this condition. Curcumin, the active constituent of turmeric, is known to exhibit antioxidant activity. This pilot study was therefore undertaken to evaluate the effect of oral curcumin with piperine on the pain, and the markers of oxidative stress in patients with tropical pancreatitis (TP). METHODS: Twenty consecutive patients with tropical pancreatitis were randomised to receive 500 mg of curcumin with 5 mg of piperine, or placebo for 6 wk, and the effects on the pattern of pain, and on red blood cell levels of malonyldialdehyde (MDA) and glutathione (GSH) were assessed. RESULTS: There was a significant reduction in the erythrocyte MDA levels following curcumin therapy compared with placebo; with a significant increase in GSH levels. There was no corresponding improvement in pain. INTERPRETATION & CONCLUSION: Oral curcumin with piperine reversed lipid peroxidation in patients with tropical pancreatitis. Further studies with large sample are needed to define its effect on the pain and other manifestations of tropical pancreatitis.

Adolescent↗

[Effects of curcumin on the acetylation of histone H3, P53 and the proliferation of NB4 cells].

OBJECTIVE: To investigate the effects of curcumin on the acetylation of histone H3, P53 and the proliferation of NB4 cells. METHODS: The total protein was extracted from NB4 cells treated without or with different concentrations of curcumin ( 50, 25, 12.5, 6.25 and 3.125 micromol/L) for different time (0, 4, 8, 12, 24 h). Western blot analysis was performed to determine the levels of acetylated histone H3, P53 and acetylated P53. MTT assay was performed to examine the growth inhibition effect of curcumin on NB4 cells. RESULTS: Curcumin could inhibit the proliferation of NB4 cells in a time- and dose- dependent manner, with the IC50 at 24 h and 36 h of 40 micromol/L and 25 micromol/L, respectively. The levels of histone H3 acetylation, P53 expression and P53 acetylation were increased obviously. CONCLUSION: Curcumin functions as a deacetylase inhibitor,which could increase the level of acetylated histone H3, enhance the expression and activity of tumor suppressor P53, and inhibit the proliferation of NB4 cells.

Acetylation↗

[Inhibitory effect of curcumin on angiogenesis induced by brain derived neurotrophic factor from multiple myeloma cells].

In order to explore the probability of curcumin treating multiple myeloma (MM) via the inhibition of angiogenesis, the expressions of brain derived neurotrophic factor (BDNF) and its specific receptor in human MM cells and endothelial cells were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The angiogenic activity was evaluated by endothelial cell migration assay and tubule formation assay in vitro. The results showed that exogenous BDNF significantly induced endothelial cell tubule formation and endothelial cell migration, these two effects were inhibited by curcumin. Furthermore, BDNF was detected in the MM cell and TrkB was detected in the endothelial cell and curcumin depressed the mRNA expression of BDNF and TrkB in the dose- and time-dependent manners. It is concluded that BDNF is a novel angiogenesis protein. Curcumin interrupts the interaction between multiple myeloma cells and endothelial cells by reducing TrkB expression in endothelial cells and inhibiting BDNF production in multiple myeloma cells, eventually, resulting in inhibition of angiogenesis. This is probably one part of the mechanism of the curcumin treating MM via the inhibition of angiogenesis.

Angiogenesis Inhibitors↗

[Effect of curcumin on acetylation of histone H3 in human lymphoma cell line Raji].

BACKGROUND & OBJECTIVE: Epigenetic change is an important mechanism of oncogenesis. The inhibitors of methyltransferases and deacetylases, with epigenetic modificative effects, could inhibit proliferation and induce apoptosis of tumor cells. This study was to investigate the effects of curcumin on the acetylation of histone H3 and the expression of p21(WAF1/CIP1) gene in human lymphoma cell line Raji. METHODS: Raji cells were treated with 25 micromol/L curcumin. The levels of acetylated histone H3 and p21WAF1/CIP1 were detected by Western blot, the expression of p21(WAF1/CIP1) gene was detected by reverse transcription-polymerase chain reaction (RT-PCR), and the level of acetylated histone H3 at the site of p21(WAF1/CIP1) promoter gene was examined by chromatin immunoprecipitation assay. Cell cycle distribution was studied by flow cytometry. RESULTS: Curcumin induced hyperacetylation of histone H3 at the site of p21(WAF1/CIP1) promoter by 1.9 folds, and enhanced the levels of p21(WAF1/CIP1) mRNA by 4.2 folds and protein by 5.1 folds 24 h after treatment. Raji cells were arrested at G(2)/M phase when treated with curcumin for 24 h, and at G(0)/G(1) phase when treated for 36 h. CONCLUSION: Curcumin, with epigenetic modificative effects, could enhance the acetylayion of histone H3 at the site of p21(WAF1/CIP1) promoter gene, improve transcription of p21(WAF1/CIP1) gene, and arrest cell cycle progression of Raji cells.

