dihydroteleocidin-b and Cell-Transformation--Neoplastic

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

The indole alkaloid tumor promoter dihydroteleocidin B (DHTB) was shown to reduce the natural killer (NK) cell susceptibility of two established cell lines, U937 and K562. The decrease in NK susceptibility correlated with the induction of differentiation as documented by positive benzidine staining in the erythroleukemia K562 and by antibody-dependent cellular cytotoxicity effector function in the histiocytic lymphoma line U937, respectively. In contrast, DHTB treatment did not alter the NK sensitivity of the NK-resistant B-lymphoblastoid-cell line RPMI 8866. Cold target inhibition experiments suggested that both effector-target recognition and post-recognition steps were affected by DHTB. These results lend further support to the notion that NK susceptibility of a given tumor cell may vary with the stage of differentiation.

Topics: Alkaloids; Binding, Competitive; Carcinogens; Cell Line; Cell Transformation, Neoplastic; Cytotoxicity, Immunologic; Humans; Killer Cells, Natural; Kinetics; Leukemia, Erythroblastic, Acute; Lymphoma, Large B-Cell, Diffuse; Lyngbya Toxins

In order to understand the mechanisms of tumor promotion, the relationship between the early effects induced by promoters and the enhancement of transformation was investigated using transformable, promoter-sensitive mouse clone Balb/3T3 A31-1-1. Emphasis was placed on the measurement of all parameters in the same clonal line under the same conditions. The potentials of various derivatives of phorbol ester, indole alkaloid, and polyacetate for enhancing transformation in 3-methylcholanthrene-initiated cells were, in general, in parallel with their potentials for inhibiting phorbol-12, 13-dibutyrate-binding and for inducing early responses such as the reduction of epidermal growth factor (EGF)-binding to cell surface receptors, the increase in glucose uptake and release of arachidonic acid, and the stimulation of DNA synthesis in cells arrested at G0. There was an exception to this general rule; some agents, such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and debromoaplysiatoxin, showed very strong activities to induce most of the early responses, whereas they showed slight or no activity to enhance cell transformation. The cause of this exception was ascribed to their higher susceptibility to metabolic or physical inactivation. However, we found that the continuous suppression of EGF-binding to cell surface receptors by promoters was well correlated with the enhancement of transformation, without exception. Furthermore, continuous elevation or reduction of the number of EGF receptors by various hormones was associated with the suppression or enhancement of cell transformation. The hypothesis was proposed that a continuous decrease in the number of EGF-receptors on the cell surface, or its underlying mechanisms, plays an important role in the enhancement of transformation. The mechanisms by which activation of protein kinase C leads to the enhancement of transformation were discussed, with emphasis on cytoskeletal alteration.

Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Cells, Cultured; ErbB Receptors; Lyngbya Toxins; Methylcholanthrene; Mice; Phorbol Esters; Receptors, Cell Surface; Tetradecanoylphorbol Acetate

Teleocidin, which was isolated from mycelia of Streptomyces, is a potent tumor promoter in mouse skin. The catalytically hydrogenated compound dihydroteleocidin B markedly enhanced malignant cell transformation induced by 3-methylcholanthrene or ultraviolet radiation. Dihydroteleocidin B was at least 100 times more effective in enhancing transformation than 12-O-tetradecanoyl phorbol-13-acetate, the strongest promoter known until now, whereas both promoters showed equal capacities to induce early membrane effects and DNA synthesis.

Topics: Alkaloids; Animals; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Epidermal Growth Factor; ErbB Receptors; Lyngbya Toxins; Methylcholanthrene; Mice; Receptors, Cell Surface

Teleocidin isolated from Streptomyces mediocidicus, its catalytically hydrogenated compound dihydroteleocidin B, and lyngbyatoxin A isolated from marine blue-green alga Lyngbya majuscula as well as its hydrogenated product, tetrahydrolyngbyatoxin A were tested for their ability to induce differentiation of human promyelocytic leukemia cells (HL-60 cells) in culture. All of these indole alkaloids induced differentiation of HL-60 cells, characterized by increased phagocytosis, increased release of lysozyme, and morphological changes resembling macrophages. The concentrations required for the induction were 1-5 ng/ml, showing similarity to those of 12-O-tetradecanoylphorbol-13-acetate (TPA). Teleocidin, lyngbyatoxin A, and tetrahydrolyngbyatoxin A are suggested to be tumor promoters, like TPA and dihydroteleocidin B. The HL-60 cell system might be useful for screening for environmental tumor promoters.

Topics: Alkaloids; Carcinogens; Cell Transformation, Neoplastic; Dermotoxins; Humans; Leukemia, Myeloid, Acute; Lyngbya Toxins