The cytotoxic effects of mifepristone on tumor cell lines MDA-MB-231, MCF-7 and T47D involve both extrinsic and intrinsic apoptotic pathways

BRUNA F.; MONTT GUEVARA, M.; BONAFEDE, M.; CUELLO, D.; VARGAS ROIG, L.; JAHN, G.; CARÓN, R.

Buenos Aires

Congreso; XXXIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental; 2007

Sociedad Argentina de Farmacología Experimental

In addition to its use as a contraceptive agent, mifepristone (MF) has been used to inhibit the growth of cancer cells. The antiproliferative effect of MF is observed on MCF7 cells overexpressing estrogen (ER) and progesterone receptors (PR), on MDA-MB-231 cells lacking both steroid receptors and on T47D cells expressing receptor levels similar to those of normal cells. Thus, MF seems to produce an antitumor action independently of the binding to nuclear PR. Our main objective was to investigate the mechanisms involved in the cytotoxicity of MF on cell lines of human breast cancer. Thus, we compared the cytotoxic potency of MF on three tumor cell lines and on the non-tumor cell line MCF10A. We studied by western blot the involvement of the intrinsic or extrinsic cascades of apoptosis. Our results show that cells MDA-MB-231 are more resistant and T47D cells are more sensitive to MF, and that MCF7 cells has a middle sensitivity. Moreover, MCF10A cells showed a high resistance to MF, comparable to that of MDA-MB-231 cells. Thus, the absence of PR is related to a minimal effect of MF, while their presence is associated to a higher cytotoxic response, although without linearity. The cytotoxic mechanism of MF involved both the extrinsic and the intrinsic pathways, since it produced cleavage and activation of procaspase 8, the proapoptotic protein Bid and decreased the expression of the antiapoptotic protein BclXL in a dose-dependent fashion. The later result may indicate that both pathways seem to be activated by MF.