Acetylation↗

[Effect of three different curcumin pigmens on the prdiferation of vascular smooth muscle cells by ox-LDL and the expression of LDL-R].

OBJECTIVE: To investigate the anti-proliferation of three different structural curcumin pigmen monomers on the bovine VSMC stimulated by ox-LDL and the effect on the expression of LDL-R. METHOD: MTT and FCM were used to observe the anti-proliferation of three different on the bovine VSMC stimulated by ox-LDL and the effect on the expression of LDL-R. RESULT: ox-LDL(2.5,5, 10 mg x L(-1)) had obvious proliferative effect on VSMC, P < 0.05, curcumin (16.5,33,66 micromol x L(-1)), demethoxycurcumin (33,66 micromol x L(-1)) and bisdemethoxycurcumin (66 micromol x L(-1)) had obvious inhibition effect on the proliferation of VSMC stimulated by 10 mg x L(-1) ox-LDL (P < 0.05, curcumin > demethoxycurcumin > bisdemethoxycurcumin) . Three curcumin (16.5,33,66 micromol x L(-1)) could obviously activate the expression of LDLR of VSMC. CONCLUSION: The three different structural curcumin pigmen monomers can not only inhibit the proliferation of bovine VSMC obviously stimulated by ox-LDL, but also promote the expression of LDL-R on bovine VSMC, that may be the mechanism of delaying the development of arteriosclerosis.

Animals↗

Curcumin protects mouse brain from oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

We tested the hypothesis that curcumin, a polyphenolic antioxidant, acts as a powerful free radical scavenger in vivo in the brain, and interferes with oxidative stress caused by the parkinsonian neurotoxin, (MPTP) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We measured the (GSH) reduced glutathione levels, (TBARS) glutathione lipid peroxidation, (CAT) catalase and (SOD) superoxide dismutase activity in the (ST) striatum and (MB) mid brain 3rd day and 7th day following MPTP and curcumin administration. MPTP treatment caused a significant depletion in GSH and increased the specific activity of SOD, CAT and lipid peroxidation in both ST and MB on the 3rd and 7th day. MPTP induced GSH depletion and lipid peroxidation in ST and MB was blocked by curcumin treatment. Curcumin exhibited a synergistic effect on SOD and CAT activities in the ST and MB regions. The present study provides direct evidence for the involvement of curcumin in neuroprotection against oxidative stress.

Animals↗

Regulation of LDL receptor expression by the effect of curcumin on sterol regulatory element pathway.

To investigate the molecular mechanisms of the effect of curcumin on up-regulation of LDL receptor expression, a sterol regulatory report system was established in Xenopus laevis oocytes by microinjection of a plasmid pLXRN-4SRE-fPA, in which green fluorescence protein (GFP) gene was constructed downstream from the sterol regulatory element-1 (SRE-1), in the nucleus of the oocytes. The oocytes were treated with different kinds of natural medicines: curcumin, tea polyphenols, tanshinone, ligustrazine, ginkgolide, astragalosides. The expression of GFP was induced only by curcumin. In addition, it was also proved that the curcumin can increase the expression of functional LDL receptors in human liver hepatoma cell line HepG2. In conclusion, curcumin may up-regulate the expression of LDL receptor by its effect on SRE pathway.

Animals↗

Biliary proteins from hepatic bile of rats fed curcumin or capsaicin inhibit cholesterol crystal nucleation in supersaturated model bile.

Following our earlier observations that curcumin and capsaicin are antilithogenic in mice and hamsters, attempts were now made to understand the manner in which these spice principles were acting. For this purpose, the hepatic biles of rats fed a control, lithogenic, and lithogenic diet supplemented with curcumin or capsaicin were subjected to gel filtration chromatography (sepharose-4B-Cl) and the LMW protein fractions were tested for their ability to influence cholesterol crystal growth in model bile. The LMW protein fraction from the lithogenic group bile shortened the nucleation time and increased the crystal growth rate and final crystal concentration. But with the LMW protein fractions from the biles of rats on the lithogenic group supplemented with curcumin or capsaicin, the nucleation times were prolonged and the crystal growth rates and final crystal concentrations were decreased. The LMW fractions were further purified into three different sugar specific proteins by affinity chromatography. A higher proportion of LMW proteins from the lithogenic group bile was bound to Con-A whereas higher proportions of LMW proteins from the groups fed with curcumin and capsaicin were respectively bound to wheat germ agglutinin and Helix pomatia lectin. The Con-A bound fraction obtained from the lithogenic group showed a pro-nucleating effect. In contrast, the WGA-bound fraction obtained from curcumin group or the Helix pomatia lectin bound fraction obtained from capsaicin group showed a potent antinucleating activity.

