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PubMed2003

Dietary ginger constituents, galanals A and B, are potent apoptosis inducers in Human T lymphoma Jurkat cells.

The effects of the constituents isolated from ginger species including curcumin, 6-gingerol and labdane-type diterpene compounds on cell proliferation and the induction of apoptosis in the cultured human T lymphoma Jurkat cells were studied. Among the tested compounds, galanals A and B, isolated from the flower buds of a Japanese ginger, myoga (Zingiber mioga Roscoe), showed the most potent cytotoxic effect. Exposure of Jurkat human T-cell leukemia cells to galanals resulted in the induction of apoptotic cell death characterized by DNA fragmentation and caspase-3 activation. The mitochondrial damage pathway was suggested to be involved in galanal-induced apoptosis because the treatment of cells with galanals induced mitochondrial transmembrane potential (DeltaPsim) alteration and cytochrome c release. The anti-apoptotic Bcl-2 protein was downregulated by the galanal treatment together with enhancement of the Bax expression. In conclusion, the results from this study provide biological evidence that ginger-specific constituents other than curcuminoids are potential anticancer agents.

Apoptosis↗

PubMed2001

Unusually large numbers of electrons for the oxidation of polyphenolic antioxidants.

Reaction mechanisms of polyphenolic antioxidants were studied using electrochemical methods (flow column electrolysis and cyclic voltammetry). In flow column electrolysis, the numbers (ns) of electrons involved in the oxidation of catechols (chlorogenic acid and caffeic acid) became larger than two (i.e. the number of -OH moieties) at pH > 7; the n-values finally reached ca. 4 at pH 10. Other polyphenols including catechin, ellagic acid, and curcumin exhibited higher n-values than the numbers of -OH moieties in the whole pH range studied (4 < pH < 10). Such unusually large n-values for polyphenols were found to correlate to their irreversible behavior in cyclic voltammetry. A digital simulation analysis of the voltammograms of chlorogenic acid clearly showed that the electrode reaction at higher pHs can be elucidated in terms of a quasi-reversible electron transfer followed by a chemical reaction and also suggested that the chemical reaction is of second order to the concentration of chlorogenic acid, i.e. a dimerization reaction. In a similar manner, polyphenolic antioxidants generally undergo certain chemical reactions on the occasion of their oxidation. As a result, some oxidizable, phenolic -OH moieties are reproduced in the polymeric products. The unusually large n-values of polyphenols and thus their higher radical scavenging activities may be ascribed to such reproduction of -OH moieties by oxidative polymerization.

Antioxidants↗

PubMed2002

Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes.

Interleukin-1 (IL-1), the main cytokine instigator of cartilage degeneration in arthritis, induces matrix metalloproteinase-3 (MMP-3) and MMP-13 RNA and protein in chondrocytes. The molecular mechanisms of this induction were investigated with specific inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and activating protein (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors. IL-1 rapidly induced the activation of extracellular-signal regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK) MAPKs in the first-passage human femoral head OA chondrocytes. The ERK-MAPK pathway inhibitor, PD98059, attained 46-53% (MMP-3) and 59-66% (MMP-13) inhibition of RNA induction in human OA and 47-52% (MMP-3) and 69-73% (MMP-13) inhibition in bovine chondrocytes. U0126 conferred 37-77% (MMP-3) and 43-73% (MMP-13) suppression in human and 77-100% (MMP-3) and 96-100% (MMP-13) in bovine chondrocytes. P38 and JNK inhibitor, SB203580 caused 35-37% reduction of MMP-3 and MMP-13 RNA in human and 36-46% (MMP-3) and 60-88% (MMP-13) in bovine chondrocytes. Inhibitor of JNK, AP-1 and NF-kappa B, curcumin, achieved 48-99% suppression of MMP-3 and 45-97% of MMP-13 in human and 8-100% (MMP-3) and 32-100% (MMP-13) in bovine chondrocytes. NF-kappaB inhibitor, pyrrolidine dithiocarbamate yielded 83-84% reduction of MMP-3 and 38-55% for MMP-13 in human chondrocytes. In bovine chondrocytes, the induction decreased by 54-64% for MMP-3 and 74-93% for MMP-13 RNA. These results suggest the involvement of MAPKs, AP-1 and NF-kappa B transcription factors in the IL-1 induction of MMPs in chondrocytes. Inhibition of IL-1 signal transduction by these agents could be useful for reducing cartilage resorption by MMPs in arthritis.

