Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells.

WEMPE SL; GAMARRA LUQUES C; TELLERIA CM

Washington, DC

Congreso; Annual Meeting of American Association for Cancer Research (AACR); 2013

American Association for Cancer Research (AACR)

We have previously shown that the antiprogestin/antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells. In this work, we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided because of a compensatory activation of the PI3K/Akt survival pathway.To investigate the role of this pathway in mifepristone-induced growth inhibition, human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor, LY294002. Mifepristone-induced growth arrest of ovarian cancer cells was associated with phosphorylation of Akt (Ser473), which was prevented by treatment with LY294002. The combination mifepristone/LY294002, but not the individual drugs, killed ovarian cancer cells via apoptosis, as attested by genomic DNA fragmentation and cleavage of caspase-3, and the concomitant downregulation of anti-apoptotic proteins Bcl-2 and XIAP. From a pharmacological standpoint, when assessing cell growth inhibition using a median-dose analysis algorithm, the interaction between mifepristone and LY294002 was synergistic. The lethality caused by the combination mifepristone/LY294004 in two dimensional cell cultures was recapitulated in organized, tri-dimensional spheroids. This study demonstrates that mifepristone and LY294002, when used individually cause cell growth arrest, yet when combined, they cause lethality. This work further provides proof-of-concept that in combination, targeted cytostatic therapies can be an efficient tool to engage cancer cells in a death program.