Animals↗

Prevention of ischaemia-induced biochemical changes by curcumin & quinidine in the cat heart.

Effect of myocardial ischaemia on the bioantioxidants levels in the cat heart was evaluated. In addition, effect of curcumin, an anti-inflammatory and anti-thrombotic drug, and quinidine, a standard antiarrhythmic drug, was also studied in the cat. Myocardial ischaemia was induced by the ligation of left descending coronary artery. Quinidine (1 mg/kg, iv) was administered 15 min prior to while curcumin (100 mg/kg, ip) was given 30 min before ligation. Hearts were removed 4 h post coronary artery ligation. Levels of glutathione (GSH), malonaldelhyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT) and lactate dehydrogenase (LDH) were estimated in the ischaemic and non-ischaemic zones. Both the drugs protected the animals against decrease in the heart rate and blood pressure following ischaemia. In the ischaemic zone, after 4 h of ligation, an increase in the level of MDA and activities of MPO and SOD (cytosolic fraction) were observed. Quinidine and curcumin pretreatment prevented the ischaemia-induced elevation in MDA contents and LDH release. Curcumin pretreatment did not prevent the increase in MPO activity while quinidine did. Results obtained indicate alterations in the bioantioxidants following ischaemia and both curcumin and quinidine prevented ischaemia induced changes in the cat heart.

Animals↗

Suppression of protein kinase C and nuclear oncogene expression as possible molecular mechanisms of cancer chemoprevention by apigenin and curcumin.

Apigenin, a less-toxic and non-mutagenic flavonoid, suppressed 12-0-tetradecanoyl-phorbol-13-acetate-(TPA)-mediated tumor promotion of mouse skin. TPA had the ability to activate protein kinase C (PKC) and induced nuclear proto-oncogene expression. Our study indicates that apigenin inhibited PKC by competing with adenosine triphosphate (ATP). Apigenin also reduced the level of TPA-stimulated phosphorylation of cellular proteins and inhibited TPA-induced c-jun and c-fos expression. Curcumin, a dietary pigment phytopolyphenol, is also a potent inhibitor of tumor promotion induced by TPA in mouse skin. When mouse fibroblast cells were treated with TPA alone, PKC translocated from the cytosolic fraction to the particulate fraction. Treatment with 15 or 20 microM curcumin for 15 min inhibited TPA-induced PKC activity in the particulate fraction by 26-60%. Curcumin also inhibited PKC activity in vitro by competing with phosphatidylserine. Curcumin (10 microM) suppressed the expression of c-jun in TPA-treated cells. Fifteen flavonoids were examined for their effects on morphological changes in soft agar and cellular growth in v-H-ras transformed NIH3T3 cells. The results demonstrated that only apigenin, kaempferol, and genistein exhibited the reverting effect on the transformed morphology of these cells. Based on these findings, it is suggested that the suppression of PKC activity and nuclear oncogene expression might contribute to the molecular mechanisms of inhibition of TPA-induced tumor promotion by apigenin and curcumin.

Animals↗

Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin).

It is estimated that one-third of Americans use dietary herbal supplements on a regular basis. Diets rich in bioactive phytochemicals are associated with reduced risk of certain cancers, notably, colon cancer. Herbal supplements have not been directly tested as sources of bioactive cancer preventives. Hence, this study compares the ability of four herbal flavonoids (quercetin, curcumin, rutin and silymarin) and one whole herb mixture (ginseng powder) to suppress aberrant crypt foci (ACF) in an azoxymethane (AOM)-induced rat colon cancer model. Second, this study examines the effect of these herbal compounds on apoptosis and the mechanisms by which these compounds evoke apoptosis. The results of this study show that diets containing quercetin, curcumin, silymarin, ginseng and rutin decreased the number of ACFs by 4-, 2-, 1.8-, 1.5- and 1.2-fold, respectively compared with control. Histological analysis of the colon mucosa revealed that all the herbal supplements, except silymarin, induced apoptosis, with quercetin being the most potent (3x increase compared with control). Furthermore, ginseng and curcumin were region-specific in inducing apoptosis. The ability of quercetin and curcumin to modulate ACFs correlates well with their ability to induce apoptosis. Western blot analysis of caspase 9, Bax (proapoptotic) and Bcl-2 (antiapoptotic) proteins from the colon scraping suggests that quercetin and curcumin induce apoptosis via the mitochondrial pathway. Taken together, the results of this study suggest that these herbal supplements may exert significant and potentially beneficial effects on decreasing the amount of precancerous lesions and inducing apoptosis in the large intestine.

Animals↗