Animals↗

PubMed2003

Involvement of p38 MAPK, JNK, p42/p44 ERK and NF-kappaB in IL-1beta-induced chemokine release in human airway smooth muscle cells.

Asthma is an inflammatory disease, in which eotaxin, MCP-1 and MCP-3 play a crucial role. These chemokines have been shown to be expressed and produced by IL-1beta-stimulated human airway smooth muscle cells (HASMC) in culture. In the present study we were interested to unravel the IL-1beta-induced signal transduction leading to chemokine production. Using Western blot, we observed an activation of p38 MAPK, JNK kinase and p42/p44 ERK when HASMC were stimulated with IL-1beta. We also observed a significant decrease in the expression and the release of eotaxin, MCP-1 and MCP-3 in the presence of SB203580, an inhibitor of p38 MAPK (71 +/- 6%, P < 0.05, n = 8 and 39 +/- 10% P < 0.01, n = 10 respectively), curcumin, an inhibitor of JNK kinase (83 +/- 4.9% and 88 +/- 3.4% respectively, P < 0.01, n = 4). U0126, an inhibitor of p42/p44 ERK, also produced a significant decrease in chemokine production (46.3 +/- 9%, P < 0.01 n = 10 and 67.8 +/- 12%, P < 0.01, n = 12). Pyrrolydine dithiocarbamate, an inhibitor of NF-kappaB was also able to reduce the eotaxin, MCP-1 and MCP-3 expression and production (50 +/- 13%, P < 0.05, n = 10 and 23 +/- 7%, P < 0.05, n = 12). We conclude that p38 MAPK, JNK kinase, ERK and NF-kappaB are involved in the IL-1beta-induced eotaxin, MCP-1, and MCP-3 expression and release in HASMC.

Asthma↗

PubMed1999

Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances.

Recently, considerable attention has been focused on identifying naturally occurring chemopreventive substances capable of inhibiting, retarding, or reversing the multi-stage carcinogenesis. A wide array of phenolic substances, particularly those present in dietary and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of these naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient of hot chili pepper, protects against experimentally-induced mutagenesis and tumorigenesis. It also induces apoptosis in various immortalized or malignant cell lines. Plants of ginger family (Zingiberaceae) have been frequently and widely used as spices and also, in traditional oriental medicine. Curcumin, a yellow ingredient from turmeric (Curcuma longa L., Zingiberaceae), has been extensively investigated for its cancer chemopreventive potential. Yakuchinone A [1-(4'-hydroxy-3'-methoxyphenyl)-7-phenyl-3-heptanone] and yakuchinone B [1-(4'-hydroxy-3'-methoxyphenyl)-7-phenylhept-1-en-3-one] present in Alpinia oxyphylla Miquel (Zingiberaceae) have inhibitory effects on phorbol ester-induced inflammation and skin carcinogenesis in mice, and oxidative stress in vitro. These diarylheptanoids suppress phorbol ester-induced activation of ornithine decarboxylase and production of tumor necrosis factor-alpha or interleukin-1alpha and their mRNA expression. They also nullified the phorbol ester-stimulated induction of activator protein 1 (AP-1) in cultured human promyelocytic leukemia (HL-60) cells. In addition, both yakuchinone A and B induced apoptotic death in HL-60 cells. Ginger (Zingiber officinale Roscoe, Zingiberaceae) contains such pungent ingredients as [6]-gingerol and [6]-paradol, which also have anti-tumor promotional and antiproliferative effects. Resveratrol (3, 5,4'-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other dietary and medicinal plants, and (-)-epigallocatechin gallate, a major antioxidative green tea polyphenol, exert striking inhibitory effects on diverse cellular events associated with multi-stage carcinogenesis. In addition, these compounds have ability to suppress proliferation of human cancer cells via induction of apoptosis.

Animals↗

PubMed2003

Extraction of essential oil and pigments from Curcuma longa [L] by steam distillation and extraction with volatile solvents.

