dihydroteleocidin-b and phorbol-12-13-didecanoate

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

The tumor promoters, 12-O-tetradecanoylphorbol-13-acetate (TPA), phorbol-12,13-didecanoate, teleocidin, and dihydroteleocidin, at nM levels, but not the non-tumor-promoting 4 alpha-phorbol-12,13-didecanoate even at microM concentrations, stimulated arachidonic acid metabolism in cultured rat liver cells. These liver cells synthesize primarily prostaglandin I2 [measured as its nonenzymatic hydrolytic product, 6-keto-prostaglandin F1 alpha (PGF1 alpha)]. The production of 6-keto-PGF1 alpha increased with time of incubation with TPA and was essentially complete in 4 hr. Cycloheximide, at nM levels, blocked the TPA-stimulated 6-keto-PGF1 alpha production in a dose-dependent manner; this inhibition was related to inhibition of protein synthesis. Chelation of Ca2+ by ethyleneglycol-bis(beta-aminoethyl ether)-N,N'-tetraacetic acid, treatment of the cells with the Ca2+ channel blocker, nifedipine, or inhibition of intracellular Ca2+ mobilization by 8-(diethylamine)octyl-3,4, 5-trimethoxybenzoate hydrochloride also inhibited TPA-stimulated 6-keto-PGF1 alpha production. The steroidal antiinflammatory drug, dexamethasone, a potent in vivo inhibitor of tumor promotion, was an inhibitor of 6-keto-PGF1 alpha stimulation by TPA.

Topics: Alkaloids; Animals; Calcium; Carcinogens; Cycloheximide; Dexamethasone; Liver; Lyngbya Toxins; Phorbol Esters; Prostaglandins; Protein Biosynthesis; Rats; Tetradecanoylphorbol Acetate