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.
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.


CONCLUSIONS
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.
Villedieu
M
M
Groupe 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
Briand
M
M
Duval
M
M
Héron
J F
JF
Gauduchon
P
P
Poulain
L
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
C483320:2-((3-(2,3-dichlorophenoxy)propyl)amino)ethanol; C494811:BCL2L1 protein, human; C493956:CDKN1A protein, human; D002722:Chlorobenzenes; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004983:Ethanolamines; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin