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PubMed2004

Involvement of mitogen-activated protein kinases and protein kinase C in cadmium-induced prostaglandin E2 production in primary mouse osteoblastic cells.

We previously reported that cadmium (Cd) induced prostaglandin E2 (PGE2) biosynthesis through the activation of cytosolic phospholipase A2 (cPLA2) and induction of cyclooxygenase 2 (COX-2) in primary mouse osteoblastic cells. In the present study, we further investigated the mechanism of PGE2 production by Cd focusing on the main mitogen-activated protein kinase (MAPK) subfamilies that mediate prostaglandin synthesis, extracellular signal-regulated kinase (ERK1/2 MAPK), c-jun-amino-terminal kinase (JNK MAPK) and p38 MAPK, and protein kinase C (PKC) which is activated by Cd in several kinds of cells. Cd at 2 microM and above stimulated PGE2 production in osteoblastic cells and its production was inhibited by the kinase-specific inhibitors PD98059, SB203580, curcumin, and calphostin C. Calphostin C also inhibited the production of PGE2 by phorbol 12-myristate 13-acetate (PMA), which is a potent activator of PKC. PD98059 inhibited PGE2 production stimulated by PMA as well as Cd, indicating that activation of PKC by ERK1/2 MAPK was necessary for Cd-stimulated PGE2 production. Moreover, Cd stimulated the phosphorylation of these three MAPKs, and inhibition of the phosphorylation of ERK1/2 MAPK by calphostin C was also observed. On the other hand, Cd was found to phosphorylate cPLA2 and the phosphorylation was inhibited by PD98059, indicating that cPLA2 was activated by Cd through ERK1/2 MAPK and released arachidonic acid (AA), a substrate of COX-2, from membranous phospholipids. From these results, it was suggested that activation of each of the ERK1/2, p38, and JNK MAPK cascades in addition to that of PKC and cPLA2 played an important role in the Cd-stimulated biosynthesis of PGE2 in mouse osteoblastic cells.

Animals↗

PubMed2005

Overexpression of cyclin D1-CDK4 in silica-induced transformed cells is due to activation of ERKs, JNKs/AP-1 pathway.

Silica has been known to be a factor inducing acute injury and chronic pulmonary fibrosis. Silica has also been listed as a human carcinogen in 1996 by International Agency for Research on Cancer (IARC). However, the molecular mechanisms involved its pathologic effects are not well understood. In these studies, we found that exposure of human embryonic lung fibroblasts (HELF) to crystalline silica could cause increases in activation of extracellular signal-regulated kinases (ERKs), p38K, and c-Jun NH2-terminal amino kinases (JNKs), and HELF transformation. Interestingly, silica-induced transformation of HELF (S-HELF) led to increases in activated levels of ERKs and p46 of JNKs, and decrease in p38K activation, and no effect on activation of p54 of JNKs, as compared with those in parental HELF. Further studies showed that there are differential effects of ERKs, JNKs and p38K, as well as their downstream transcription factor AP-1, in regulation of expression of cyclin D1 and CDK4 and cell cycle alternations induced by silica. Cyclin D1 and CDK4 were increased in S-HELF as compared with those in HELF. Inhibition of ERKs activation by AG126, JNK by SP600125, and AP-1 by curcumin could reduced the induction of cyclin D1 and CDK4. There is no significant difference for cell cycle distribution between groups. These results demonstrate that ERKs and JNKs, but not p38K is responsible for induction of cyclin D1 and CDK4 in S-HELF, suggesting that overexpression of cyclin D1 and CDK4 caused by silica is mediated by ERK, JNK/AP-1signaling pathway.

Blotting, Western↗

PubMed2004

Enhancement by other compounds of the anti-cancer activity of vitamin D(3) and its analogs.

