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Carcinogenesis Advance Access originally published online on August 19, 2004
Carcinogenesis 2004 25(12):2345-2351; doi:10.1093/carcin/bgh262
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Carcinogenesis vol.25 no.12 © Oxford University Press 2004; all rights reserved.

ARTICLE

Inhibition of rat liver regeneration after partial hepatectomy and induction of ERK phosphorylation by Cpd 5, a K vitamin-based anticancer compound

Siddhartha Kar, Meifang Wang, Kathryn S. Rosi1, Craig S. Wilcox1 and Brian I. Carr2

Department of Surgery, Liver Cancer Center, Starzl Transplantation Institute and 1 Department of Chemistry, University of Pittsburgh, E1552 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15260, USA

2 To whom correspondence should be addressed. Tel: +1 412 624 6684; Fax: +1 412 624 6666; Email: carrbi{at}upmc.edu

Thioalkyl K vitamin derivatives, like 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone (Cpd 5), have been shown to inhibit both hepatoma cell growth and DNA synthesis in rat hepatocytes in vitro. We have here examined the tissue distribution, in vivo tolerance and growth inhibitory effects of a single injected dose of Cpd 5 in rats. Cpd 5 administered i.p. was sufficient to cause a 90% inhibition of the peak in DNA synthesis in rat liver 24 h after two-thirds partial hepatectomy (PH). However, DNA synthesis in post-PH, Cpd 5-treated rat livers did occur, but with a delay of 36 h. Dual phosphorylation of ERK2 was induced in rat liver dose-dependently as early as 0.5 h, but gradually returned to almost basal levels by 6 h after Cpd 5 treatment. The MEK1/2 inhibitor PD098059, administered in vivo 1 h prior to Cpd 5 treatment, antagonized both induction of ERK2 phosphorylation and inhibition of DNA synthesis in rat liver. Liver protein lysates post-PH exhibited protein phosphatase activity for phospho-ERK2, which was inhibited by Cpd 5. These results show that induction of ERK2 phosphorylation is likely involved in the mechanism by which Cpd 5 inhibits PH-induced DNA synthesis, probably as a result of its ability to inhibit the activity of ERK phosphatase(s).


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