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Gynecol Oncol. 2007 May;105(2):373-84. Epub 2007 Feb 5.

Anticancer and chemosensitizing effects of 2,3-DCPE in ovarian carcinoma cell lines: link with ERK activation and modulation of p21WAF1/CIP1, Bcl-2 and Bcl-xL expression.

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  • 1Groupe Régional d'Etudes sur le Cancer (EA 1772, Université de Caen Basse-Normandie), Unité Biologie et Thérapies Innovantes des Cancers Localement Agressifs, Centre de Lutte Contre le Cancer François Baclesse, Caen, France. m.villedieu@baclesse.fr

Abstract

OBJECTIVE:

Emergence of chemoresistance in the course of treatments with platinum drugs remains a major hurdle to ovarian carcinoma therapy. We have previously shown that acquisition of cisplatin resistance by OAW42-R ovarian carcinoma cells was associated with the loss of ERK activation in response to cisplatin. To try to sensitize this cell line by restoring ERK activation, we tested a new synthetic compound, 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol (2,3-DCPE), which was described to induce ERK activation and to display anticancer properties.

METHODS:

We treated four ovarian carcinoma cell lines with 2,3-DCPE, alone or combined with cisplatin. We characterized its effects on apoptosis induction and proliferation and correlated them with molecular modulations.

RESULTS:

We showed that 2,3-DCPE induced cell death and ERK phosphorylation in a time- and concentration-dependent manner in OAW42-R cells. 2,3-DCPE-triggered apoptosis was also associated with the inhibition of Bcl-2 expression and, to a less extent, with that of Bcl-xL. Treatment with 2,3-DCPE also elicited a strong G0/G1 cell cycle arrest, accompanied with p21WAF1/CIP1 up-regulation. All of these effects revealed to be irreversible. Moreover, 2,3-DCPE exerted a cytostatic effect on OAW42, IGROV1-R10 and SKOV3 ovarian carcinoma cells, the sensitivity to 2,3-DCPE appearing in particular linked with a low basal level of P-ERK. Finally, we showed that 2,3-DCPE increased the cytotoxic effect of cisplatin in OAW42-R resistant cells.

CONCLUSION:

Our results emphasized the potential interest of 2,3-DCPE, used alone or combined with cisplatin, for ovarian carcinoma treatment. The absence of basal P-ERK may constitute a predictive marker of response to this novel therapy.

PMID:
17276501
[PubMed - indexed for MEDLINE]
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