Differentiation therapy holds promise as an alternative to cytotoxic drug therapy of cancer. Among compounds under scrutiny for this purpose is the physiologically active form of vitamin D(3), 1,25-dihydroxyvitamin D(3), and its chemically modified derivatives. However, the propensity of vitamin D(3) and its analogs to increase the levels of serum calcium has so far precluded their use in cancer patients except for limited clinical trials. This article summarizes the range of compounds that have been shown to increase the differentiation-inducing and antiproliferative activities of vitamin D(3) and its analogs, and discusses the possible mechanistic basis for this synergy in several selected combinations. The agents discussed include those that have differentiation-inducing activity of their own that is increased by combination with vitamin D(3) or analogs, such as retinoids or transforming growth factor-beta and plant-derived compounds and antioxidants, such as curcumin and carnosic acid. Among other compounds discussed here are dexamethasone, nonsteroidal anti-inflammatory drugs, and inhibitors of cytochrome P450 enzymes, for example, ketoconazole. Thus, recent data illustrate that there are extensive, but largely unexplored, opportunities to develop combinatorial, differentiation-based approaches to chemoprevention and chemotherapy of human cancer.

Animals↗

PubMed2003

Inhibition of arachidonate 5-lipoxygenase triggers prostate cancer cell death through rapid activation of c-Jun N-terminal kinase.

Previously, we reported that inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in both androgen-sensitive (LNCaP) and androgen-refractory (PC3) human prostate cancer cells within hours of treatment [Proc. Natl. Acad. Sci. USA 95 (1998) 13182-13187]. Apoptosis was prevented by exogenous 5(S)-HETE, a product of 5-lipoxygenase, indicating a role of this eicosanoid as an essential survival/anti-apoptotic factor for prostate cancer cells. However, nothing was clearly known about details of the underlying molecular mechanisms or events mediating the induction of fulminating apoptosis in these cells. This report documents the fact that inhibition of arachidonate 5-lipoxygenase induces rapid activation of c-Jun N-terminal kinase (JNK) in human prostate cancer cells which is prevented by the 5-lipoxygenase metabolite, 5(S)-HETE. Activation of JNK is unaffected by the cell-permeable tetra-peptide inhibitors of caspase 8 or caspase 3 (IETD-FMK and DEVD-FMK), though these inhibitors effectively blocked apoptosis triggering, suggesting that activation of JNK is independent or upstream of caspase activation. Both 5-lipoxygenase inhibition-induced activation of JNK and induction of apoptosis are prevented by curcumin, an inhibitor of JNK-signaling pathway. Apoptosis is also blocked by SP600125, a specific inhibitor of JNK activity, indicating that JNK activity is required for the induction of apoptosis in these cells. These findings suggest that the metabolites of arachidonate 5-lipoxygenase promote survival of prostate cancer cells involving down-regulation of stress-activated protein kinase.

Apoptosis↗

PubMed2002

Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: regulation by estrogen.

OBJECTIVES: (a) To identify the subtype of estrogen receptor (ER) expressed in neutrophils from premenopausal women and in neutrophils from men under different estrogen conditions and (b) to analyze the association between the modifications in the expression of ER subtypes and neuronal nitric oxide synthase (nNOS) expression induced by estrogen. METHODS: Neutrophils were isolated from pre-menopausal women during different stages of the menstrual cycle and from ten men for in vitro estrogen incubations. RESULTS: Neutrophils from premenopausal women expressed both ERalpha and ERbeta subtypes which were increased in the ovulatory phase of the menstrual cycle. Neutrophils derived from men also expressed ERalpha and ERbeta but only ERalpha expression was enhanced by in vitro incubation with 17beta-estradiol (10(-8) mol/l). In vitro incubation of neutrophils from women with 17beta-estradiol enhanced expression of both ER-alpha and ER-beta subtypes. nNOS protein was overexpressed in neutrophils from premenopausal women during the ovulatory phase. 17beta-Estradiol (10(-8) mol/l) also increased nNOS protein expression in neutrophils derived from men. Mithramycin A (10(-6) mol/l) and curcumin (10(-6) mol/l), prevented the upregulation of nNOS and ERalpha in neutrophils derived from men, suggesting the involvement of AP-1 and Sp-1 transcription factors. CONCLUSIONS: Although the in vivo levels of circulating estrogen concentrations seem to be associated with overexpression of both ERalpha and ERbeta in neutrophils from premenopausal women, which was further confirmed by the in vitro experiments with neutrophils from women, in vitro incubation of neutrophils from men with 17beta-estradiol only increased ERalpha protein expression which was associated with enhanced expression of nNOS protein.

Adult↗

PubMed2001

Preventive effects of anthraquinone food pigments on the DNA damage induced by carcinogens in Drosophila.

