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.

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.

• Authors: M Villedieu, M Briand, M Duval, J F Héron, P Gauduchon, L Poulain
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 105 Issue 2 Pg. 373-84 (May 2007) ISSN: 0090-8258 [Print] United States
• PMID: 17276501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-((3-(2,3-dichlorophenoxy)propyl)amino)ethanol
• BCL2L1 protein, human
• CDKN1A protein, human
• Chlorobenzenes
• Cyclin-Dependent Kinase Inhibitor p21
• Ethanolamines
• Proto-Oncogene Proteins c-bcl-2
• bcl-X Protein
• Extracellular Signal-Regulated MAP Kinases
• Cisplatin

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Chlorobenzenes (administration & dosage, pharmacology)
• Cisplatin (administration & dosage)
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
• Drug Synergism
• Enzyme Activation (drug effects)
• Ethanolamines (administration & dosage, pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• G1 Phase (drug effects)
• Humans
• Ovarian Neoplasms (drug therapy, enzymology, metabolism, pathology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis)
• Resting Phase, Cell Cycle (drug effects)
• bcl-X Protein (antagonists & inhibitors, biosynthesis)