[Influence of mifepristone on DNA repair genes and cisplatin sensitivity in human ovarian cancer drug-resistance cells].
OBJECTIVE
To study the changes of DNA repair genes and enhanced anti-tumor effect of cisplatin induced by mifepristone in human ovarian cancer drug resistance cells.


METHODS
The alterations of cisplatin concentration producing 50% inhibition (IC50 ) in the COC1/DDP cell lines were examined by methyl thiazolyl tetrazolium (MTT) assay. RT-PCR and flow cytometry were used to analyze the changes of the mRNA of ERCC1, BRCA1, hMLH1 genes and cell cycle and apoptosis. Subcutaneous implantation of COC1/DDP was established in nude mice and the enhanced anti-tumor effect of cisplatin by mifepristone was observed in vivo.


RESULTS
Cisplatin IC50 values of COC1/DDP cell were decreased from (3.71 +/- 0.38) microg/ml to (3.18 +/- 0.46), (1.95 +/- 0.14), (0.64 +/- 0.18) microg/ml respectively when treated with 2.5, 5.0, 10.0 micromol/L mifepristone. Mifepristone could down-regulate the mRNA levels of ERCC1, BRCA1, hMLH1 genes and enhance G0/G1 phase block effect of cisplatin, and 2.5, 5.0, 10.0 micromol/L mifepristone combined with cisplatin increased rate of cell apoptosis from 0.08% to 5.11%, 9.13% and 12.24% respectively. The percentage of inhibition of xenograft tumor volume in combined treatment group was 70.1%, which was significantly different (P < 0.05).


CONCLUSIONS
By down-regulating ERCC1, BRCA1, hMLH1 genes, blocking G0/G1 phase, and increasing apoptosis rate, mifepristone could enhance anti-tumor effect of cisplatin.
Liu
Guo-Yan
GY
Department of Obstetrics and Gynecology, General Hospital, Tianjin Medical University, Tianjin 300052, China. liuguoyan211@126.com
Qu
Quan-Xin
QX
Mi
Ruo-Ran
RR
Qi
Jing
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology*; D000070957:MutL Protein Homolog 1; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015735:Mifepristone; C071447:ERCC1 protein, human; D004720:Endonucleases; D000070957:MutL Protein Homolog 1; D002945:Cisplatin