We have previously demonstrated the inhibitory effect of chlorophyllin, a green food additive, on the genotoxicities of various carcinogens in Drosophila. Recently, we reported that purpurin, a component of a red food additive produced from madder root (Rubia tinctorium), inhibits the bacterial mutagenicity of heterocyclic amines. In the present study, we examined antigenotoxic activities of various pigments that are either constituents of food or food additives, using Drosophila in vivo DNA repair assay. Third instar larvae of Drosophila were fed a mutagen with or without pigment. The resulting adult flies were monitored for their male (repair deficient)/female (repair proficient) ratios, which reflect the DNA damage. We tested a total of 20 pigments, which are mainly of plant origins, including flavonoids, carotenoids, anthocyanins, anthraquinones and beta-diketone (curcumin)-derivatives, against the genotoxicities of eight carcinogens; IQ, MeIQx, AFB1, NDMA, 2-AAF, DMBA, 4NQO, and MNU. Four anthraquinone pigments (alizarin, purpurin, lac color, and cochineal extract) showed significant antigenotoxic activities. Alizarin and purpurin suppressed the DNA damage induced by IQ, MeIQx, AFB1, NDMA, 2-AAF, DMBA, and MNU. Lac color and cochineal extract showed inhibition against IQ, MeIQx, AFB1, 2-AAF and DMBA. In these inhibitions, suppression of metabolic enzymes may be involved. Since purpurin and alizarin suppressed the activity of MNU, a direct alkylating agent, there may also be a mechanism distinct from enzyme inhibitions in these anthraquinone-mediated suppressions of DNA damage.

Animals↗

PubMed2001

Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cells.

Proto-oncogenes such as c-fos, c-jun and c-myc are known to relate to cell proliferation and differentiation. Some oriental herbal medicines like Glycyrrhizae radix or Juzen-taiho-to were found to suppress estradiol-17 beta (E2)-induced expression of c-fos/jun in uterine corpus and inhibited N-methyl-N-nitrosourea and E2-induced endometrial carcinogenesis in mice. It is suggested that the effects of such oriental drugs are exerted probably through suppression of estrogen-induced c-fos/jun expression and they are promising preventing agents for endometrial cancers. In the combined in vitro assay for cell proliferation (MTS assay) and apoptosis (DNA fragmentation) in human colorectal cancer cells (Colo 320), a number of naturally occurring chemopreventive agents such as curcumin, quercetin, auraptene, 1'-acetoxychavicol acetate (ACA) and indole-3-carbinol were shown to generate apoptosis as well as to inhibit cell proliferation. The results suggest a mode of action of these chemopreventive agents and also imply that such in vitro short term assay is useful for detection of new agents for cancer prevention.

Adenocarcinoma↗

PubMed2002

Putative identification of functional interactions between DNA intercalating agents and topoisomerase II using the V79 in vitro micronucleus assay.

Clastogenicity is frequently observed following treatment of mammalian cells with new chemical entities. This clastogenicity, unless proven otherwise, is assumed to result from the imperfect repair of DNA lesions produced from covalent chemical/DNA interaction. However, clastogenicity can also arise via other mechanisms such as non-covalent chemical intercalation into DNA resulting in poisoning of cellular DNA topoisomerase II (topo II) and stabilization of DNA double strand breaks. We have recently reported modifications to the V79 in vitro micronucleus assay which allow an indirect evaluation of both the intercalative and topoisomerase-interactive activities of chemical agents. In the present studies we have used these modified assays to further assess the validity of this approach in an evaluation of a number of intercalating and non-intercalating polycyclic compounds. It is shown that intercalating agents may be catalytic topo II inhibitors (e.g. chloroquine (CHL), tacrine (TAC), 9-aminoacridine (9AA), ethidium bromide (EB)) or topo II poisons (e.g. proflavine (PROF), auramine O (AUR) and curcumin (CURC)). Still other intercalators are shown to lack detectable topo II-interactions, (e.g. imipramine (IMP), quinacrine (QUIN), 2-aminoanthracene (AA), iminostilbene (IMN) and promethazine (PHE)). It is concluded that (1) the clastogenicity of three agents, PROF (a typical DNA intercalating agent), and AUR and CURC (both structurally atypical intercalating agents, with unknown clastogenic mechanisms), may be due to topo II poisoning; (2) other intercalating agents may either act as catalytic topo II inhibitors or exhibit no functional topo II interaction; (3) The use of these cell-based approaches may provide a logical first step in determining if unexpected clastogenicity associated with test article exposure is due to a topo II interaction.

