Search PubMed⌕ Search

Biomedical subjects

H Fujiki

Publications and source records attributed to H Fujiki.

At least 217 records · Page 12Linked to original sources
PubMed1986

Modulation of phorbol ester receptors in mouse skin by application of quercetin.

The topical application of quercetin, an anti-tumor promoter, to mouse skin reduced the number of phorbol ester receptors, although quercetin did not inhibit specific 3H-12-O-tetradecanoylphorbol-13-acetate binding to a mouse skin particulate fraction. Quercetin, morin, kaempferol and luteolin inhibited activation of protein kinase C by teleocidin, and caused half-maximal activation at 25 microM. (+)-Catechin, which has been reported not to inhibit tumor-promoting activity, did not have any effect on these reactions. The modulation of phorbol ester receptors and inhibition of activation of protein kinase C are considered to be involved in the anti-tumor-promoting effect of quercetin in mouse skin. Diet containing 4% or 1% quercetin did not influence the action of teleocidin on mouse skin in a two-stage carcinogenesis experiment.

Animals↗
PubMed1986

Cell-mediated immune response in mice during the two-step carcinogenesis experiment by 7,12-dimethylbenz(a)anthracene and 12-O-tetradecanoylphorbol-13-acetate.

Cell mediated immune response in ICR mice during the two step carcinogenesis experiment induced by DMBA plus TPA was followed by determining the delayed type hypersensitivity to two antigens, i.e. DNFB applied to skin and SRBC injected intraperitoneally. In mice developing tumors from 3 to 15 weeks after DMBA initiation, delayed type hypersensitivity to DNFB was suppressed to as low as 30% that of normal mice. This suppression was not recovered by treatment of indomethacin. No difference in delayed type hypersensitivity to SRBC was observed on between the mice on the two-step carcinogenesis experiment and normal mice.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

[The active structure of tumor promoters].

Diterpene esters containing 12-0-tetradecanoylphorbol-13-acetate (TPA) and the alkaloid teleocidins are structurally unrelated natural products that exhibit similar potent skin tumor-promoting activity. These promoters are classified as TPA-type promoters because they bind equally to the phorbol ester receptor. TPA can be considered as an amphiphilic compound, with a hydrophilic domain spanning the C-3 to C-20 region of the molecule and a lipophilic domain consisting of the acyl substituents on C-12 and C-13. Teleocidins can also be considered as amphiphilic compounds, with the hydrophilic domain spanning the C-11 to C-14 region of the molecule and the lipophilic domain consisting of the alkyl substituents on C-6, C-7 and C-12. Teleocidins exist in two conformational states, the TWIST form and the SOFA form, in solution. From the ratio of the two conformations in solution, the free-energy difference between them was calculated to be 0-1.5 kcal/mol. Therefore a possible role of one of the two conformations should be considered in the modeling of receptor mapping. Computer modeling of the SOFA form of teleocidins and TPA showed a marked similarity with regards to the hydrogen bonding sites of the hydrophilic substituents. In this case, good superposition of the lipophilic regions of both types of compounds was obtained.

Carcinogens↗
PubMed1986

[Chemoprevention of cancer].

This article is based on the experimental results obtained on the inhibition of tumor promotion by the application of certain compounds. Retinoids are well investigated anti-tumor promoters which inhibit the tumor promotion of 12-O-tetradecanoylphorbol-13-acetate applied to mouse skin. We screened a number of possible anti-tumor promoters by short-term tests. The compounds which gave positive results in the tests were subjected to a long-term iu vivo two-stage carcinogenesis experiment with DMBA plus teleocidin on mouse skin. We found that a calmodulin antagonist, quercetin, anti-inflammatory agents and tannic acids were able to act as new anti-tumor promoters. One of the tannic acids tested is (-)-epigallocatechin gallate, a tannic acid contained in tea. However, the short-term tests have still not been able to detect the anti-tumor promoter satisfactorily. Recently, we found that sarcophytol A inhibits tumor promotion in mouse skin with an equimolar ratio of teleocidin. A study on the action of sarcophytol A is now under investigation. In addition, the primary and the secondary chemoprevention of cancer were also briefly mentioned.

