Biomedical subjects

A H Conney

Publications and source records attributed to A H Conney.

At least 73 records · Page 4Linked to original sources

PubMed1993

Inhibition of tumor promoter-mediated processes in mouse skin and bovine lens by caffeic acid phenethyl ester.

Caffeic acid phenethyl ester (CAPE) was isolated from propolis (a product of honeybee hives) that has been used in folk medicine as a potent antiinflammatory agent. CAPE is cytotoxic to tumor and virally transformed but not to normal cells. Our main goal was to establish whether CAPE inhibits the tumor promoter (12-O-tetradecanoylphorbol-13-acetate)-induced processes associated with carcinogenesis. Topical treatment of SENCAR mice with very low doses (0.1-6.5 nmol/topical treatment) of CAPE strongly inhibits the following 12-O-tetradecanoylphorbol-13-acetate-mediated oxidative processes that are considered essential for tumor promotion: (a) polymorphonuclear leukocyte infiltration into mouse skin and ears, as quantified by myeloperoxidase activity; (b) hydrogen peroxide (H2O2) production; and (c) formation of oxidized bases in epidermal DNA, as measured by 5-hydroxymethyluracil and 8-hydroxylguanine. A 0.5-nmol dose of CAPE suppresses the oxidative burst of human polymorphonuclear leukocytes by 50%. At higher doses (1-10 mumol), CAPE inhibits edema and ornithine decarboxylase induction in CD-1 and SENCAR mice. Interestingly, we discovered that 12-O-tetradecanoylphorbol-13-acetate-induced H2O2 production in bovine lenses also is inhibited by CAPE. Cumulatively, these findings point to CAPE as being a potent chemopreventive agent, which may be useful in combating diseases with strong inflammatory and/or oxidative stress components, i.e., various types of cancer and possibly cataract development.

Animals↗

PubMed1993

Bacterial and mammalian cell mutagenicity of four optically active bay-region 10,11-diol-8,9-epoxides of the nitrogen heterocycle dibenz[a,h]acridine.

The mutagenic activities of the enantiomers of the diastereomeric pair of bay-region 10,11-diol-8,9-epoxides of dibenz[a,h]acridine (DB[a,h]ACR) were evaluated in histidine-dependent strains of Salmonella typhimurium and in cultured Chinese hamster V79 cells. In strains TA98 and TA100 of S.typhimurium, the (-)-[8S,9R,10R,11S] diol-epoxide was the most mutagenic compound, inducing 1200 and 6900 His+ revertants/nmol respectively. The mutagenic activity of each of the remaining three isomers was essentially independent of the bacterial strain used and had 14-72% of the activity of the [S,R,R,S] isomer. However, in Chinese hamster V79 cells, the (+)-[8R,9S,10S,11R] diol-epoxide was the most mutagenic compound (68 8-azaguanine resistant variants/nmol/10(5) cells), inducing from 2 to 11 times as many mutations as the other three isomers. These results are analogous to previous studies with the bay-region diol-epoxides of other polycyclic hydrocarbons in that the isomer with [R,S,S,R] absolute configuration has had variable activity in the bacterial assays, but has generally been the most active in the mammalian cells. Furthermore, this isomer has almost always been highly tumorigenic in the mouse.

Acridines↗

PubMed1993

Inhibitory effect of curcumin on 12-O-tetradecanoylphorbol-13-acetate-induced increase in ornithine decarboxylase mRNA in mouse epidermis.