Animals↗

PubMedDate not supplied

Mechanism-based in vitro screening of potential cancer chemopreventive agents.

Identification and use of effective cancer chemopreventive agents have become an important issue in public health-related research. For identification of potential cancer chemopreventive constituents we have set up a battery of cell- and enzyme-based in vitro marker systems relevant for prevention of carcinogenesis in vivo. These systems include modulation of drug metabolism (inhibition of Cyp1A activity, induction of NAD(P)H:quinone reductase (QR) activity in Hepa1c1c7 murine hepatoma cell culture), determination of radical scavenging (DPPH scavenging) and antioxidant effects (scavenging of superoxide anion-, hydroxyl- and peroxyl-radicals), anti-inflammatory mechanisms (inhibition of lipopolysaccharide (LPS)-mediated nitric oxide (NO) generation by inducible NO synthase (iNOS) in Raw 264.7 murine macrophages, cyclooxygenase-1 (Cox-1) inhibition), and anti-tumor promoting activities (inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity in 308 murine keratinocytes). We have tested a series of known chemopreventive substances belonging to several structural classes as reference compounds for the identification of novel chemopreventive agents or mechanisms. These include organosulfur compounds (phenethylisothiocyanate (PEITC), diallylsulfide, diallyldisulfide), terpenes (limonene, perillyl alcohol, oleanolic acid, 18-beta-glycyrrhetinic acid), short-chain fatty acids (sodium butyrate), indoles (indole-3-carbinol), isoflavonoids (quercetin, silymarin, genistein), catechins ((-)-epigallocatechin gallate (EGCG)), simple phenols (ellagic acid, resveratrol, piceatannol, curcumin), pharmaceutical agents (piroxicam, acetylsalicylic acid, tamoxifen), and vitamins/derivatives (ascorbic acid, Trolox). We confirmed known chemopreventive mechanisms of these compounds. Additionally, we could demonstrate the usefulness of our approach by identification of hitherto unknown mechanisms of selected agents. As an example, we detected anti-inflammatory properties of PEITC, based on NF-kappaB-mediated inhibition of NO production. Further, PEITC inhibited phorbol ester-induced superoxide anion radical production in granulocytes, and ODC induction in the 308 cell line. These mechanisms might contribute to the chemopreventive potential of PEITC.

Animals↗

PubMed2002

Estradiol protects dopaminergic neurons in a MPP+Parkinson's disease model.

The prevalence of Parkinson's disease is higher in males than in females. Although the reason for this gender difference is not clear, the level of female steroid hormones or their receptors may be involved in the pathogenesis. The estrogen receptor subtype expressed in the midbrain is limited to the novel beta subtype, whose role in the central nervous system has not been resolved. We demonstrated that ligand-activated estrogen receptor beta suppressed dopaminergic neuronal death in an in vitro Parkinson's disease model which uses 1-methyl-4-phenylpyridinium ions (MPP(+)). MPP(+) treatment caused the upregulation of c-Jun amino-terminal kinase (JNK) and dopaminergic neuronal death, the latter being blocked by curcumin, an inhibitor of the c-Jun/AP-1 cascade. 17alpha- and 17beta-estradiol both protected dopaminergic neurons from MPP(+)-induced neuronal death and this was blocked by a pure antagonist of the estrogen receptor, ICI 182,780, but not by an inhibitor of estrogen receptor dimerization, YP537. These data indicated that the neuroprotection provided by 17alpha-estradiol was via inhibitory transcriptional regulation at the activator protein-1 (AP-1) site mediated by estrogen receptor beta. Thus, 17alpha-estradiol is a suitable candidate for neuroprotective therapy of Parkinson's disease because it is associated with few undesirable feminizing effects.

1-Methyl-4-phenylpyridinium↗

PubMed2003

Inhibition of LPS-induced NO production by the oleogum resin of Commiphora wightii and its constituents.

