debromoaplysiatoxin and aplysiatoxin

Topics: Alkaloids; Animals; Cell Adhesion; Cell Aggregation; Cell Transformation, Neoplastic; Enzyme Induction; Humans; Isomerism; Lactones; Lyngbya Toxins; Marine Toxins; Mice; Mollusk Venoms; Neoplasms; Ornithine Decarboxylase; Phorbols; Tetradecanoylphorbol Acetate

Neo-debromoaplysiatoxin C (

Topics: Cyanobacteria; Cytotoxins; Lactones; Lyngbya Toxins; Magnetic Resonance Spectroscopy; Molecular Structure; Potassium Channel Blockers; Protein Kinase C-delta; Seaweed

Topics: Adult; Cohort Studies; Diarrhea; Female; Hawaii; Humans; Lyngbya Toxins; Male; Nausea; Plant Poisoning; Retrospective Studies; Seaweed; Vomiting

The causative toxins of a red alga Gracilaria coronopifolia poisonings in Hawaii, which broke out in succession in September of 1994, were studied. Two major toxins were isolated from both extracts of the two original algal samples which caused separate poisonings. By spectroscopic method, these toxins were shown to be completely identical with aplysiatoxin and debromoaplysiatoxin which have previously been obtained from the sea hare and also from blue green algae. The human symptoms and the amount of these toxins in the original algal samples indicate that aplysiatoxin and debromoaplysiatoxin were the causative agents of the human poisoning incidents. This is the first reported case of the implication of aplysiatoxin and debromoaplysiatoxin in food poisoning. The existence of these toxins in the residue of algae washed in saline was confirmed by HPLC analysis. Furthermore, we observed blue-green algal parasitism on the surface of the toxic G. coronopifolia. Therefore, epiphytic organisms such as blue-green algae might be the true origin of the toxins in G. coronopifolia.

Topics: Carcinogens; Chromatography, High Pressure Liquid; Foodborne Diseases; Hawaii; Lyngbya Toxins; Magnetic Resonance Spectroscopy; Rhodophyta; Seawater; Seaweed

The growth inhibitory effect of tumour promoters on human leukaemia and lung cancer cell lines was examined using the [3-(4,5 dimethylthiazol)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. The four cell lines used were the K562 human leukaemia cell line, its adriamycin (ADM)-resistant subline (K562/ADM), which shows the mdr phenotype, PC-9 (a human lung adenocarcinoma cell line) and its cisplatin (CDDP)-resistant subline (PC-9/CDDP), which does not show the mdr phenotype. Phorbol 12-tetradecanoate-13-acetate (TPA) and the TPA-type tumour promoters, aplysiatoxin and debromoaplysiatoxin, inhibited the growth of the two parental cell lines, K562 and PC-9. The non-TPA-type tumour promoter, okadaic acid, also inhibited the growth of the two parental cell lines in a dose-dependent manner. TPA-type and okadaic acid inhibited the growth of K562/ADM more weakly than that of K562, and showed no growth inhibition in PC-9/CDDP. Anhydrodebromoaplysiatoxin, an inactive derivative of the TPA-type tumour promoter, could suppress the growth of K562 and K562/ADM only at high concentration (more than 50 pM) and it showed similar growth inhibitory effects on the two cell lines. Okadaic acid tetramethyl ether, the inactive form of the non-TPA-type tumour promoter did not inhibit the growth of any of the cell lines. The growth inhibitory effect of these compounds was well correlated with their tumour-promoting activity. A study of the accumulation of okadaic acid revealed that the amount of 3H-okadaic acid in K562/ADM and PC-9/CDDP was similar to that in their parental cells indicating that cross-resistance to this tumour promoter in the drug-resistant cell lines is not due to a difference in the amount of drug accumulated in sensitive and resistant cells. These results suggest the presence of another common mechanism for resistance to ADM and CDDP as well as to TPA- or non-TPA-type tumour promoters.