Application of 5 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) to the skin of female CD-1 mice led to a rapid increase in the concentration of epidermal ornithine decarboxylase (ODC) mRNA from an undetectable level in control mice to a high maximum level at 4-5 h after TPA administration. The concentration of epidermal ODC mRNA then decreased rapidly during the next 5 h. The time course for TPA-induced increases in epidermal ODC enzyme activity paralleled very closely the time course for TPA-induced increases in ODC mRNA. Topical administration of 1, 3 or 10 mumol curcumin together with 5 nmol TPA inhibited by 66, 81 and 91% respectively TPA-induced increases in epidermal ODC enzyme activity measured 5 h later. In a parallel study, TPA-induced increases in the concentration of epidermal ODC mRNA was inhibited by 54, 85 and 82% respectively. Intraperitoneal injection of 10 or 30 mumol curcumin 1h before topical application of 5 nmol TPA inhibited TPA-induced increases in epidermal ODC enzyme activity by 75 or 89% respectively. In a parallel study, the induction of epidermal ODC mRNA was inhibited by 53 and 65% respectively. The results indicate that curcumin inhibits TPA-induced increases in epidermal ODC enzyme activity by inhibiting the synthesis and/or enhancing the breakdown of ODC mRNA.

Animals↗

PubMed1992

Inhibitory effect of green tea on the growth of established skin papillomas in mice.

In 10 separate experiments, mice with established chemically induced or UV light-induced skin papillomas were treated continuously with green tea in the drinking water or with i.p. injections of a green tea polyphenol fraction or (-)-epigallocatechin gallate three times a week for 4-10 weeks. Partial tumor regression or > 90% inhibition of tumor growth, as measured by changes in tumor volume per mouse, was observed in 5 experiments, and marked inhibition of tumor growth (46-89%) was observed in 5 additional experiments. Treatment of the mice with green tea or green tea constituents had an inhibitory effect on body weight increases in several but not all of the studies. Examination of the data from all ten experiments revealed that complete tumor regression occurred in 14 of 346 papilloma-bearing mice (4%) that were treated with green tea in the drinking water or with i.p. injections of green tea constituents, whereas none of the 220 papilloma-bearing control mice treated with only vehicle exhibited complete tumor regression. These observations indicate that oral administration of green tea, i.p. administration of a green tea polyphenol fraction, or i.p. administration of (-)-epigallocatechin gallate inhibited the growth and/or caused the regression of established experimentally induced skin papillomas.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1992

Effect of dietary curcumin and ascorbyl palmitate on azoxymethanol-induced colonic epithelial cell proliferation and focal areas of dysplasia.

Curcumin, a major yellow pigment of turmeric obtained from powdered rhizomes of the plant Curcuma longa Linn., is commonly used as a coloring agent in foods, drugs and cosmetics. Ascorbyl palmitate is a lipid soluble derivative of ascorbic acid. Both curcumin and ascorbyl palmitate have antioxidant activity and are potent inhibitors of 12-O-tetradecanoyl-phorbol-13-acetate-induced tumor promotion in mouse skin. The effects of dietary curcumin and ascorbyl palmitate on azoxymethanol (AOM)-induced hyperproliferation of colonic epithelial cells and the incidence of focal areas of dysplasia (FADs) were evaluated in female CF-1 mice fed an AIN 76A diet. Subcutaneous injections of AOM (10 mg/kg body wt. once weekly for 6 weeks) caused hyperplasia and the formation of FADs in the colon. Administration of 2% curcumin in the diet inhibited AOM-induced formation of FADs while administration of 2% ascorbyl palmitate in the diet did not demonstrate inhibition. This result suggests that dietary curcumin may inhibit AOM-induced colonic neoplasia in mice.

Animals↗

PubMed1992

Inhibition of N-nitrosodiethylamine- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tumorigenesis in A/J mice by green tea and black tea.