Curcuma longa [Linn] (turmeric), of the Zingiberaceae family, has a great importance in the food, textile, and pharmaceutical industries. The aim of this work was to identify the best processing conditions to maximize the yields of essential oil and pigments, as well as their content of ar-turmerone, (alpha and beta)-turmerone, and the curcuminoids, respectively. Autoclave pressure and distillation time were the variables studied for the steam distillation process. The highest yields of essential oil (0.46 wt %) and pigment (0.16 wt %)-expressed as curcumin, demethoxycurcumin, and bisdemethoxycurcumin-were obtained at a pressure of 1.0 x 10(5) Pa and a time of 2 h. On the other hand, with extraction by volatile solvents, the best yield of essential oil (5.49 wt %) was obtained when using 0.175, 0.124, 0.088 mm particles (Foust, A. S.; Wenzel, L. A.; Clump, C. W.; Maus, L.; Andersen, L. B. Princípios das Operações Unitárias; Editora Guanabara Dois S.A.: Rio de Janeiro, Brazil, 1982), at 40 degrees C, and 6 h of extraction. However, the best yield of pigment (7.98 wt %) was obtained under the same conditions, except for the temperature (30 degrees C).

Curcuma↗

PubMed2005

Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice.

Turmeric, the rhizome of Curcuma longa L., has a wide range of effects on human health. The chemistry includes curcuminoids and sesquiterpenoids as components, which are known to have antioxidative, anticarcinogenic, and antiinflammatory activities. In this study, we investigated the effects of three turmeric extracts on blood glucose levels in type 2 diabetic KK-A(y) mice (6 weeks old, n = 5/group). These turmeric extracts were obtained by ethanol extraction (E-ext) to yield both curcuminoids and sesquiterpenoids, hexane extraction (H-ext) to yield sesquiterpenoids, and ethanol extraction from hexane-extraction residue (HE-ext) to yield curcuminoids. The control group was fed a basal diet, while the other groups were fed a diet containing 0.1 or 0.5 g of H-ext or HE-ext/100 g of diet or 0.2 or 1.0 g of E-ext/100 g of diet for 4 weeks. Although blood glucose levels in the control group significantly increased (P < 0.01) after 4 weeks, feeding of 0.2 or 1.0 g of E-ext, 0.5 g of H-ext, and 0.5 g of HE-ext/100 g of diet suppressed the significant increase in blood glucose levels. Furthermore, E-ext stimulated human adipocyte differentiation, and these turmeric extracts had human peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand-binding activity in a GAL4-PPAR-gamma chimera assay. Also, curcumin, demethoxycurcumin, bisdemethoxycurcumin, and ar-turmerone had PPAR-gamma ligand-binding activity. These results indicate that both curcuminoids and sesquiterpenoids in turmeric exhibit hypoglycemic effects via PPAR-gamma activation as one of the mechanisms, and suggest that E-ext including curcuminoids and sesquiterpenoids has the additive or synergistic effects of both components.

Adipocytes↗

PubMed2005

Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid.

Beta-amyloid (betaA)-induced oxidative toxicity on neuronal cells is a principal route in Alzheimer's disease (AD), and its toxicity occurs after fibril formation. Inhibitory or promoting effects of naturally occurring compounds on betaA fibril formation were evaluated. Among 214 tested compounds, curcuminoids, flavone type flavonoids, and naphthoquinones were shown to be potent inhibitors of betaA fibrilization. The addition of the curcuminoids, curcumin, demethoxycurcumin, and bisdemethoxycurcumin strongly inhibited betaA fibril formation. Flavonoids such as quercetin, rhamnetin, and fisetin strongly inhibited betaA fibril formation. Limonoids, cinnamic acids, and catechins enhanced fibril formation in vitro. Anthothecol possessed the most enhancing activity on fibril formation of the compounds tested. On the other hand, it was found that curcuminoids showed cytotoxicity with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and did not protect HT22 murine neuroblastoma cells from betaA(25-35) insult. Two flavone type flavonoids, morin and quercetin, exhibited no cytotoxicity and strongly protected HT22 murine neuroblastoma cells from betaA(25-35) oxidative attack. Conclusively, morin or quercetin could be a key molecule for the development of therapeutics for AD.

