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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2003

01-03-2003 | Original Article

Growth suppression of a tumorigenic rat liver cell line by the anticancer agent, ET-18-O-CH3, is mediated by inhibition of cytokinesis

Authors: Hye-Kyung Na, Chia-Cheng Chang, James E. Trosko

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2003

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Abstract

Purpose

This study was undertaken to elucidate the potential mechanism of the antitumor activity of ET-18-O-CH3, a synthetic analogue of lysophosphatidyl choline, and a known antitumor agent and specific inhibitor of phosphoinositide phospholipase C (PI-PLC).

Methods

A normal rat liver epithelial "oval" cell line (WB-F344) was neoplastically transformed by the H-ras oncogene (WB-ras2) and treated with a series of ET-18-O-CH3 concentrates for a number of days. Cell growth, morphological "differentiation", cell cycle regulation, karyotypic changes, growth in soft agar (anchorage-independent growth) and the expression of cdk2, cdc2 and ERK genes were studied to determine the effect of ET-18-O-CH3 on these neoplastic cells.

Results

ET-18-O-CH3 at 5 and 10 μg/ml was found to cause an increase in cell size, suppress cell growth, reduce the colony-forming efficiency and inhibit the anchorage-independent growth of the WB-ras2 cells. Significantly, flow-cytometric analysis revealed that while control cells and cells treated with concentrations of ET-18-O-CH3 below 5 μg/ml were diploid, cell populations treated with 5 and 10 μg/ml ET-18-O-CH3 comprised 33–37% diploid cells and over 60% tetraploid cells (4n–8n cycle cells). ET-18-O-CH3 was found to induce aberrant cytokinesis as evidenced by the presence of a high frequency of enlarged cells, which were binucleated or multinucleated and mitotic cells with 4n and 8n numbers of chromosomes. ET-18-O-CH3 was also capable of inhibiting both the expression of cdk2 and cdc2 and the activation of ERK1/2, while no effect was found on the expression of p21 ras.

Conclusions

The effect of ET-18-O-CH3 on neoplastically transformed H-ras rat liver cells has been interpreted as the result of an altered phenotype characterized by an enlarged and flattened cell morphology with ploidy changes caused by inhibition of cytokinesis.
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Metadata
Title
Growth suppression of a tumorigenic rat liver cell line by the anticancer agent, ET-18-O-CH3, is mediated by inhibition of cytokinesis
Authors
Hye-Kyung Na
Chia-Cheng Chang
James E. Trosko
Publication date
01-03-2003
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2003
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-003-0577-0

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