The effect of p.o. administration of tea on nitrosamine-induced carcinogenesis was investigated. Female A/J mice were given N-nitrosodiethylamine (NDEA) (10 mg/kg) p.o. once a week for 8 weeks and were killed 16 weeks after the last dose. More than 90% of the mice had forestomach and lung tumors. The animals had an average of 8.3 forestomach and 2.5 lung tumors/mouse. With 0.63 or 1.25% green tea infusion (12.5 g green tea leaves brewed with 1 liter of boiling water) as the sole source of drinking water for the entire experimental period, the pulmonary tumor incidence was decreased by 18 or 44%, and the tumor multiplicity was reduced by 36 or 60%, respectively. The treatments also decreased the forestomach tumor incidence by 18 or 26% and tumor multiplicity by 59 or 63%, respectively. Administration of 0.63 or 1.25% green tea infusion, either during the NDEA treatment period only or starting 1 week after the completion of NDEA treatment, also decreased the pulmonary tumor incidence and multiplicity and the forestomach tumor multiplicity. The inhibitory effects of green tea infusion were also observed in a similar experiment using a higher dosage of NDEA (20 mg/kg). Treatment of female A/J mice with a single dose (103 mg/kg) of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) resulted in the formation of pulmonary adenomas in almost all of the animals with an average of 9.3 tumors/mouse after 16 weeks. When 0.6% decaffeinated green tea or black tea extract was given during the NNK-treatment period, tumor multiplicity was reduced by 67 or 65%, respectively. When the tea extract was given after the NNK-treatment period until the end of the experiment, 0.6% green tea extract decreased the tumor incidence and multiplicity by 30 and 85%, respectively. In this protocol, 0.6% black tea extract reduced tumor multiplicity by about 63% but did not significantly affect the tumor incidence. The results clearly demonstrated an inhibitory action of green tea and black tea on nitrosamine-induced tumorigenesis.

Animals↗

PubMed1992

Inhibitory effect of green tea in the drinking water on tumorigenesis by ultraviolet light and 12-O-tetradecanoylphorbol-13-acetate in the skin of SKH-1 mice.

Green tea was prepared by extracting 12.5 g of green tea leaves twice with 500 ml of boiling water, and the extracts were combined. This 1.25% green tea extract (1.25 g of tea leaves/100 ml of water) contained 4.69 mg of green tea extract solids per ml and was similar in composition to some green tea beverages consumed by humans. A 2.5% green tea extract (2.5 g of tea leaves/100 ml of water) was prepared similarly. Treatment of female SKH-1 mice with 180 mJ/cm2 of ultraviolet B light (UVB) once daily for 7 days resulted in red sunburn lesions of the skin. The intensity of red color and area of these lesions were inhibited in a dose-dependent fashion by the administration of 1.25 or 2.5% green tea extract as the sole source of drinking water before and during UVB treatment. Treatment of female SKH-1 mice with 180 mJ/cm2 of UVB once daily for 10 days followed 1 wk later by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate for 25 wk resulted in the development of skin tumors. The formation of skin tumors was inhibited by administration of 1.25% green tea extract as the sole source of drinking water prior to and during the 10 days of UVB treatment and for 1 wk after UVB treatment. In additional experiments, female SKH-1 mice were treated with 200 nmol of 7,12-dimethylbenz(a)anthracene followed 3 wk later by irradiation with 180, 60, or 30 mJ/cm2 of UVB twice weekly for 30 wk. UVB-induced formation of skin tumors and increased spleen size were inhibited by administration of 1.25% green tea extract as the sole source of drinking water prior to and during the 30 wk of UVB treatment. In these experiments, treatment of the animals with the green tea extract not only decreased the number of skin tumors but also decreased substantially the size of the tumors. In additional studies, SKH-1 mice were initiated by topical application of 200 nmol of 7,12-dimethylbenz(a)anthracene followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate for 25 wk. Administration of 1.25% green tea extract as the sole source of drinking water during promotion with 12-O-tetradecanoylphorbol-13-acetate reduced the number and incidence of skin tumors.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1992

Inhibitory effect of green tea on tumorigenesis by chemicals and ultraviolet light.

