aplysiatoxin and palytoxin

Topics: Acrylamides; Animals; Carcinogens; Cnidarian Venoms; Cocarcinogenesis; Lyngbya Toxins; Neoplasms, Experimental; Oncogenes; Protein Kinase C

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.

Topics: Acrylamides; Animals; Arachidonic Acid; Arachidonic Acids; Carcinogens; Cnidarian Venoms; Enzyme Activation; Humans; Lyngbya Toxins; Mice; Neoplasms, Experimental; Phorbols; Plant Extracts; Protein Kinase C; Receptors, Cell Surface; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Thapsigargin

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.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acrylamides; Animals; Carcinogens; Cnidarian Venoms; Enzyme Induction; Female; Lyngbya Toxins; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Skin Neoplasms; Tetradecanoylphorbol Acetate

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.

Topics: Acrylamides; Animals; Carcinogens; Cnidarian Venoms; Cycloheximide; Dinoprostone; Lyngbya Toxins; Macrophages; Male; Phorbols; Prostaglandins E; Rats; Rats, Inbred Strains; Tetradecanoylphorbol Acetate

Teleocidin and aplysiatoxin, which are structurally different from 12-O-tetradecanoylphorbol-13-acetate (TPA), were found to be potent tumor promoters in two-step mouse skin carcinogenesis. The class of teleocidin includes dihydroteleocidin B, teleocidin, and lyngbyatoxin A. Teleocidin, which is a mixture of 93% teleocidin A and 7% teleocidin B, was isolated from Streptomyces mediocidicus as a strong skin irritant. Teleocidin A consists of C-14S-teleocidin A and C-14R-teleocidin A. One teleocidin A-isomer corresponds to lyngbyatoxin A, which was isolated from the blue-green alga, Lyngbya majuscula. Teleocidin B has four isomers, C-14, C-17-diastereomers. The two teleocidin A-isomers and three of the teleocidin B-isomers (all but one, which was obtained in too low yield) were shown to be biologically active and also potent tumor promoters. Synthetic analogues (indolactams) of teleocidin were obtained and their structure-activity relations were examined by several biological tests. The finding that only (-)-indolactam-V was active showed that the S, S configuration of native teleocidin was necessary for expression of the activity. The class of aplysiatoxin, which was isolated from the blue-green alga, L. majuscula, includes debromoaplysiatoxin, aplysiatoxin, bromoaplysiatoxin, and oscillatoxin A (nordebromoaplysiatoxin). The former three were potent tumor promoters, while oscillatoxin A was a moderate one. Dibromoaplysiatoxin, which is a chemically brominated derivative of debromoaplysiatoxin, in addition to aplysiatoxin and bromoaplysiatoxin, possessed the same promoting activity as that of oscillatoxin A.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acrylamides; Animals; Carcinogens; Cnidarian Venoms; Humans; Lyngbya Toxins; Stereoisomerism; Structure-Activity Relationship