Cisplatin cytotoxicity is increased by mifepristone in cervical carcinoma: an in vitro and in vivo study.
We investigated the ability of mifepristone, an anti-progestin drug, to modulate the cytotoxic effect of cisplatin in two cervical cancer cell lines and in human xenograft cervical tumors. The effect of cisplatin alone or combined with mifepristone on cellular proliferation was studied with the XTT assay which use a tetrazolium dye {sodium3'-[1-(phenylamino-carbonyl)-3,4-tetrazolium],XTT}. Before and after treatment with mifepristone, the intracellular accumulation of cisplatin in cancer cells and tumors of mice was evaluated by HPLC. The expression of Bcl-2 and Bax genes was also assessed by a reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. In addition, single agents and combination treatment in vivo studies were performed with the xenograft cervical model. Tumor measurements were carried out weekly. Analysis of the data by the isobologram method shows a synergistic antiproliferative effect produced by the combination of mifepristone with cisplatin only in the HeLa cervical cancer cell line but not in CaSki cells. The effect of mifepristone on cytotoxicity of cisplatin could be mediated, at least partially, by an increase of intracellular cisplatin accumulation, but not by changes in Bcl-2/Bax gene relation expression in these cells. In vivo studies showed that the combination of these agents has a significant antitumor activity against HeLa xenograft tumors. Our results suggest that mifepristone can improve the efficacy of the antiproliferative effect of cisplatin in vitro and in vivo. This anti-hormonal drug therapy may be a useful candidate for further evaluation in combination with other antineoplastic drugs in the treatment of cancer, particularly with cisplatin.
Laboratorio de Farmacología, Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), México D.F., Mexico.
Rafael
R
Jurado
Angelica
A
Lopez-Flores
Aaron
A
Alvarez
Patricia
P
García-López
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D015153:Blotting, Western; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D004357:Drug Synergism; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014018:Tissue Distribution; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D006727:Hormone Antagonists; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D015735:Mifepristone; D002945:Cisplatin