Topics: Cell Division; Cell Line; Chemical Phenomena; Chemistry; Cisplatin; Cross Reactions; Doxorubicin; Drug Resistance; Ethers, Cyclic; Humans; Leukemia, Myeloid; Lung Neoplasms; Lyngbya Toxins; Okadaic Acid; Tetradecanoylphorbol Acetate

The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), teleocidin and two polyacetate tumor promoters (aplysiatoxin and debromoaplysiatoxin) have been tested for their effect on colony forming efficiency (CFE) of rat tracheal and nasal turbinate epithelial cells. In rat tracheal epithelial (RTE) cells, all four compounds stimulated colony formation by up to 8-fold using picomolar concentrations of aplysiatoxin and teleocidin, whereas TPA and debromoaplysiatoxin were effective in the nanomolar range. In addition, teleocidin and the other promoters increased the number of cells in colonies by 3- to 5-fold resulting in larger colonies, most notably above concentrations that maximally stimulated CFE. In contrast, rat nasal epithelial cells were only marginally stimulated by these tumor promoters to form colonies. The results indicate that there is regional specificity in responses to tumor promoters and RTE cells can act as very sensitive biological indicators of the presence of these three classes of tumor promoters with diverse structure.

Topics: Animals; Cell Division; Colony-Forming Units Assay; Epithelial Cells; Lyngbya Toxins; Nasal Mucosa; Rats; Tetradecanoylphorbol Acetate; Trachea

Two polyacetates, aplysiatoxin and debromoaplysiatoxin, as well as 12-O-tetradecanoylphorbol-13-acetate (TPA), mezerein and teleocidin enhance nitroblue tetrazolium (NBT) reduction in mouse peritoneal macrophages in vitro. The ED50 values for NBT reduction of these 5 TPA-type tumor promoters were 4.2 ng/ml for TPA, 36 ng/ml for mezerein, 0.53 ng/ml for teleocidin, 1.5 ng/ml for aplysiatoxin and 108 ng/ml for debromoaplysiatoxin. The NBT reduction induced by the 5 tumor promoters is inhibited by 2 inhibitors of tumor promotion, retinoic acid and dibromoacetophenone. The possibility that tumor promotion by TPA-type tumor promoters involves similar mechanisms such as superoxide anion radicals release in cell membranes is discussed.

Topics: Acetophenones; Animals; Carcinogens; Cells, Cultured; Diterpenes; Female; Free Radicals; Lyngbya Toxins; Macrophages; Mice; Mice, Inbred Strains; Nitroblue Tetrazolium; Superoxides; Terpenes; Tetradecanoylphorbol Acetate; Tetrazolium Salts; Tretinoin

The effects of aplysiatoxin and debromoaplysiatoxin on the clonal growth rate, cross-linked envelope formation and plasminogen activator secretion of normal human bronchial epithelial cells were studied. Neither compound was mitogenic over a wide range of concentrations (10(-13) to 10(-7)M). Both aplysiatoxin and debromoaplysiatoxin inhibited clonal growth rate with 50% inhibitory concentrations of 3 x 10(-11)M and 10(-10)M, respectively. Both compounds induced the formation of cross-linked envelopes and increased plasminogen activator secretion with equal potency. These data are similar to those previously obtained with 12-O-tetradecanoylphorbol-13-acetate and teleocidin B and suggest that aplysiatoxin and debromoaplysiatoxin induce terminal squamous differentiation in normal human bronchial epithelial cells.

Topics: Bronchi; Cell Division; Cells, Cultured; Epithelium; Humans; Lyngbya Toxins

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

The cellular activities and responses of aplysiatoxin in vitro and in vivo are very similar to those of the diterpene 12-O-tetradecanoylphorbol-13-acetate (TPA) and the indole aklaloids teleocidin B and lyngbyatoxin A. Even though aplysiatoxin, TPA, and teleocidin B are chemically and structurally quite distinct from one another, all three compounds produce essentially the same plethora of biological effects by apparently binding to the same receptor on the cell membrane, the so-called phorboid receptor. Several aplysiatoxin-type compounds have been studied in three test systems for evaluating potential tumor-promoting activity, viz. mouse ear skin for irritation, murine dorsal skin for the induction of ornithine decarboxylase (ODC) activity, and an epidermal particulate fraction of dorsal mouse skin for the inhibition of specific binding of [3H]-TPA. Some of the compounds were tested in a 30-week two-step carcinogenesis experiment in mice. In most cases the results of the 30-week test correlated with the activities of the three preliminary tests. The overall study indicated that the hydroxyl groups on C-3, C-20, and C-30 are essential for maximum activity. Inspection of Dreiding models showed that the oxygens on C-27, C-3, and C-30 of aplysiatoxin are aligned with the oxygens on C-3, C-4, and C-20 of TPA, respectively. The latter oxygens are in functional groups that are known to be necessary for the high activity of TPA.