Animals↗
PubMed1985

Stimulation of prostaglandin E2 production by 12-O-tetradecanoylphorbol 13-acetate (TPA)-type and non-TPA-type tumor promoters in macrophages and its inhibition by cycloheximide.

The effects of TPA (12-O-tetradecanoylphorbol 13-acetate)-type and non-TPA-type tumor promoters on prostaglandin E2 production by peritoneal macrophages of rats were examined. Among the TPA-type tumor promoters, aplysiatoxin was most potent in stimulating prostaglandin E2 production followed by dihydroteleocidin B, teleocidin, TPA and debromoaplysiatoxin. Prostaglandin E2 production by aplysiatoxin treatment was stimulated at doses up to 0.1 ng/ml. Palytoxin, a non-TPA-type tumor promoter, also stimulated both prostaglandin E2 production and the release of radioactivity from [3H]arachidonic acid-labeled macrophages. However, the dose required for the expression of these effects by palytoxin was up to 3 pg/ml. It was suggested that the tumor promoters are associated with the activity to stimulate arachidonic acid metabolism, irrespective of their type. Cycloheximide, a protein synthesis inhibitor, inhibited both prostaglandin E2 production and the release of radioactivity from prelabeled macrophages stimulated either by the TPA-type tumor promoters or by the non-TPA-type tumor promoter. It is possible that the tumor promoters may induce the synthesis of some proteins responsible for the stimulation of arachidonate metabolism.

Acrylamides↗
PubMed1985

Stimulation of arachidonic acid metabolism by different types of tumor promoters.

Skin tumor-promoting agents, including the 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, such as diterpine phorbol esters, teleocidin and aplysiatoxin, and a non-TPA-type tumor promoter (the newly described palytoxin, present in the coelenterate of the genus Palythoa), stimulated arachidonic acid metabolism by rat liver cells in culture. Palytoxin was 1000-3000 times more effective than TPA-type tumor promoters. The stimulations of arachidonic acid metabolism by palytoxin and the TPA-type tumor promoters were synergistic, whereas the stimulations among the TPA-type tumor promoters were not. The stimulation of arachidonic acid metabolism by palytoxin was synergistic with that of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and transforming growth factor-beta (TGF-beta). An antiserum to the EGF-receptor that blocks EGF binding partially inhibited the synergistic responses to palytoxin and EGF and palytoxin and TGF-alpha, whereas an antiserum to the EGF-receptor that does not block EGF binding or a non-immune rabbit serum did not.

Acrylamides↗
PubMed1985

Inhibition of teleocidin-caused epidermal ornithine decarboxylase induction by phospholipase A2-, cyclooxygenase- and lipoxygenase-inhibitors.

Teleocidin (5 micrograms/mouse), a potent tumor promoting indole alkaloid from Streptomyces, induced epidermal ornithine decarboxylase (ODC) in CD-1 mice. Teleocidin-caused ODC induction was inhibited by the treatment of indomethacin (2 mumol/mouse), a selective cyclooxygenase inhibitor, and p-bromophenacyl bromide (BPB) (30 mumol/mouse), a phospholipase A2 inhibitor. Teleocidin-caused ODC induction inhibited by indomethacin was completely restored by concurrent application of prostaglandin E2 (PGE2) (140 nmol/mouse). On the other hand, teleocidin-caused ODC induction inhibited by BPB was not restored by the treatment of mice with PGE2, but partially restored by the treatment with arachidonic acid (1 mumol/mouse). Treatment of mice with lipoxygenase inhibitors such as BW755C (30 mumol/mouse), nordihydroguaiaretic acid (NDGA) (30 mumol/mouse), quercetin (10 mumol/mouse), and 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) (10 mumol/mouse) clearly suppressed ODC induction by teleocidin. Moreover, both NDGA (30 mumol/mouse) and quercetin (10 mumol/mouse) inhibited the restoring effect of PGE2. Therefore, our present results suggest that arachidonate metabolites, i.e., not only cyclooxygenase product(s) but also lipoxygenase product(s), are involved in the mechanism of ODC induction by teleocidin.

