Life Extension Skin Care Sale

Life Extension Magazine

LE Magazine September 2001


Page 2 of 4

Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines.

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.

Nutr Cancer 1996;26(1):111-20

Inhibitory effects of curcumin on tumorigenesis in mice.

Curcumin (diferuloylmethane), the naturally occurring yellow pigment in turmeric and curry, is isolated from the rhizomes of the plant Curcuma longa Linn. Curcumin inhibits tumorigenesis during both initiation and promotion (post-initiation) periods in several experimental animal models. Topical application of curcumin inhibits benzo[a]pyrene (B[a]P)-mediated formation of DNA-B[a]P adducts in the epidermis. It also reduces 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in skin inflammation, epidermal DNA synthesis, ornithine decarboxylase (ODC) mRNA level, ODC activity, hyperplasia, formation of c-Fos, and c-Jun proteins, hydrogen peroxide, and the oxidized DNA base 5-hydroxymethyl-2’-deoxyuridine (HmdU). Topical application of curcumin inhibits TPA-induced increases in the percent of epidermal cells in synthetic (S) phase of the cell cycle. Curcumin is a strong inhibitor of arachidonic acid-induced edema of mouse ears in vivo and epidermal cyclooxygenase and lipoxygenase activities in vitro. Commercial curcumin isolated from the rhizome of the plant Curcuma longa Linn contains 3 major curcuminoids (approximately 77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin). Commercial curcumin, pure curcumin, and demethoxycurcumin are about equipotent as inhibitors of TPA-induced tumor promotion in mouse skin, whereas bisdemethoxycurcumin is somewhat less active. Topical application of curcumin inhibits tumor initiation by B[a]P and tumor promotion by TPA in mouse skin. Dietary curcumin (commercial grade) inhibits B[a]P-induced forestomach carcinogenesis, N-ethyl-N’-nitro-N-nitrosoguanidine (ENNG)-induced duodenal carcinogenesis, and azoxymethane (AOM)-induced colon carcinogenesis. Dietary curcumin had little or no effect on 4-(methylnitosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis and 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast carcinogenesis in mice. Poor circulating bioavailability of curcumin may account for the lack of lung and breast carcinogenesis inhibition.

J Cell Biochem Suppl 1997;27:26-34

Curcumin is an in vivo inhibitor of angiogenesis.

BACKGROUND: Curcumin is a small-molecular-weight compound that is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. The genetic changes in carcinogenesis in these organs involve different genes, but curcumin is effective in preventing carcinogenesis in both organs. A possible explanation for this finding is that curcumin may inhibit angiogenesis. MATERIALS AND METHODS: Curcumin was tested for its ability to inhibit the proliferation of primary endothelial cells in the presence and absence of basic fibroblast growth factor (bFGF), as well as its ability to inhibit proliferation of an immortalized endothelial cell line. Curcumin and its derivatives were subsequently tested for their ability to inhibit bFGF-induced corneal neovascularization in the mouse cornea. Finally, curcumin was tested for its ability to inhibit phorbol ester-stimulated vascular endothelial growth factor (VEGF) mRNA production. RESULTS: Curcumin effectively inhibited endothelial cell proliferation in a dose-dependent manner. Curcumin and its derivatives demonstrated significant inhibition of bFGF-mediated corneal neovascularization in the mouse. Curcumin had no effect on phorbol ester-stimulated VEGF production. CONCLUSIONS: These results indicate that curcumin has direct antiangiogenic activity in vitro and in vivo. The activity of curcumin in inhibiting carcinogenesis in diverse organs such as the skin and colon may be mediated in part through angiogenesis inhibition.

Mol Med 1998 Jun;4(6):376-83

Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress.

Curcumin, a widely used spice and coloring agent in food, has been shown to possess potent antioxidant, antitumor promoting and anti-inflammatory properties in vitro and in vivo. The mechanism(s) of such pleiotropic action by this yellow pigment is unknown; whether induction of distinct antioxidant genes contributes to the beneficial activities mediated by curcumin remains to be investigated. In the present study we examined the effect of curcumin on endothelial heme oxygenase-1 (HO-1 or HSP32), an inducible stress protein that degrades heme to the vasoactive molecule carbon monoxide and the antioxidant biliverdin. Exposure of bovine aortic endothelial cells to curcumin (5-15 microM) resulted in both a concentration- and time-dependent increase in HO-1 mRNA, protein expression and heme oxygenase activity. Hypoxia (18 h) also caused a significant (P < 0.05) increase in heme oxygenase activity which was markedly potentiated by the presence of low concentrations of curcumin (5 microM). Interestingly, prolonged incubation (18 h) with curcumin in normoxic or hypoxic conditions resulted in enhanced cellular resistance to oxidative damage; this cytoprotective effect was considerably attenuated by tin protoporphyrin IX, an inhibitor of heme oxygenase activity. In contrast, exposure of cells to curcumin for a period of time insufficient to up-regulate HO-1 (1.5 h) did not prevent oxidant-mediated injury. These data indicate that curcumin is a potent inducer of HO-1 in vascular endothelial cells and that increased heme oxygenase activity is an important component in curcumin-mediated cytoprotection against oxidative stress.