Amyloid beta-Peptides↗

PubMed2000

Spice extracts as dose-modifying factors in radiation inactivation of bacteria.

Three spices, chili, black pepper, and turmeric, were tested for the effect of their aqueous extracts on the sensitivity of three bacteria, Escherichia coli, Bacillus megaterium, and Bacillus pumilusspores, to gamma-radiation. It was found that the extracts of the three spices offered protection to these organisms against inactivation by gamma-radiation. These spice extracts were also tested for their protection of naked plasmid DNA. Radiation-induced degradation of plasmid pUC18 DNA was reduced in the presence of the spice extracts. The maximum protection was offered by the chili extract followed by that of black pepper and turmeric. The two known antioxidants, curcumin and piperine from turmeric and black pepper, respectively, were shown to protect the plasmid DNA from the degradation by gamma-radiation. Experiments with the plasmid pUC18 DNA indicated that the spice extracts probably protected microorganisms by protecting their DNA. These studies indicated the importance of spices among ingredients in food as dose-modifying factors during radiation processing.

Alkaloids↗

PubMed2002

Discovery of natural products from Curcuma longa that protect cells from beta-amyloid insult: a drug discovery effort against Alzheimer's disease.

From Curcuma longa, two novel compounds, 4' '-(3' "-methoxy-4' "-hydroxyphenyl)-2' '-oxo-3' '-enebutanyl 3-(3'-methoxy-4'hydroxyphenyl)propenoate (calebin-A, 1) and 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (2), and seven known compounds, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin, 3), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (demethoxycurcumin, 4), 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (bisdemethoxycurcumin, 5), 1-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-6-heptene-3,5-dione (6), 1,7-bis(4-hydroxyphenyl)-1-heptene-3,5-dione (7), 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (8), and 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (9), were isolated following a bioassay-guided fractionation scheme utilizing an assay to detect protection of PC12 cells from beta-amyloid insult. Compounds 1, 3-5, and 7 were found to more effectively protect PC12 cells from betaA insult (ED(50) = 0.5-10 microg/mL) than Congo red (10) (ED(50) = 37-39 microg/mL).

Alzheimer Disease↗

PubMed1998

Synthesis of (+/-)-cassumunins A and B, new curcuminoid antioxidants having protective activity of the living cell against oxidative damage.

A chemical synthesis of cassumunins A (1) and B (2), natural curcuminoid antioxidants, was developed. The synthesis was started from o-vanillin and after nine reaction steps resulted in 20% and 26% overall yields of 1 and 2, respectively. The synthetic cassumunins showed stronger protective activity than curcumin against oxidative cell death induced by hydrogen peroxide in a rat thymocyte system.

Animals↗

PubMed1998

Cytotoxicity of curcuminoids and some novel compounds from Curcuma zedoaria.

Bioassay-directed fractionation of an EtOH extract of Curcuma zedoaria led to isolation of an active curcuminoid, which was identified as demethoxycurcumin (2) by comparison of its 1H and 13C NMR spectra with literature data and by direct comparison with synthetic material. Curcumin (1) and bisdemethoxycurcumin (3) were also obtained. Curcuminoids (1-3) were synthesized and demonstrated to be cytotoxic against human ovarian cancer OVCAR-3 cells. The observed CD50 values of 1, 2, and 3 were 4.4, 3.8, and 3.1 microg/mL, respectively. Three additional novel compounds, 3, 7-dimethylindan-5-carboxylic acid (4), curcolonol (5), and guaidiol (6), were also isolated from the EtOH extract. The structures and relative stereochemistry of 4-6 were determined by spectroscopic methods and X-ray crystallographic analysis.

Antineoplastic Agents, Phytogenic↗

PubMed1999

Prolonged activation of transcription factor AP-1 during NGF-mediated rescue from apoptotic cell death in PC12 cells.