Topical application of a green tea polyphenol fraction inhibited 12-O-tetradecanoyl-phorbol-13-acetate-induced tumor promotion in CD-1 mice previously initiated with 7,12-dimethylbenz[a]anthracene (DMBA). Oral administration of a green tea infusion as the sole source of liquid sustenance to SKH-1 mice inhibited ultraviolet B light (UVB)-induced sunburn lesions, UVB-induced initiation of skin tumors, UVB-induced formation of skin tumors in mice previously initiated with DMBA, and nitrosodiethylamine-induced forestomach and lung tumors in A/J mice. In addition to inhibiting UVB-induced formation of skin tumors in DMBA-initiated mice, oral administration of green tea markedly decreased tumor size.

Animals↗

PubMed1992

Inhibitory effects of curcumin on tumor initiation by benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene.

The effects of topical administration of curcumin on the formation of benzo[a]pyrene (B[a]P)-DNA adducts and the tumorigenic activities of B[a]P and 7,12-dimethylbenz[a]anthracene (DMBA) in epidermis were evaluated in female CD-1 mice. Topical application of 3 or 10 mumol curcumin 5 min prior to the application of 20 nmol [3H]B[a]P inhibited the formation of [3H]B[a]P-DNA adducts in epidermis by 39 or 61% respectively. In a two-stage skin tumorigenesis model, topical application of 20 nmol B[a]P to the backs of mice once weekly for 10 weeks followed a week later by promotion with 15 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 21 weeks resulted in the formation of 7.1 skin tumors per mouse, and 100% of the mice had tumors. In a parallel group of mice, in which the animals were treated with 3 or 10 mumol curcumin 5 min prior to each application of B[a]P, the number of tumors per mouse was decreased by 58 or 62% respectively. The percentage of tumor-bearing mice was decreased by 18-25%. In an additional study, topical application of 3 or 10 mumol curcumin 5 min prior to each application of 2 nmol DMBA once weekly for 10 weeks followed a week later by promotion with 15 nmol TPA twice weekly for 15 weeks decreased the number of tumors per mouse by 37 or 41% respectively.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1991

Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis.

Topical application of curcumin, the yellow pigment in turmeric and curry, strongly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase activity, DNA synthesis, and tumor promotion in mouse skin (Huang et al., Cancer Res., 48: 5941-5946, 1988). Chlorogenic acid, caffeic acid, and ferulic acid (structurally related dietary compounds) were considerably less active. In the present study, topical application of curcumin markedly inhibited TPA- and arachidonic acid-induced epidermal inflammation (ear edema) in mice, but chlorogenic acid, caffeic acid, and ferulic acid were only weakly active or inactive. The in vitro addition of 3, 10, 30, or 100 microM curcumin to cytosol from homogenates of mouse epidermis inhibited the metabolism of arachidonic acid to 5-hydroxyeicosatetraenoic acid (5-HETE) by 40, 60, 66, or 83%, respectively, and the metabolism of arachidonic acid to 8-HETE was inhibited by 40, 51, 77, or 85%, respectively [IC50 (concentration needed for 50% inhibition) = 5-10 microM]. Chlorogenic acid, caffeic acid, or ferulic acid (100 microM) inhibited the metabolism of arachidonic acid to 5-HETE by 36, 10, or 16%, respectively, and these hydroxylated cinnamic acid derivatives inhibited the metabolism of arachidonic acid to 8-HETE by 37, 20, or 10%, respectively (IC50 greater than 100 microM). The metabolism of arachidonic acid to prostaglandin E2, prostaglandin F2 alpha, and prostaglandin D2 by epidermal microsomes was inhibited approximately 50% by the in vitro addition of 5-10 microM curcumin. Chlorogenic acid, caffeic acid, and ferulic acid (100 microM) were inactive. In vitro rat brain protein kinase C activity was not affected by 50-200 microM curcumin, chlorogenic acid, caffeic acid, or ferulic acid. The inhibitory effects of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on TPA-induced tumor promotion in mouse epidermis parallel their inhibitory effects on TPA-induced epidermal inflammation and epidermal lipoxygenase and cyclooxygenase activities.

