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Biomedical subjects

H Fujiki

Publications and source records attributed to H Fujiki.

At least 199 records · Page 11Linked to original sources
PubMed1987

Synthetic analogues (indolactams) of (-)-indolactam-V are new congeners of the teleocidin class of tumor promoters.

(-)-Indolactam-V, which has the partial structure of teleocidins A and B, and has tumor-promoting activity, is a good model for use in studies on the relation between structure and tumor-promoting activity, whereas (+)-indolactam-V has no tumor-promoting activity. In this work, five racemic indolactams differing only in their alkyl group at C-12 of (-)-indolactam-V were synthesized and tested for biological and biochemical activities related to tumor promotion. The activities tested were inductions of ornithine decarboxylase in mouse skin and human promyelocytic leukemia (HL-60) cell adhesion, inhibition of specific [3H]12-O-tetradecanoyl-phorbol-13-acetate binding to a mouse particulate fraction and activation of protein kinase C in vitro. The results showed that (+/-)-indolactam-L and (+/-)-indolactam-F had almost the same activities as (+/-)-indolactam-V, suggesting that (-)-indolactam-L and (-)-indolactam-F are new tumor promoters with as high potency as (-)-indolactam-V. (+/-)-Indolactam-t-L, which has a highly lipophilic group at C-12 of (-)-indolactam-V, showed the highest activities in the above tests. (-)-Indolactam-t-L might have stronger tumor-promoting activity than (-)-indolactam-V. Furthermore, the results with (-)-indolactam-t-L indicated the possibility of designing new tumor promoters with stronger activity than teleocidin.

Animals↗
PubMed1986

Involvement of sulfatide in activation of protein kinase C by tumor promoters.

Sulfatide (cerebroside sulfate) activated protein kinase C to the same extent as phosphatidylserine did with the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate (TPA), teleocidin and debromoaplysiatoxin. Sulfatide and phosphatidylserine both induced specific binding of [3H]TPA to protein kinase C, although the ratios of specific to non-specific [3H]TPA binding to protein kinase C with the two were not the same. It is concluded that sulfatide is involved in activation of protein kinase C by tumor promoters in a slightly different way from phosphatidylserine.

Animals↗
PubMed1986

Absence of phosphorylation of retinoid-binding proteins by protein kinase C in vitro.

Cellular retinol-binding protein, cellular retinoic acid-binding protein, and fetal cellular retinol-binding protein were purified to homogeneity and each polypeptide had a molecular weight of 16,000. Their apoproteins were not phosphorylated under the same conditions. Their holoproteins did not inhibit the phosphorylation of histone III-S by protein kinase C. Each of these observations is contrary to the results reported by Cope et al. (Biochem. Biophys. Res. Commun., 120, 593-601, 1984).

Animals↗
PubMed1986

Synergistic stimulation of histamine release from rat peritoneal mast cells by 12-O-tetradecanoylphorbol 13-acetate (TPA)-type and non-TPA-type tumor promoters.

Thapsigargin, a non-TPA (12-O-tetradecanoylphorbol 13-acetate)-type tumor promoter, provoked histamine release from rat peritoneal mast cells at concentrations above 30 ng/ml, but not at 10 ng/ml. TPA-type tumor promoters such as TPA, teleocidin and aplysiatoxin released very little, if any, histamine even at 100 ng/ml. When mast cells were incubated in medium containing thapsigargin at 10 ng/ml and varying concentrations of TPA-type tumor promoters, histamine release was increased synergistically. Maximum synergistic effects were observed at 10 ng/ml of each TPA-type tumor promoter. Palytoxin, another non-TPA-type tumor promoter, having no effect on histamine release at up to 10 pg/ml, also induced histamine release in the presence of 10 ng/ml of each TPA-type tumor promoter. However, no synergistic effect on histamine release was observed when mast cells were incubated in medium containing two different non-TPA-type tumor promoters, e.g., 10 ng/ml thapsigargin and 10 pg/ml palytoxin, or in medium containing two different TPA-type tumor promoters, e.g., TPA and teleocidin, TPA and aplysiatoxin, or teleocidin and aplysiatoxin (all at 10 ng/ml). These results suggest that the release of histamine from mast cells is stimulated synergistically under the mutual influence of TPA-type tumor promoters and non-TPA-type tumor promoters.

Animals↗
PubMed1986

Thapsigargin, a histamine secretagogue, is a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type tumor promoter in two-stage mouse skin carcinogenesis.