Topics: Animals; Caenorhabditis elegans Proteins; Carcinogens; Carrier Proteins; Humans; Lyngbya Toxins; Molecular Conformation; Protein Kinase C; Receptors, Drug; Receptors, Immunologic; Structure-Activity Relationship

We have compared the activities of aplysiatoxin and debromoaplysiatoxin, two polyacetate marine algae toxins, with teleocidin, a tumor-promoting indole alkaloid from Streptomyces, with respect to inhibition of specific binding of epidermal growth factor, and phorbol-12,13-dibutyrate to their respective receptors and ability to stimulate the release of radioactivity from cells prelabeled with choline or arachidonic acid. Although these compounds have chemical structures that are quite different from the phorbol esters, both aplysiatoxin and teleocidin are essentially equipotent with the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate in all four assays. The fact that aplysiatoxin and teleocidin inhibit phorbol-12,13-dibutyrate-receptor binding suggests that their biological activities are mediated by binding to the same receptors utilized by the phorbol esters. Debromoaplysiatoxin, a debrominated form of aplysiatoxin, is about 10-fold weaker than aplysiatoxin in inhibiting epidermal growth factor and phorbol-12,13-dibutyrate-receptor binding, but is equipotent with aplysiatoxin in stimulating the release of lipid metabolites from the prelabeled cells. The results are discussed in terms of possible heterogeneity of cellular receptors for this group of compounds.

Topics: Alkaloids; Animals; Caenorhabditis elegans Proteins; Carcinogens; Carrier Proteins; Cell Line; Epidermal Growth Factor; ErbB Receptors; Kinetics; Lactones; Lyngbya Toxins; Marine Toxins; Mice; Mollusk Venoms; Phorbols; Phospholipids; Protein Kinase C; Rats; Receptors, Cell Surface; Receptors, Drug; Tetradecanoylphorbol Acetate

A variety of tumor promoters such as the phorbol esters were found to be capable of inducing the viral cycle in cell lines latently infected with Epstein-Barr virus (EBV). We tested two classes of new tumor promoters; indole alkaloids and polyacetates, for their ability to induce the synthesis of the Epstein-Barr virus determined early antigen (EA) complex. Teleocidin and lyngbyatoxin A are indole alkaloids. Aplysiatoxin and debromoaplysiatoxin are polyacetates. Of these four tumor promoters all but debromoaplysiatoxin induced the synthesis of the EA complex. However, in combination with 3 mM n-butyrate, all four induced EA synthesis. The potent tumor promoters teleocidin, lyngbyatoxin A and aplysiatoxin induced maximal synthesis of EA at the concentration of 5 to 10 ng/ml, whereas the weak tumor promoter debromoaplysiatoxin required a concentration of 250 ng/ml to achieve maximal induction. Phorbol esters induce quick morphological changes and aggregation of human blood lymphocytes. The latter phenomenon has been interpreted as the expression of a "cell binding phenotype" (Patarroyo et al., in press). We showed that all four promoters induced aggregation of human lymphocytes at similar concentrations. The induction seemed to be a common effect which could be induced by both strong and weak tumor promoters.