Animals↗
PubMed1985

Teleocidin, a tumour promoter, stimulates synthesis of primate retroviruses in persistently infected human cells.

The naturally occurring tumour promoter teleocidin produces a pronounced but transient enhancement of the synthesis of extracellular viral particles in human cells chronically infected with simian retroviruses of type C (baboon endogenous virus, simian sarcoma virus) or type D (Mason-Pfizer monkey virus) or a human cell line-derived type D isolate (PMF virus), respectively. The retrovirus-stimulating activity of teleocidin is very similar to that previously described for the tumour-promoting phorbol ester TPA in the same cell systems.

Carcinogens↗
PubMed1985

Induced secretion of a Mr 46,000 protein by cultured human hepatoma cells treated with tumor promoters.

Human hepatoma cells, HuH-6 Cl-5, were treated with 12-O-tetradecanoylphorbol-13-acetate at concentrations of 1 ng/ml to 10 micrograms/ml for 6 h in the presence of [35S]methionine. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the labeled proteins secreted into the medium showed that this treatment induced marked secretion of a polypeptide with a molecular weight of about 46,000 (p46). When the labeled proteins were analyzed by two-dimensional polyacrylamide gel electrophoresis, p46 was composed of three isoproteins which had different isoelectric points. The two new classes of tumor promoters, teleocidin and aplysiatoxin, also induced secretion of this protein, although the amount of p46 induced by debromoaplysiatoxin was less than that induced by 12-O-tetradecanoylphorbol-13-acetate, teleocidin, and aplysiatoxin, judging from densitometric scanning of bands on a fluorogram. The nonpromoting phorbol esters, such as 4 beta-phorbol and phorbol-13-monoacetate, did not induce p46. The induction of p46 secretion involved de novo RNA synthesis, since actinomycin D (1 microgram/ml) completely and selectively blocked the incorporation of [35S]-methionine into the protein. "Pulse-chase" experiments indicated that p46 was not a degradation product induced by these potent tumor promoters. In an attempt to identify p46, the total proteins released were treated with two kinds of rabbit anti-human whole serum antisera, but although some proteins were precipitated, p46 was not.

Carcinogens↗
PubMed1985

Effect of reductones on cyclic 3', 5'-adenosine monophosphate phosphodiesterase.

The effect of some reductones such as ascorbic acid (AsA), triose reductone (TR), epinephrine (Ep) and their derivatives on cyclic 3', 5'-adenosine monophosphate phosphodiesterase (cAMP PDE) was studied in the presence or absence of Cu2+. AsA, TR, Ep and the reductones related to them inhibited cAMP PDE activity. Among the reductones, TR showed the highest inhibition. AsA, 5-methyl-3,4-dihydroxytetrone, pyrocatechol, p-hydroxyquinone and resorcinol had a relatively high inhibiting activity. The type of inhibition of AsA, TR and Ep was uncompetitive, competitive and noncompetitive, respectively. Cu2+ enhanced the inhibitory action of the reductones markedly and altered the type of inhibition of the reductones.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

A blue-green alga from Okinawa contains aplysiatoxins, the third class of tumor promoters.

The causative agents of swimmer's itch were isolated from the marine blue-green alga, Lyngbya majuscula, which grows off the coast of the Okinawa islands, Japan. Nuclear magnetic resonance and mass spectral studies revealed that these agents were identical with aplysiatoxin and debromoaplysiatoxin, which were previously shown to be the causative agents of swimmer's itch in Hawaii. Aplysiatoxin and debromoaplysiatoxin were recently found to be potent tumor promoters in two-stage carcinogenesis in mouse skin. This is the first report that humans are directly affected by these potent environmental tumor promoters in Japan.

Animals↗
PubMed1984

Reduction by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a calmodulin antagonist, in the number of phorbol ester receptors in mouse skin.

A calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), reduced the number of phorbol ester receptors in mouse skin in a dose- and time-dependent manner. The reduction occurred immediately after topical application of 30 mumoles of W-7, reaching a maximum of 86% after 5 min. Reduction in specific binding of 12-O-tetra-decanoylphorbol-13-acetate can explain the antitumor promoting activity of W-7 in mouse skin.

