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Cytokinetic and morphologic differences in ovarian cancer cells treated with ET-18-OCH3 and the DNA-interacting
K Fujiwara1, H Koike, Y Ohishi
1Department of Obstetrics and Gynecology, Kawasaki Medical School, Kurashiki-City, Japan.
Abstract:
New antineoplastic agents with different cytotoxic mechanisms are of interest for their ability to overcome resistance to conventional DNA-interacting agents. Ether lipids are known to be active against ovarian carcinoma both in vitro and in vivo, and the cell membrane is believed to be the target of their antitumor activity. In this study we have investigated the different cytokinetic and morphologic responses of human ovarian carcinoma cells (BG-1) to one of the ether lipids (ET-18-OCH3) and to etoposide. Etoposide induced a significantly greater G2/M block. However, the proportion of the cycling cell fraction decreased significantly in cells treated by ET-18-OCH3 and induction of the hypodiploid traction was strongly correlated with reduction of the cycling cell fraction. On the other hand, the hyperdiploid fraction was found to correlate with reduction of the cycling cell fraction in etoposide treated cells. Despite the significant appearance of the hypodiploid fraction, apoptosis was not observed by DNA-gel assay. Microscopic study showed that the hyperdiploid fraction represented cells with multiple nuclei. These observations support the unique lethal effect of ET-18-OCH3 on ovarian carcinoma cells, distinguishing it from the action of a typical DNA-interacting agent. The membrane-targeted ether lipids deserve consideration for the future chemotherapy of ovarian carcinoma, perhaps in combination with the appropriate DNA-interacting agent. New antineoplastic agents with different cytotoxic mechanisms are of interest not only for their unique inhibitory properties but also for their potential of overcoming resistance to conventional DNA-interacting agents. Ether lipids are known to be active against ovarian carcinoma both in vitro (1, 2, 3) and in vivo (4, 5), and the cell membrane is believed to be the target of their antitumor activity. Etoposide, a DNA-interacting agent, is also active against human ovarian cancer cells in vitro (6) or in clinical trials either as a single agent (7) or in combination with cisplatin (8). We have reported that a cytotoxic dose of one of the ether lipids, ET-18-OCH3, induces a G2/M block in BG-1 human ovarian cancer cells, and also a hypodiploid fraction as shown on DNA analysis by flow cytometry (FCM) (9). The G2/M block was also observed in BG-1 cells following etoposide treatment (6). In the present study, we have investigated the differences in the cytokinetic and morphologic responses of BG-1 cells to ET-18-OCH3 and to etoposide.
Insights
Ether lipids offer a unique mechanism against ovarian cancer by targeting cell membranes, unlike DNA-interacting agents like etoposide. This study reveals ET-18-OCH3
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- New antineoplastic agents are needed to overcome resistance to conventional DNA-interacting agents.
- Ether lipids demonstrate activity against ovarian carcinoma, with the cell membrane as a suspected target.
- Etoposide is a DNA-interacting agent also active against ovarian cancer.
Purpose of the Study:
- To investigate the distinct cytokinetic and morphologic responses of human ovarian carcinoma cells (BG-1) to the ether lipid ET-18-OCH3 and etoposide.
- To differentiate the cellular mechanisms of action between membrane-targeted ether lipids and DNA-interacting agents.
Main Methods:
- Treatment of BG-1 human ovarian carcinoma cells with ET-18-OCH3 and etoposide.
- Analysis of cell cycle progression (cytokinetics) using flow cytometry.
- Morphologic assessment of cellular changes, including multinucleation and apoptosis detection via DNA-gel assay.
Main Results:
- Etoposide induced a significant G2/M cell cycle block.
- ET-18-OCH3 treatment led to a decrease in the cycling cell fraction and induced a hypodiploid fraction, correlated with cell death.
- Etoposide treatment resulted in a hyperdiploid fraction correlated with reduced cycling cells, representing multinucleated cells, not apoptosis.
Conclusions:
- ET-18-OCH3 exhibits a unique lethal effect on ovarian carcinoma cells, distinct from DNA-interacting agents like etoposide.
- The membrane-targeting mechanism of ether lipids warrants consideration for ovarian carcinoma chemotherapy, potentially in combination with DNA-interacting agents.