Topics: Alkaloids; Antigens, Viral; Caenorhabditis elegans Proteins; Carcinogens; Carrier Proteins; Cell Aggregation; Herpesvirus 4, Human; Humans; In Vitro Techniques; Lactones; Lymphocytes; Lyngbya Toxins; Marine Toxins; Phorbol Esters; Protein Kinase C; Receptors, Cell Surface; Receptors, Drug; Virus Activation

Aplysiatoxin and debromoaplysiatoxin, which are isolated from the seaweed, Lyngbya gracilis, differ in their chemical structure only by the presence or absence of a bromine residue in the hydrophilic region. The function and the structure-activity relation of the hydrophilic region are not known. Aplysiatoxin increased malignant transformation, stimulated DNA synthesis, and inhibited the binding of phorbol-12,13-dibutyrate and epidermal growth factor to cell receptors. Debromoaplysiatoxin inhibited the binding of these two substances as strongly as aplysiatoxin but did not increase malignant transformation or stimulate DNA synthesis. These results indicate that a slight change in the chemical structure of the hydrophilic region of aplysiatoxin affects its abilities to increase cell transformation and stimulate DNA synthesis and that the abilities of the tumor promoters to inhibit the binding of phorbol-12,13-dibutyrate and epidermal growth factor are dissociable from their abilities to increase cell transformation and stimulate DNA synthesis under some circumstances.

Topics: Animals; Caenorhabditis elegans Proteins; Carcinogens; Carrier Proteins; Cell Line; Cell Transformation, Neoplastic; Chemical Phenomena; Chemistry; DNA; Epidermal Growth Factor; ErbB Receptors; Lactones; Lyngbya Toxins; Mice; Phorbol 12,13-Dibutyrate; Phorbol Esters; Protein Kinase C; Receptors, Cell Surface; Receptors, Drug; Structure-Activity Relationship

Previous studies showed that the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and several structurally related tumor-promoting compounds stimulate lymphocytes to produce immune interferon (IFN-gamma) and interleukin 2 (IL-2). This study shows that three compounds structurally unrelated to TPA, previously shown to mimic TPA in some other biological activities, are similar to TPA in stimulating IFN-gamma and Il-2 production in cultures of human peripheral blood lymphocytes. The production of another lymphokine, termed lymphotoxin (LT), was also enhanced by TPA and the other three compounds examined. Maximal enhancement of lymphokine production was observed in cultures costimulated with TPA or one of the other tested compounds and phytohemagglutinin (PHA). TPA was separated from IFN-gamma during a multistep purification procedure.

Topics: Alkaloids; Animals; Humans; Interferon Inducers; Interferon-gamma; Interleukin-2; Lactones; Lymphocyte Activation; Lymphotoxin-alpha; Lyngbya Toxins; Marine Toxins; Mice; Phytohemagglutinins; Tetradecanoylphorbol Acetate

Three potent tumor promoters of different classes, 12-O-tetradecanoylphorbol-13-acetate, dihydroteleocidin B, and aplysiatoxin, and two moderate tumor promoters, mezerein and debromoaplysiatoxin, enhanced the frequency of appearance of cadmium-resistant Chinese hamster lung cells when the cells were exposed to cytotoxic levels of CdCl2. With these compounds, the activity to induce cadmium-resistant cells correlated well with the potency of tumor-promoting activity. Cadmium resistance, which persisted after removal of the tumor promoters, was associated with the overproduction of metallothionein I messenger RNA. The amplified metallothionein I genes were shown by Southern blotting experiments. The relevance of the gene amplification caused by tumor promoters is discussed in relation to cancer development and progression.

Topics: Alkaloids; Animals; Cadmium; Carcinogens; Cell Line; Cricetinae; Cricetulus; Diterpenes; Gene Amplification; Genes; Lactones; Lung; Lyngbya Toxins; Metallothionein; Mollusk Venoms; Phorbol Esters; Terpenes; Tetradecanoylphorbol Acetate

Aplysiatoxin is a new class of potent tumor promoter and debromoaplysiatoxin may be a weak promoter. Aplysiatoxin and debromoaplysiatoxin showed the same potency on irritation of mouse ear and induction of ornithine decarboxylase activity on mouse skin, but debromoaplysiatoxin was much weaker than aplysiatoxin in induction of adhesion of HL-60 cells.

Topics: Animals; Carcinogens; Cell Adhesion; Cell Aggregation; Cell Line; Enzyme Induction; Lactones; Lyngbya Toxins; Marine Toxins; Mice; Mollusk Venoms; Neoplasms, Experimental; Ornithine Decarboxylase; Skin; Structure-Activity Relationship