Animals↗
PubMed1984

Stimulation of hepatic glycogenolysis by 12-O-tetradecanoylphorbol-13-acetate (TPA) via a calcium requiring process.

12-O-Tetradecanoylphorbol-13-acetate (TPA) stimulated glycogenolysis in perfused rat liver which was perfused with Krebs-Ringer-bicarbonate buffer containing 1 mM CaCl2 but no substrate. Verapamil (100 microM), diltiazem (100 microM) and trifluoperazin (100 microM), all inhibited the effect of TPA in the presence of CaCl2. Omission of CaCl2 from the perfusate or the addition of EGTA markedly attenuated the effect of TPA. TPA decreased net release of 45Ca from 45Ca-preloaded liver. The effect of maximal concentration of TPA (20 ng/ml) was not additive to that of 0.6 microM A23187. These data suggest that TPA increases calcium influx into hepatocytes and stimulates glycogenolysis through a calcium-calmodulin dependent mechanism.

Animals↗
PubMed1984

Activation of calcium-activated, phospholipid-dependent protein kinase (protein kinase C) by new classes of tumor promoters: teleocidin and debromoaplysiatoxin.

The new potent tumor promoters teleocidin and debromoaplysiatoxin , which are structurally unrelated to phorbol esters, activate Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C). The concentrations of 12-O-tetradecanoylphorbol-13-acetate, teleocidin and debromoaplysiatoxin for half-maximum activation of protein kinase C were found to be approximately 3 ng/ml, 40 ng/ml and 400 ng/ml, respectively. These three types of tumor promoters bind to protein kinase C, and appear to exhibit their pleiotropic actions through activation of this enzyme.

Alkaloids↗
PubMed1984

Mitogenic and comitogenic properties of the indole alkaloid class of tumor promotors.

We determined the mitogenic and comitogenic properties of tumor promoters in the indole alkaloid series; agents that differ structurally from 12-0-tetradecanoylphorbol-13-acetate (TPA), which is known to be a lymphocyte mitogen. Teleocidin and dihydroteleocidin B were mitogenic for human lymphocytes, and lyngbyatoxin A elicited little or no mitogenesis. Catalase enhanced the mitogenicity of teleocidin and dihydroteleocidin B, and lyngbyatoxin A was also mitogenic in the presence of catalase. The potency of the agents was TPA = teleocidin greater than dihydroteleocidin B greater than lyngbyatoxin A. Dimethylsulfoxide and butyric acid markedly inhibited proliferation induced by these agents in human lymphocytes. The indole alkaloid tumor promoters were all comitogenic for murine thymocytes and induced production of interleukin-2. While the comitogenic effect of teleocidin was similar to that of TPA in its susceptibility to inhibition by dimethylsulfoxide and butyric acid, the comitogenic effect of dihydroteleocidin B and lyngbyatoxin A were less susceptible to these agents. These findings may facilitate the identification of cellular sites responsible for the inhibitory effect of differentiating agents on proliferative responses of lymphocytes.

Alkaloids↗
PubMed1984

A two-stage mouse skin carcinogenesis study of lyngbyatoxin A.

A strong skin irritant, lyngbyatoxin A, isolated from the marine blue-green alga Lyngbya majuscula is structurally related to teleocidin. Since lyngbyatoxin A satisfied our short-term screening tests for possible tumor promoters, viz. irritation of mouse ear, induction of ornithine decarboxylase (ODC) in mouse skin, and adhesion of human promyelocytic leukemia cells (HL-60), a two-stage carcinogenesis experiment was carried out. Tumor incidences in the groups treated with 7,12-dimethylbenz(a)anthracene (DMBA) plus lyngbyatoxin A and with DMBA plus 12-O-tetradecanoylphorbol-13-acetate (TPA) were 86.7% and 93.3% in week 30, respectively. The average number of tumors per mouse was 3.7 in the former group and 10.5 in the latter group. This paper reports for the first time the potent tumor-promoting activity of lyngbyatoxin A and also the histological examination of tumors.

9,10-Dimethyl-1,2-benzanthracene↗