Three new (1-3) and five known compounds (4-8) were isolated from the oleogum resin of Commiphora wightii (Arnott.) Bhanol. Their structures were elucidated by spectroscopic and chemical methods. The MeOH extract and the EtOAc-sol. fraction were found to demonstrate significant inhibition of NO formation in lipopolysaccharide (LPS)-activated murine macrophages J774.1 in vitro (IC(50) values of 16.4 and 12.8 microg/ml, respectively). When compared with curcumin (IC(50) value of 12.3 microM), Z- and E-Guggulsterones (4 and 5, respectively) were the most potent inhibitors of NO production (IC(50) values of 1.1 and 3.3 microM, respectively), followed by myrrhanol A (7) and myrrhanone A (8) (IC(50) values of 21.1 and 42.3 microM, respectively). Guggulsterone-M (1) and its didehydro derivative (2) were weak inhibitors, while guggulsterols I (6) and Y (3) were inactive (IC(50) >500 microM).

Animals↗

PubMed1998

Induction of the differentiation of HL-60 promyelocytic leukemia cells by nonsteroidal anti-inflammatory agents in combination with low levels of vitamin D3.

Previous experiments have shown that a variety of agents that interfere with the activity of the transcription factor NF-kB significantly enhanced the differentiation of HL-60 leukemia cells when combined with low levels of the monocytic/macrophagic differentiating agent vitamin D3. These include an antisense phosphorothioate oligonucleotide to the Rel A subunit of NF-kB, vitamin E and other antioxidants, and curcumin. Acetylsalicylic acid and other nonsteroidal anti-inflammatory agents represent another group of agents that have been reported to inhibit NF-kB at serum levels approximating those obtained during long-term therapy of chronic inflammatory states. To determine whether nonsteroidal anti-inflammatory agents also were capable of enhancing the differentiation of HL-60 leukemia cells produced by vitamin D3, we measured the effects of a variety of nonsteroidal anti-inflammatory agents on the maturation of HL-60 cells produced by low levels of vitamin D3. Acetylsalicylic acid by itself had no significant effect on the differentiation of HL-60 cells; however, this agent markedly increased the degree of differentiation produced by low levels of vitamin D3. Furthermore, a variety of other nonsteroidal anti-inflammatory agents of different chemical classes exhibited similar enhancements of the maturation of HL-60 cells when combined with vitamin D3. An analogous increase in the differentiation of HL-60 cells was also obtained by combination of several nonsteroidal anti-inflammatory agents with the granulocytic inducing agent, retinoic acid, but not with dimethylsulfoxide. The nonsteroidal anti-inflammatory agents also enhanced the differentiation of HL-60 cells when combined with vitamin D analogs which share the receptor binding properties of vitamin D3; however, a vitamin D analog which caused significant calcium mobilization, but was less effective in receptor binding than vitamin D3, did not induce the differentiation of HL-60 cells in the presence or absence of anti-inflammatory agents. The findings suggest that the nonsteroidal anti-inflammatory agents may have utility in the treatment of acute promyelocytic leukemia when used with the D vitamins or retinoic acid.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

Plant products as topical microbicide candidates: assessment of in vitro and in vivo activity against herpes simplex virus type 2.

There is considerable interest in developing topical microbicides; products to be used intravaginally by women for protection against sexually transmitted diseases. Many compounds derived from plants have been shown to have antimicrobial properties. We examined 19 such compounds in vitro by plaque reduction assay to determine their activity against a common sexually transmitted pathogen, herpes simplex virus type 2. Compounds with an ED50 < or = 7.0 mg/ml were tested for efficacy in vivo. Four compounds, carrageenan lambda type IV, cineole, curcumin, and eugenol, provided significant protection (P < 0.05) in a mouse model of intravaginal HSV-2 challenge. Eugenol, which provided the greatest protection in mice was also evaluated using the guinea pig model of genital HSV-2 infection where it also demonstrated significant protection. Based on these results, several plant-derived compounds appear to warrant further evaluation as potential microbicides.

Animals↗

PubMed1998

Synergistic effects of 13-cis retinoic acid and arachidonic acid cascade inhibitors on growth of head and neck squamous cell carcinoma in vitro.