Animals↗

PubMed1991

Inhibitory effect of curcumin and some related dietary compounds on tumor promotion and arachidonic acid metabolism in mouse skin.

Topical application of curcumin, the major yellow pigment in turmeric and curry, has a potent inhibitory effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in mouse skin. The structurally related compounds chlorogenic acid, caffeic acid and ferulic acid are less potent inhibitors. Curcumin is a potent inhibitor of TPA-induced ornithine decarboxylase activity and inflammation in mouse skin whereas chlorogenic acid, caffeic acid and ferulic acid are only weakly active or inactive. Curcumin is a potent inhibitor of arachidonic acid-induced inflammation in vivo in mouse skin, and this compound is also a potent inhibitor of epidermal lipoxygenase and cyclooxygenase activity in vitro. Although chlorogenic acid is only weakly active as an inhibitor of epidermal lipoxygenase activity and TPA-induced ear inflammation, it is more active than caffeic acid and ferulic acid. The inhibitory effects of curcumin, chlorogenic acid, caffeic acid and ferulic acid on TPA-induced tumor promotion in mouse skin parallel their inhibitory effects on TPA-induced epidermal inflammation and epidermal lipoxygenase and cyclooxygenase activities. Examination of the structural features of curcumin required for its biological activity indicate that free hydroxyl groups on the benzene rings are not required for inhibition of TPA-induced ornithine decarboxylase activity and inflammation in mouse skin.

Arachidonic Acid↗

PubMed1991

Effects of protein and carbohydrate content of diet on drug conjugation.

Eight healthy subjects were fed a high-protein-low-carbohydrate diet and, after a 3-day washout period, an isocaloric low-protein-high-carbohydrate diet. They received acetaminophen and oxazepam, drugs metabolized primarily by conjugation, on days 11 and 13, respectively, of each diet. Changing the diets of subjects from the high-protein-low-carbohydrate diet to the low-protein-high-carbohydrate diet resulted in a 14% increase in urinary recovery of acetaminophen glucuronide and a 32% increase in urinary recovery of oxazepam glucuronide (p less than 0.05). The increases in glucuronidation were at the expense of other pathways of metabolism, and there were no significant changes in the metabolic clearance rates of acetaminophen and oxazepam. Mean renal clearances of acetaminophen glucuronide, acetaminophen sulfate, and oxazepam glucuronide decreased 45%, 32%, and 54%, respectively (p less than 0.05), when the subjects were switched to the low-protein-high-carbohydrate diet.

Acetaminophen↗

PubMed1991

The FAD-containing monooxygenase-catalyzed N-oxidation and demethylation of trimethylamine in rat liver microsomes.

Trimethylaminuria (TMAuria), the excessive urinary excretion of the odorous trimethylamine (TMA), accompanies elimination of TMA in sweat and corresponding "fish-odor" syndrome. TMA was oxidized in vitro in rat liver microsomes from male Sprague-Dawley rats to TMA N-oxide and N-demethylated to dimethylamine (DMA). Both reactions were inhibited to 1-3% of normal activity by preincubation of microsomes without NADPH-generating system at 37 degrees C for 10 minutes indicating the FAD-containing monooxygenase-catalyzed reactions. On the other hand, the reactions were not inhibited by gas phase containing up to 80% carbon monoxide/20% oxygen mixture. The results are compatible with the hypothesis that in rat liver microsomes the N-oxygenation and N-demethylation of TMA are catalyzed only or predominantly by FAD-containing monooxygenases, and the cytochrome P-450 monooxygenases play a negligible, if any, role.

Animals↗

PubMed1990

Identification of epidermal cell subpopulations with increased ornithine decarboxylase activity following treatment of murine epidermis with 12-O-tetradecanoylphorbol-13-acetate.