Free Radic Biol Med 2000 Apr 15;28(8):1303-12

Mechanisms of cancer chemoprevention by curcumin.

Curcumin is a major component of the Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Recently, curcumin has been considered by oncologists as a potential third generation cancer chemopreventive agent, and clinical trials using it have been carried out in several laboratories. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes, such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C, EGF-receptor tyrosine kinase and IkappaB kinase. In addition, curcumin inhibits the activation of NFkappaB and the expression of c-jun, c-fos, c-myc and iNOS. It is proposed that curcumin may suppress tumor promotion by blocking signal transduction pathways in the target cells. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin, and these compounds were subsequently convened into monoglucuronide conjugates. The experimental results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are major metabolites of curcumin in mice.

Proc Natl Sci Counc Repub China B 2001 Apr;25(2):59-66

Neuroprotective role of curcumin from curcuma longa on ethanol-induced brain damage.

In the present study, curcumin from Curcuma longa was screened for neuroprotective activity using ethanol as a model of brain injury. Oral administration of curcumin to rats caused a significant reversal in lipid peroxidation, brain lipids and produced enhancement of glutathione, a non-enzymic antioxidant in ethanol intoxicated rats, revealing that the antioxidative and hypolipidaemic action of curcumin is responsible for its protective role against ethanol induced brain injury.

Phytother Res 1999 Nov;13(7):571-4

The inhibitory effect of curcumin, genistein, quercetin and cisplatin on the growth of oral cancer cells in vitro.

Epidemiological evidence indicates that plant derived flavonoids and other phenolic antioxidants protect against heart disease and cancer. In the current investigation utilizing human oral squamous carcinoma cell line (SCC-25), we have evaluated the potency of three different plant phenolics, viz., curcumin, genistein and quercetin in comparison with that of cisplatin on growth and proliferation of SCC-25. Test agents were dissolved in DMSO and incubated in triplicates in 25 cm2 flasks in DMEM- HAM’s F-12 (50:50) supplemented with 10% calf serum and antibiotics in an atmosphere 5% CO2 in air for 72 hours cell growth was determined by counting the number of cells in a hemocytometer. Cell proliferation was determined by measuring DNA synthesis by the incorporation of [3H]-thymidine in nuclear DNA. Cisplatin (0.1, 1.0, 10.0 microM) and curcumin (0.1, 1.0, 10.0 microM) induced significant dose-dependent inhibition in both cell growth as well as cell proliferation. Genistein and quercetin (1.0, 10.0, 100.0 microM) had biphasic effect, depending on their concentrations, on cell growth as well as cell proliferation. Based on these findings, it is concluded that curcumin is considerably more potent than genistein and quercetin, but cisplatin is five fold more potent than curcumin in inhibition of growth and DNA synthesis in SCC-25.

Anticancer Res 2000 May-Jun;20(3A):1733-8

Effect of curcumin on the apoptosis of rodent and human nonproliferating and proliferating lymphoid cells.

Curcumin, a major active component of turmeric, has been recognized as an anticarcinogenic agent because of its propensity to induce apoptosis in vivo and in vitro. Previously, we showed that curcumin protects cells against oligonucleosomal DNA fragmentation and induces a novel apoptosis-like pathway in Jurkat cells (Piwocka et al. Exp Cell Res 249, 299-307, 1999). Here, we have studied the ability of curcumin to induce cell death in other human and rodent transformed as well as normal cells. Normal cells were quiescent or stimulated to proliferate. We showed that 50 microM pigment is able to induce cell death in all studied cells, but cell death symptoms varied for different cells. All the cells died as assessed by the TdT-mediated UTP nick end labeling method or trypan blue exclusion test. No one type of cells showed oligonucleosomal DNA fragmentation (DNA “ladder”) due to curcumin action, although in HL-60 cells, we were able to observe sub-G1 formation and caspase-3 activation. Together, these data showed that curcumin induces cell death in all tested cells that can be classified as apoptosis-like, and only in HL-60 cells can it be recognized as classical apoptosis.

Nutr Cancer 2000;38(1):131-8

Suppressive effect of curcumin on trichloroethylene-induced oxidative stress.

In vivo antioxidative effects of curcumin were investigated using a trichloroethylene (TCE)-induced oxidative stress model in mouse liver. Increases in the contents of peroxisome and thiobarbituric acid reactive substances (TBARS) and decreases in GSH content of mouse liver by the TCE administration were suppressed by the pre-administration of curcumin. TCE-induced changes in the activities of antioxidative enzyme, such as Cu/Zn-SOD, catalase, glutathione reductase, glutathione peroxidase (GPx) and D-glucose-6-phosphate dehydrogenase (G6PD), were also diminished by curcumin. These results indicate that curcumin significantly suppresses TCE-induced oxidative stress by scavenging various free radicals, and its antioxidative activity seems to be derived from its suppressive effects on the increase in peroxisome content and decrease in GPx and G6PD activities.

J Nutr Sci Vitaminol (Tokyo) 2000 Oct;46(5):230-4

Continued on Page 3 of 4

Back to the Magazine Forum