The cytotoxic effects of mifepristone on tumor cell lines MDA-MB-231, MCF7 and T47D involve both extrinsic and intrinsic apoptotic pathways

BRUNA F; MONTT GUEVARA M; BONAFEDE M.; CUELLO D; VARGAS ROIG LM; JAHN GA; CARON C

Buenos Aires

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

Sociedad Argentina de Farmacología Experimental.

In addition to its use 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 antitumor action independently of de binding to nuclear PR. Our main objective was to investigate the mechanism involved in the cytotoxicity of Mf on cells lines human breast cancer. Thus, we compared the cytotoxic potency of MF in three tumor cell lines and on the non-tumor cell line MCF-10A. We studied by Western Blot the involvement of the intrinsic or extrinsinc cascades of apoptosis. Our results show that cells MDA-MB-231 are more resistant and T47D cells are more 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 citotoxic 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 Bcl xl, in a dose- dependent fashion. The later result may indicate that both pathways seem to be activated by MF.