Products of arachidonic acid metabolism can influence normal and malignant cell growth. In vivo, inhibitors of arachidonic acid metabolism have been associated with inhibition of tumor growth, including head and neck squamous cell carcinoma (HNSCC). This has not been evaluated extensively in vitro in an HNSCC model. Therefore we investigated the effects of several arachidonic acid cascade inhibitors (AACIs) (indomethacin, curcumin, phenidone, nordihydroguaiaretic acid, 5,8,11,14-eicosatetraynoic acid, and 13-cisretinoic acid) on the growth of two HNSCC cell lines (MDA 886Ln and 1483). We found that AACIs caused dose-dependent growth inhibition of both cell lines. In an effort to inhibit HNSCC cell growth at lower concentrations of these drugs, we evaluated the effects of a variety of AACIs in combination with 13-cis retinoic acid. We observed synergistic growth inhibition when the drugs were used in all combinations, with the exception of indomethacin. These results suggest that AACIs may have some utility in the direct treatment of HNSCC, and a strategy combining 13-cis retinoic acid with other AACIs may prove to be even more effective.

Arachidonic Acid↗

PubMed2002

Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics.

Dietary polyphenolics in fruits, vegetables, wines, spices and herbal medicines have beneficial antioxidant, anti-inflammatory and anticancer effects. However, we have observed that dietary polyphenolics with phenol rings were metabolized by peroxidase to form prooxidant phenoxyl radicals which, in some cases were sufficiently reactive to cooxidize GSH or NADH accompanied by extensive oxygen uptake and reactive oxygen species formation. The order of catalytic effectiveness found for oxygen activation when polyphenolics were metabolized by peroxidase in the presence of GSH was phloretin>phloridzin>4,2'-dihydroxy chalcone>p-coumaric acid>naringenin>apigenin>curcumin>resveratrol>isoliquiritigenin>capsaicin>kaempferol. Ascorbate was also cooxidized by the phenoxyl radicals but without oxygen activation. Polyphenolics with catechol rings also cooxidized ascorbate, likely mediated by semiquinone radicals. The order of catalytic effectiveness found for ascorbate cooxidation was fisetin luteolin, quercetin, >eriodictyol, caffeic acid, nordihydroguaiaretic acid>catechin>taxifolin, catechol. NADH was stoichiometrically oxidized without oxygen uptake which, suggests that o-quinone metabolites were responsible. GSH was not cooxidized and GSH conjugates were formed, likely mediated by the o-quinone metabolites. Incubation of hepatocytes with dietary polyphenolics containing phenol rings was found to partially oxidize hepatocyte GSH to GSSG while polyphenolics with a catechol ring were found to deplete GSH through formation of GSH conjugates. Dietary polyphenolics with phenol rings also oxidized human erythrocyte oxyhemoglobin and caused erythrocyte hemolysis more readily than polyphenolics with catechol rings. It is concluded that polyphenolics containing a phenol ring are generally more prooxidant than polyphenolics containing a catechol ring.

Animals↗

PubMed2000

Inhibition of benzo[a]pyrene- and 1,6-dinitropyrene-DNA adduct formation in human mammary epithelial cells bydibenzoylmethane and sulforaphane.