Thapsigargin, a hexaoxygenated tetraacylated sesquiterpene lactone, induced irritation of mouse ear and histidine decarboxylase (HDC) activity in mouse skin, but it did not induce ornithine decarboxylase in mouse skin or adhesion of human promyelocytic leukemia (HL-60) cells. Although thapsigargin did not give consistent positive results in a short-term screening system for tumor promoters, it was tested in a two-stage carcinogenesis experiment on mouse skin. The potency of thapsigargin to induce HDC in mouse skin was used to determine the dose in this experiment. Application of 10 micrograms (17 nmol) thapsigargin induced HDC activity of 139 pmol CO2/mg protein per 60 min. Tumors were found in the skin of 53.5% of the mice treated with DMBA plus 5 micrograms (8.5 nmol) thapsigargin in week 22, in none of those treated with thapsigargin alone by week 30. One tumor appeared in 1 of 15 mice treated with DMBA alone in week 21. Thapsigargin cannot bind to the phorbol ester receptor in the particulate fraction of mouse skin and so is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type tumor promoter. It is a new tumor promoter differing in many respects from the well-defined TPA type tumor promoters. Several naturally occurring analogues of thapsigargin, such as thapsigargicin and thapsitranstagin, might also be new non-TPA type tumor promoters, because thapsigargicin and thapsitranstagin induced irritation of mouse ear and HDC activity in mouse skin.

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

Combinations of palytoxin or 12-O-tetradecanoylphorbol-13-acetate and recombinant human insulin growth factor-I or insulin synergistically stimulate prostaglandin production in cultured rat liver cells and squirrel monkey aorta smooth muscle cells.

In the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA) or the non-TPA-type tumor promoter, palytoxin, recombinant human insulin growth factor-I (IGF-I) and insulin synergistically stimulate prostaglandin production in rat liver cells (the C-9 cell line). Combinations of palytoxin or TPA with recombinant human IGF-I or insulin also synergistically stimulate deesterification of cellular lipids in C-9 cells prelabelled with [3H]arachidonic acid. With both types of stimulations, prostaglandin production or deesterification, the synergistic response of the IGF-I and insulin is greater with palytoxin than with TPA. Production of prostaglandin E2 and F2 alpha by squirrel monkey smooth muscle cells incubated in the presence of TPA and insulin also is greater than the sum of the two effects taken independently.

Acrylamides↗
PubMed1986

A combination of palytoxin with 1-oleoyl-2-acetyl-glycerol (OAG) or insulin or interleukin-1 synergistically stimulates arachidonic acid metabolism, but combinations of 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters with OAG do not.

The combination of palytoxin and 1-oleoyl-2-acetyl-glycerol (OAG) synergistically stimulates production of 6-keto-PGF1 alpha and PGF2 alpha by rat liver cells (the C-9 cell line). In contrast, the combination of 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters (TPA, dihydroteleocidin B, aplysiatoxin, phorbol-12,13-didecanoate) and OAG does not. Production of 6-keto-PGF1 alpha by palytoxin added with recombinant murine interleukin-1 (IL-1) or with insulin is also greater than the sum of the two effects taken independently. Palytoxin and OAG individually stimulate the release of radiolabeled compounds from the rat liver cells pre-labeled with [3H]arachidonic acid and also act synergistically to release labeled metabolites. After separation by h.p.l.c., these materials co-chromatograph with authentic 6-keto-PGF1 alpha and arachidonic acid. The synergistic stimulation by palytoxin and OAG is biphasic; a rapid synergistic production of 6-keto-PGF1 alpha or release of radiolabel from [3H]arachidonic acid prelabeled cells is followed, after approximately 2-4 h, by a prolonged synergistic response.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Binding studies of [3H]lyngbyatoxin A and [3H]debromoaplysiatoxin to the phorbol ester receptor in a mouse epidermal particulate fraction.

The preparation of [3H]lyngbyatoxin A by catalytic triton-proton exchange of lyngbyatoxin A and [3H]debromoaplysiatoxin by tritiation-debromination of aplysiatoxin is described. The dose-response curves for the binding of [3H]lyngbyatoxin A and [3H]debromoaplysiatoxin to a mouse epidermal particulate fraction are virtually the same as the one previously described for [3H]12-O-tetradecanoylphorbol-13-acetate ([3H]TPA). The specific binding of [3H]TPA, [3H]-lyngbyatoxin A and [3H]debromoaplysiatoxin to the mouse epidermal particulate fraction is inhibited to the same degree by unlabeled TPA, teleocidin, lyngbyatoxin A, aplysiatoxin and debromoaplysiatoxin. This study indicates that TPA, lyngbyatoxin A and debromoaplysiatoxin bind to the same high affinity receptor in mouse skin.

Animals↗
PubMed1986

Palytoxin is a non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter in two-stage mouse skin carcinogenesis.

Palytoxon, which is a toxin with a molecular weight of 2681 daltons isolated from a marine coelenterate, is a potent skin irritant. However, it did not induce ornithine decarboxylase in mouse skin, or adhesion of human promyelocytic leukemia cells (HL-60). Moreover, it did not inhibit the specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to a mouse skin particulate fraction or activate protein kinase C isolated from mouse brain in vitro. Since palytoxin showed strong irritation on mouse ear in one short-term screening test for a promoter, it was examined in a two-stage carcinogenesis experiment. The incidence of tumors in a group of mice treated with 7,12-dimethylbenz[a]anthracene plus palytoxin was 62.5% in week 25. These tumors were identified histologically as seven papillomas and one carcinoma. This paper reports the potent tumor-promoting activity of palytoxin, which is classified as a non-TPA-type tumor promoter.

