dinoprost and palytoxin

Cell transforming activity of palytoxin, a non-TPA type tumor-promoter, was investigated with the two-stage transformation assay using Balb/c 3T3 cells. Palytoxin showed potent promoting activity; treatment at 1.9 pM or more increased the number of transformed foci after initiation by 3-methylcholanthrene (MCA). Determination of prostaglandin (PG) E2 and PGF(2alpha) concentrations in the culture medium revealed that palytoxin (1.9-3.7 pM for 24 h) stimulated the production of PG in Balb/c 3T3 cells (the concentration reached 3-4 microM), and treatment with PGE2 or PGF(2alpha) itself increased the number of transformed foci of Balb/c 3T3 cells after initiation by MCA. Neither palytoxin nor PGs showed initiating activity. Indomethacin suppressed the promoting activity of palytoxin, but not that of PGE2 and PGF(2alpha). Interestingly, concomitant treatment with PGE2 or PGF(2alpha) in addition to indomethacin markedly reversed the suppressive effect of indomethacin. These findings indicated that the in vitro transformation model could reproduce experiments that have been performed in animal models regarding the inhibitory effect of indomethacin on carcinogenic responses and reversal of indomethacin's effect by exogenous prostaglandin and, therefore, may provide insight into molecular modes of action of palytoxin. In the present study, palytoxin also induced prostaglandin synthesis, and therefore, the Balb/c 3T3 cell model should provide insight into the molecular mechanism by which palytoxin regulates prostaglandin biosynthesis.

Topics: Acrylamides; Animals; BALB 3T3 Cells; Carcinogens; Cell Transformation, Neoplastic; Cnidarian Venoms; Dinoprost; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Antagonism; Drug Combinations; Indomethacin; Methylcholanthrene; Mice

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.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylamides; Animals; Arachidonic Acid; Arachidonic Acids; Carcinogens; Cell Line; Cnidarian Venoms; Diglycerides; Dinoprost; Drug Synergism; Glycerides; Insulin; Interleukin-1; Kinetics; Liver; Phorbols; Prostaglandins F; Rats; Structure-Activity Relationship; Tetradecanoylphorbol Acetate