Rat pheochromocytoma (PC12) cells exhibit apoptotic cell death when deprived of serum and can be rescued by nerve growth factor (NGF). We characterized AP-1 DNA binding activity in PC12 cells after serum deprivation in the presence or absence of NGF or other neurotrophic agents. There was a decline in AP-1 DNA binding activity concomitant with apoptosis in PC12 cells after serum deprivation. Treatment of serum-deprived PC12 with NGF induced persistent AP-1 binding activity that was blocked by the Trk receptor inhibitor K252a. PC12 cells treated with dibutyryl cyclic AMP or insulin also displayed increased AP-1 DNA binding activity. While NGF somewhat increased c-Fos and c-Jun protein levels transiently, it had a more robust and persistent stimulatory effect on Jun B protein levels. AP-1 transcriptional activity increased after NGF, dibutyryl cAMP, or insulin treatment under serum free conditions. Curcumin, which inhibits AP-1 activity, blocked the NGF-mediated rescue. These results would suggest that the rescue of serum-deprived PC12 cells from apoptosis requires increasing endogenous levels of specific Fos/Jun components of AP-1.

Animals↗

PubMed2000

Role of transcriptional factor activation protein-1 in endogenous expression of the interleukin-1 beta gene involved in Porphyromonas gingivalis fimbria-stimulated bone resorption in the mouse calvarial system.

We previously suggested that endogenous interleukin-1 beta (IL-1 beta) produced by Porphyromonas gingivalis fimbriae stimulation in calvarial bone cell cultures plays a role in bone resorption as a major cytokine. Therefore, in the present study, we initiated experiments to clarify the stimulatory mechanism of IL-1 beta gene expression in fimbria-stimulated bone resorption. Fimbria-stimulated bone resorption was dramatically inhibited by curcumin, a potent inhibitor of activation protein-1 (AP-1). In fact, the fimbriae induced markedly both the expression of c-fos and c-jun genes and their protein production in the calvarial cells. In addition, a mixture of antisense oligonucleotides against c-fos and c-jun significantly inhibited not only the fimbria-induced expression of the IL-1 beta gene but also the fimbria-induced bone resorption. Therefore, the present study demonstrates that transcriptional factor AP-1 plays a functional role in P. gingivalis fimbria-stimulated bone resorption via endogenous IL-1 beta in the mouse calvarial system.

Animals↗

PubMed2001

Effect of ultraviolet A on ornithine decarboxylase and metallothionein gene expression in mouse skin.

BACKGROUND: Ultraviolet A (UVA) is known to induce the expression of many stress responsive genes due to the generation of reactive oxygen species (ROS). However, UVA's role in inducing metallothionein (MT) gene expression has not been studied. Furthermore, our group demonstrated that UVA enhanced 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated induction of ornithine decarboxylase (ODC) activity in mouse skin (1). METHODS: We examined the interaction of UVA, TPA and antioxidants on the induction of MT and ODC mRNA in mouse skin. Female CD-1 mice were exposed to UVA (19 J/cm2) and total RNA was isolated from the skin. Northern blot analysis for MT and ODC mRNAs was performed. ODC activity in mouse epidermis was also determined in some experiments. RESULTS: UVA induced MT mRNA in mouse skin; however, it did not increase ODC mRNA. 1,4-Diazabicylo-[2,2,2]-octane (DABCO), a singlet oxygen scavenger, reduced UVA-mediated induction of MT mRNA by 40%. The data suggest that ROS produced by UVA exposure may contribute to its ability to induce MT mRNA. UVA slightly enhanced TPA-mediated ODC mRNA induction, while it enhanced ODC enzyme activity 70%. UVA additively intensified TPA-mediated MT mRNA induction. alpha-Tocopherol pretreatment inhibited the induction of ODC enzyme activity by TPA treatment combined with UVA exposure (TPA + UVA); however, alpha-tocopherol had less of an inhibitory effect on ODC mRNA induction by TPA + UVA. Curcumin, a plant pigment, dramatically inhibited both TPA- and TPA + UVA-induced expression of ODC and MT genes. CONCLUSIONS: These results demonstrate that UVA can induce MT gene expression and enhance TPA-induced ODC and MT gene expression. The data further suggest that these effects are partially mediated by ROS.

Animals↗

PubMed2001

c-Jun N-terminal kinase is involved in motility of endothelial cell.