Ornithine decarboxylase (ODC), the initial enzyme in the polyamine biosynthetic pathway, has been used as a marker for the hyperplasia that occurs following exposure of mouse epidermis to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Using flow cytometry in combination with polyclonal antibodies to ODC, we examined the levels of ODC-associated immunoreactive protein present within mouse epidermal cells at 4 and 24 h after a single topical application of TPA, as well as following chronic exposure to TPA and in papillomas. Basal levels of ODC-specific antibody binding were detectable in acetone-treated CD-1 mouse epidermis and were increased 3-fold at 4 h after TPA treatment. The amount of ODC antibody binding detected after exposure to 17 nmol TPA twice weekly for 3 weeks was similar to that detected within cells isolated from papillomas and was 2.5-fold higher than in cells isolated at 4 h after a single topical treatment of mice with TPA. These observations support the hypothesis that specific subpopulations of keratinocytes constitutively express high levels of ODC following chronic exposure to TPA. The novel method for ODC detection described in these studies provides a means to identify, isolate, and further characterize epidermal cells that may give rise to papillomas and carcinomas.

Animals↗

PubMed1990

Flow cytometric detection of ornithine decarboxylase activity in epidermal cell subpopulations.

Using flow cytometry in combination with membrane permeabilization techniques to enhance binding of antibodies with immunoreactive protein within the cytoplasm, we have developed a method to examine the ornithine decarboxylase (ODC) activity present within subpopulations of epidermal cells following acute and chronic exposure to the phorbol ester tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA). The method described has the sensitivity to detect basal levels of ODC as well as increases in ODC at early time points following treatment with TPA and has the additional advantage of allowing subpopulation identification and characterization.

Animals↗

PubMed1989

Mutagenicity of dihydrodiols and diol epoxides of dibenz[a, h]acridine in bacterial and mammalian cells.

Bay-region diol epoxides are ultimate carcinogenic metabolites of a number of polycyclic aromatic compounds. Dibenz[a, h]acridine can form two diastereomeric pairs of these diol epoxides which are not positionally equivalent as a result of the nitrogen atom at position 7. We have assessed the structure-activity relationships resulting from heterocyclic nitrogen substitution by examining the mutagenic activity of these four bay-region diol epoxides of dibenz[a,h]acridine in both bacterial and mammalian cells. In strains TA98 and TA100 of Salmonella typhimurium, the diastereomeric 10,11-diol-8,9-epoxides were 20 to 40 times more mutagenic than the corresponding 3,4-diol-1,2-epoxides. Furthermore, in strain TA100, dibenz[a,h]acridine 10,11-dihydrodiol, the expected metabolic precursor of the 10,11-diol-8,9-epoxide, was metabolically activated by rat hepatic microsomes up to a 12-fold greater extent than the 3,4-dihydrodiol. In Chinese hamster V79 cells, the 10,11-diol-8,9-epoxide diastereomers were 20 to 80 times more mutagenic than their 3,4-diol-1,2-epoxide counterparts. Quantum mechanical calculations of the predicted ease of benzylic carbocation formation at C-1 and C-8 from the diol epoxides indicate that the 3,4-diol-1,2-epoxides should be less reactive due to resonance destabilization of the C-1 carbocation as a result of the electronegative nitrogen atom. Decreased chemical reactivity of 3,4-diol-1,2-epoxides may explain their decreased mutagenic activity.

Acridines↗

PubMed1989

Synthetic lipid second messenger sn-1,2-didecanoylglycerol: a complete tumor promoter in mouse skin.