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

Berberine sulfate inhibits tumor-promoting activity of teleocidin in two-stage carcinogenesis on mouse skin.

Berberine sulfate, an isoquinoline alkaloid isolated from Hydrastis canadensis L., inhibited the effects of the tumor promoters 12-O-tetradecanoylphorbol-13-acetate and teleocidin, such as increased 32Pi-incorporation into phospholipids of cell membrane and hexose transport. Berberine sulfate also markedly suppressed the promoting effect of teleocidin on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene.

3-O-Methylglucose↗
PubMed1986

[The actions of TPA-type as well as non-TPA type tumor promoters and their mechanism(s) in tumor promotion].

Ten new tumor promoters which are structurally different from TPA but of similar biological activity were found. Based on their binding to the phorbol ester receptors of cell membranes, these new tumor promoters were classified as TPA-type tumor promoters, teleocidin and aplysiatoxin, which like TPA, activated protein kinase C in vitro, whereas two non-TPA-type tumor promoters, palytoxin and thapsigargin did not induce ODC activity in mouse skin, adhesion of HL-60 cells or activation of protein kinase C, but did show tumor-promoting activity in a two-stage carcinogenesis experiment. Although these two types of tumor promoter exert their tumor-promoting activities through different pathways, production of prostaglandin E2 by rat macrophages was induced by both the TPA-type and non-TPA-type promoters. Therefore, stimulation of arachidonic acid metabolism is suggested to be one of the important biological activities for tumor promotion.

Acrylamides↗
PubMed1986

Glycyrrhetic acid inhibits tumor-promoting activity of teleocidin and 12-O-tetradecanoylphorbol-13-acetate in two-stage mouse skin carcinogenesis.

Glycyrrhetic acid suppressed tumor promoter-induced effects in vitro, such as stimulation of 32Pi-incorporation into phospholipids of cultured cells and down-regulation of the epidermal growth factor receptor. Glycyrrhetic acid inhibited the promoting activity of both 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA). The percentage of tumor-bearing mice in the group treated with DMBA plus teleocidin was 88% at week 18, whereas that in the group treated with DMBA plus teleocidin and glycyrrhetic acid (10 mumol/painting) was 6%. Similarly, the percentage of tumor-bearing mice of the group treated with DMBA plus TPA was 97% at week 20, whereas that of the group treated with DMBA plus TPA and glycyrrhetic acid was 40%. Therefore, glycyrrhetic acid was proved to inhibit the activity of two different tumor promoters, teleocidin and TPA, in mouse skin.

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

Mouse 3T3-L1 cell variants unable to respond to mitogenic stimulation of dihydroteleocidin B: genetic evidence for the synergism of tumor promoters with growth factors.

Dihydroteleocidin B, an indole alkaloid tumor promoter, stimulates confluent, quiescent mouse 3T3-L1 fibroblasts to initiate DNA synthesis and undergo cell division. Using a mitotic shakeoff technique, we have isolated 12 clones of genetic variants which are unable to respond to the mitogenic stimulation of dihydroteleocidin B from a total of 12 million cells. Biochemical characterization of these nonresponsive variants to dihydroteleocidin B revealed that there is no change in the ability to bind [3H]phorbol dibutyrate, the activity of protein kinase C, and the turnover of phosphatidylinositol. The evidence indicates that nonresponsiveness to dihydroteleocidin B is caused by several different lesions, including defects in receptors for insulin or epidermal growth factor and in the postreceptor mechanisms. The evidence also suggests that mitogenic signal transfer via the epidermal growth factor receptor system appears to share a common step with dihydroteleocidin B whereas the signal transfer for insulin seems separate from these. These results suggest that phosphatidylinositol turnover followed by protein kinase C activation alone is not sufficient for mitogenic stimulation and that the coordination of the protein kinase C system with the receptor systems for growth factors may be necessary for "full" mitogenic response.

Animals↗
PubMed1986

Des-O-methylolivoretin C is a new member of the teleocidin class of tumor promoters.

Des-O-methylolivoretin C, a demethylated form of olivoretin C, is a naturally occurring compound in Streptomyces mediocidicus and Streptoverticillium olivoreticuli. Des-O-methylolivoretin C is a regioisomer of teleocidin B, which has the same activity as teleocidin. The tumor-promoting activity of des-O-methylolivoretin C was studied in a two-stage carcinogenesis experiment on mouse skin in comparison with that of teleocidin. Treatments with 7,12-dimethylbenz[a]anthracene (DMBA) plus des-O-methylolivoretin C and DMBA plus teleocidin induced tumors in 63.3% and 84.6% of the mice, respectively, in week 30. The difference in the tumor-promoting activities of des-O-methylolivoretin C and teleocidin is presumably related to the regioisomeric difference in the cyclohexene ring.

9,10-Dimethyl-1,2-benzanthracene↗