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).
Conclusion: By down-regulating ERCC1, BRCA1, hMLH1 genes, blocking G0/G1 phase, and increasing apoptosis rate, mifepristone could enhance anti-tumor effect of cisplatin.