sn-1,2-Didecanoylglycerol, a synthetic lipid second messenger and model diacylglycerol, was evaluated as a complete skin tumor promoter in CD-1 mice. In addition, sn-1,2-dioctanoylglycerol, sn-1,2-didecanoylglycerol, the second stage tumor promoter mezerein, and the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined for their ability to stimulate epidermal protein kinase C activity in vitro. All four compounds stimulated epidermal protein kinase C activity utilizing lysine-rich histone as the phosphate acceptor substrate. sn-1,2-Dioctanoylglycerol and sn-1,2-didecanoylglycerol stimulated epidermal protein kinase C activity to a maximum velocity similar to that obtained when the enzyme was stimulated with TPA; however, about 1000 times greater concentration of the sn-1,2-diacylglycerols was required. sn-1,2-Didecanoylglycerol was evaluated as a complete skin tumor promoter in CD-1 mice utilizing a dosing regimen demonstrated to produce epidermal hyperplasia. Mice were initiated with 200 nmol 7,12-dimethylbenz[a]anthracene. One week later the mice received twice daily topical applications of 1 nmol TPA, 2 mumol sn-1,2-didecanoylglycerol or 5 mumol sn-1,2-didecanoylglycerol, 5 days/week. Additional initiated mice received twice weekly topical applications of 2 or 5 nmol TPA. Initiated mice treated with 5 nmol TPA twice weekly or with 1 nmol TPA twice daily for 5 days/week (cumulative weekly doses of 10 nmol TPA) responded similarly, based on the tumor incidence and the average number of tumors per mouse. Initiated mice treated with 2 or 5 mumol sn-1,2-didecanoylglycerol twice daily developed tumors in a dose-dependent manner. Initiated mice treated with 5 mumol sn-1,2-didecanoylglycerol twice daily developed many tumors, and at 20 weeks there was a 74% tumor incidence and an average of 6.0 tumors/mouse. At 20 weeks, 24% of the initiated mice treated with 2 mumol sn-1,2-didecanoylglycerol twice daily developed tumors, with an average of 1.1 tumors/mouse. Mice which were not initiated but treated twice daily with 5 mumol sn-1,2-didecanoylglycerol for 20 weeks did not develop any tumors. These data demonstrate that the representative synthetic lipid second messenger sn-1,2-didecanoylglycerol, like TPA, is a complete tumor promoter in DMBA-initiated mouse skin.

Animals↗

PubMed1988

Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate.

The effects of topically applied curcumin, chlorogenic acid, caffeic acid, and ferulic acid on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors were evaluated in female CD-1 mice. Topical application of 0.5, 1, 3, or 10 mumol of curcumin inhibited by 31, 46, 84, or 98%, respectively, the induction of epidermal ornithine decarboxylase activity by 5 nmol of TPA. In an additional study, the topical application of 10 mumol of curcumin, chlorogenic acid, caffeic acid, or ferulic acid inhibited by 91, 25, 42, or 46%, respectively, the induction of ornithine decarboxylase activity by 5 nmol of TPA. The topical application of 10 mumol of curcumin together with 2 or 5 nmol of TPA inhibited the TPA-dependent stimulation of the incorporation of [3H]-thymidine into epidermal DNA by 49 or 29%, respectively, whereas lower doses of curcumin had little or no effect. Chlorogenic acid, caffeic acid, and ferulic acid were less effective than curcumin as inhibitors of the TPA-dependent stimulation of DNA synthesis. Topical application of 1, 3, or 10 mumol of curcumin together with 5 nmol of TPA twice weekly for 20 weeks to mice previously initiated with 7,12-dimethylbenz[a]anthracene inhibited the number of TPA-induced tumors per mouse by 39, 77, or 98%, respectively. Similar treatment of mice with 10 mumol of chlorogenic acid, caffeic acid, or ferulic acid together with 5 nmol of TPA inhibited the number of TPA-induced tumors per mouse by 60, 28, or 35%, respectively, and higher doses of the phenolic acids caused a more pronounced inhibition of tumor promotion. The possibility that curcumin could inhibit the action of arachidonic acid was evaluated by studying the effect of curcumin on arachidonic acid-induced edema of mouse ears. The topical application of 3 or 10 mumol of curcumin 30 min before the application of 1 mumol of arachidonic acid inhibited arachidonic acid-induced edema by 33 or 80%, respectively.

9,10-Dimethyl-1,2-benzanthracene↗