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ToxSci Advance Access published online on September 28, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi342
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 4, 2005
Accepted September 23, 2005

In Vitro Toxicology

Enhancement of Transformed Foci and Induction of Prostaglandins in Balb/c 3T3 Cells by Palytoxin: In Vitro Model Reproduces Carcinogenic Responses in Animal Models Regarding the Inhibitory Effect of Indomethacin and Reversal of Indomethacin's Effect by Exogenous Prostaglandins

Daishiro Miura 1*, Mitsuru Kobayashi 1, Satoko Kakiuchi 1, Yoshinori Kasahara 1, and Shiro Kondo 1

1 Pharmacology and Safety Research Department, Pharmaceutical Development Research Laboratories TEIJIN Pharma Limited 4-3-2, Asahigaoka, Hino, Tokyo 191-8512, Japan

* To whom correspondence should be addressed.
Daishiro Miura, E-mail: d.miura{at}teijin.co.jp


  Abstract

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 PGF2{alpha} concentrations in the culture medium revealed that palytoxin (1.9-3.7 pM for 24 hr) stimulated the production of PG in Balb/c 3T3 cells (the concentration reached 3-4 µM), and treatment with PGE2 or PGF2{alpha} 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 PGF2{alpha}. Interestingly, concomitant treatment with PGE2 or PGF2{alpha} 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.

Keywords: Palytoxin; Prostaglandin; Cell transformation assay; Tumor-promoter.
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