Cell motility is essential for a wide range of cellular activities including anigogenesis as well as metastasis of tumor cells. Ras has been implicated in cell migration and invasion, and functions at upstream of mitogen-activated protein kinase (MAPK) families, which include extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK. In the present study, we examined the role of JNK in endothelial cell motility using stable transfectant (DAR-ECV) of ECV304 endothelial cells expressing previously established oncogenic H-Ras (leu 61). DAR-ECV cells showed an enhanced angiogenic potential and motility (approximately 2-fold) compared to ECV304 cells. Western blot analysis revealed constitutive activation of JNK in DAR-ECV cells. Pretreatment of JNK specific inhibitors, curcumin and all trans-retinoic acid, decreased the basal motility of DAR-ECV cells in a dose-dependent manner. These inhibitors also suppressed the motility stimulated by known JNK agonists such as TNFalpha and anisomycin. To further confirm the role of JNK, ECV304 cells expressing dominant active SEK1 (DAS-ECV) were generated. Basal non-stimulated levels of the cellular migration were greater in DAS-ECV clones than those in control ECV304 cells. These results suggest that Ras-SEK1-JNK pathway regulates motility of endothelial cells during angiogenesis.

Anisomycin↗

PubMed2006

Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma.

Biopsies from patients with cutaneous T-cell lymphoma (CTCL) exhibit stage-dependent increase in angiogenesis. However, the molecular mechanisms responsible for the increased angiogenesis are unknown. Here we show that malignant CTCL T cells spontaneously produce the potent angiogenic protein, vascular endothelial growth factor (VEGF). Dermal infiltrates of CTCL lesions show frequent and intense staining with anti-VEGF antibody, indicating a steady, high production of VEGF in vivo. Moreover, the VEGF production is associated with constitutive activity of Janus kinase 3 (Jak3) and the c-Jun N-terminal kinases (JNKs). Sp600125, an inhibitor of JNK activity and activator protein-1 (AP-1) binding to the VEGF promoter, downregulates the VEGF production without affecting Jak3 activity. Similarly, inhibitors of Jak3 inhibit the VEGF production without affecting JNK activity. Downregulation of Stat3 with small interfering RNA has no effect, whereas curcumin, an inhibitor of both Jak3 and the JNKs, almost completely blocks the VEGF production. In conclusion, we provide evidence of VEGF production in CTCL, which is promoted by aberrant activation of Jak3 and the JNKs. Inhibition of VEGF-inducing pathways or neutralization of VEGF itself could represent novel therapeutic modalities in CTCL.

Cell Line, Tumor↗

PubMed1998

Activation of AP-1 is required for bufalin-induced apoptosis in human leukemia U937 cells.

In a previous study, we demonstrated that bufalin caused apoptosis in human leukemia U937 cells by the anomalous activation of mitogen-activated protein kinase (MAPK) via a signaling pathway that included Ras, Raf-1 and MAPK kinase-1. We report here the effect of bufalin on c-Jun N-terminal protein kinase (JNK), a member of the MAPK family, and on the signaling pathway downstream of MAPKs in U937 cells. When U937 cells were treated with 10(-8) M bufalin, the activity of JNK1 was markedly elevated 3 h after the start of treatment and remained so for 9 h. This activation of JNK and the induction of apoptosis by bufalin were suppressed by expression of antisense mRNA for MAPK kinase-1. c-Jun was translocated from the cytoplasm to the nucleus after treatment of U937 cells with bufalin. The transcriptional activity of AP-1 was transiently enhanced by the treatment with bufalin and this activation was suppressed by the expression of antisense mRNA for MAPK kinase-1. Both curcumin (1,7-bis[4-hydroxy-3-methoxy-phenyl]-1,6-heptadiene-3,5-dione), an inhibitor of the biosynthesis of AP-1, and the expression of dominant negative c-Jun inhibited the activation of AP-1 and the induction of apoptosis by bufalin. Expression of a constitutively active mutant form of MAPK kinase-1 induced the activation of AP-1 and subsequent apoptosis in U937 cells. These results suggest that the activation of AP-1 via a MAPK cascade that includes JNK is required for the induction of apoptosis by bufalin in U937 cells.

Antineoplastic Agents↗