Mifepristone inhibits ovarian cancer cell growth in vitro and in vivo.
OBJECTIVE
These studies were designed to determine whether the synthetic steroid mifepristone inhibits ovarian cancer growth in vitro and in vivo and the molecular mechanisms involved.


METHODS
The effect of mifepristone on ovarian cancer cell growth in vitro was studied in ovarian cancer cell lines of different genetic backgrounds (SK-OV-3, Caov-3, OV2008, and IGROV-1). In addition, the growth inhibition capacity of mifepristone on ovarian carcinoma xenografts was tested in nude mice.


RESULTS
Mifepristone inhibited ovarian cancer cell proliferation in a dose- and time-dependent manner. The cytostatic effect of mifepristone was confirmed in a clonogenic survival assay and was not linked to loss of viability. Mifepristone blocked DNA synthesis, arrested the cell cycle at the G(1)-S transition, up-regulated cyclin-dependent kinase (cdk) inhibitors p21(cip1)and p27(kip1), down-regulated transcription factor E2F1, decreased expression of the E2F1-regulated genes cdk1 (cdc2) and cyclin A, and modestly decreased cdk2 and cyclin E levels. The abrupt arrest in cell growth induced by mifepristone correlated with reduced cdk2 activity, increased association of cdk2 with p21(cip1) and p27(kip1), increased nuclear localization of the cdk inhibitors, and reduced nuclear abundance of cdk2 and cyclin E. In vivo, mifepristone significantly delayed the growth of ovarian carcinoma xenografts in a dose-dependent manner and without apparent toxic effects for the animals.


CONCLUSIONS
These preclinical studies show that mifepristone is effective as a single agent in vitro and in vivo, inhibiting the growth of human epithelial ovarian cancer cells. Mifepristone markedly reduces cdk2 activity likely due to increased association of cdk2 with the cdk inhibitors p21(cip1) and p27(kip1) and reduced nuclear cdk2/cyclin E complex availability. Acting as a cytostatic agent, mifepristone promises to be of translational significance in ovarian cancer therapeutics.
Goyeneche
Alicia A
AA
Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, South Dakota 57069, USA.
Carón
Rubén W
RW
Telleria
Carlos M
CM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015735:Mifepristone; D011494:Protein Kinases; C102333:histone H1 kinase