Numerous phytochemicals have been examined for their capacity to act as cancer chemopreventive agents. Dibenzoylmethane, a minor constituent of licorice and a compound structurally-related to curcumin, recently was identified as an effective inhibitor of chemically-induced rat mammary DNA-adduct formation and tumorigenesis (Carcinogenesis 19(1998)1039-1043). The present studies were conducted to examine the capacity of dibenzoylmethane to inhibit the formation of DNA adducts following exposure to benzo[a]pyrene (BP) and 1,6-dinitropyrene (1,6-DNP), and to stimulate the expression of glutathione-S-transferase (GST) and NAD(P)H-quinone reductase (QR) proteins in the human mammary epithelial cell line MCF-10F. In addition, the efficacy of dibenzoylmethane as an enzyme inducer and adduct inhibitor was compared with that of sulforaphane, a potent inducer of phase II detoxification enzymes and inhibitor of chemically-induced rat mammary tumorigenesis. Dibenzoylmethane at concentrations from 0.1 M to 2.0 microM inhibited BP-DNA adduct formation by 63 to 81%. Likewise, sulforaphane inhibited BP-DNA adduct formation by 68 to 80% over the same concentration range. DNA adduct formation following exposure to 1,6-DNP was significantly inhibited by 46 to 61% due to dibenzoylmethane treatment (0.1 to 2.0 microM) and 30 to 56% due to sulforaphane treatment at the same concentrations. The expression of QR and GSTP1-1 proteins were increased by 3 to 4-fold and 3 to 5-fold, respectively, for MCF-10F cells treated with sulforaphane (0.5-2.0 microM). Dibenzoylmethane treatment at the same concentrations did not induce GSTP1-1 expression and significantly stimulated QR expression only at the 2.0 microM concentration. These data indicate that human mammary epithelial MCF-10F cells can convert BP and 1,6-DNP to DNA-binding forms, and that DNA adduct formation can be inhibited by the phytochemicals dibenzoylmethane and sulforaphane. The inhibition of BP-DNA and 1, 6-DNP adduct formation by sulforaphane was associated with increases in QR and GST protein expression. The mechanisms underlying the capacity of dibenzoylmethane to inhibit BP-DNA and 1,6-DNP-DNA adduct formation could not be explained by changes in QR or GST expression and remain to be determined. Together these data suggest that dibenzoylmethane and sulforaphane warrant continued evaluation as breast cancer chemopreventive agents.

Anticarcinogenic Agents↗

PubMed2001

Inhibition by dietary dibenzoylmethane of mammary gland proliferation, formation of DMBA-DNA adducts in mammary glands, and mammary tumorigenesis in Sencar mice.

Dibenzoylmethane (DBM) is a minor constituent of licorice and a beta-diketone analogue of curcumin. Feeding 1% DBM in the diet to Sencar mice during both the initiation and the post-initiation periods strongly inhibited 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor multiplicity and mammary tumor incidence by 97%. In further in vivo studies to elucidate the possible mechanisms of the inhibitory action of DBM, feeding the 1% DBM in the AIN-76A diet to immature Sencar mice for 4-5 weeks decreased the uterine wet weight by 43%, inhibited the proliferation rate of mammary gland epithelial cells by 53%, uterine epithelium by 23%, and uterine stroma by 77%, when mice were killed during the first estrus phase of estrous cycle. In addition, feeding 1% DBM in the diet to Sencar mice at 2 weeks before, during and 1 week after DMBA treatment (intubation of 1 mg DMBA per mouse once a week for 5 weeks) inhibited formation of total DMBA-DNA adducts in mammary glands by 72% using a post-32P-labeling assay. Thus, feeding 1% DBM diet to Sencar mice inhibited formation of DMBA-DNA adducts in mammary glands and lowered the proliferation rate of the mammary gland in vivo. These results may explain the strong inhibitory actions of dietary DBM on mammary carcinogenesis in mice.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2002

Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45) alpha and beta messenger RNAs by histone deacetylase inhibitors trichostatin A (TSA) and butyrate in SW620 human colon carcinoma cells.

Histone deacetylase (HDAC) inhibitors such as trichostatin (TSA) and butyrate have been shown to inhibit cancer cell proliferation, induce apoptosis and regulate the expression of genes involved in cell cycle. Although the precise mechanism underlying HDAC inhibitor-induced cell growth arrest is not fully understood, induction of cell cycle related genes such as p21(cip/waf), is thought to be important. Here we showed that in the SW620 human colon cancer cell line, TSA and butyrate induced the growth arrest and DNA damage gene 45alpha (GADD45alpha) and GADD45beta. Furthermore, GADD45beta and p21(cip/waf) messenger RNA were induced in the absence of protein synthesis, indicating that both genes were immediate target genes for TSA. Cyclohexamide and TSA super-induced the expression of GADD45alpha and beta, but not p21(cip/waf). Interestingly while mitogen-activated kinase (MEK) inhibitor PD98059 and p38 kinase inhibitor SB242235 were unable to affect GADD45 induction, two serine/threonine protein kinase inhibitors (H7 and H8) as well as curcumin completely blocked the super-induction. Concomitant to the inhibition of GADD45 induction, H7 and H8 also blocked TSA-induced apoptosis. Taken together, these results suggest that GADD45 induction may play important role in TSA-induced cellular effects.

Antigens, Differentiation↗