Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells.
Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells.
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DOI：
10.4137/cgm.s11124
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Telleria CM
中科院分区：
文献类型：
--
作者：
Wempe SL;Gamarra-Luques CD;Telleria CM
我们先前已经证明抗孕激素和抗糖皮质激素米非司酮抑制卵巢癌细胞的生长。在这项工作中，我们假设米非司酮引起的细胞应激仅限于细胞停滞，并且由于PI3K/Akt生存通路的持续活性而避免了细胞杀伤。为了研究这一途径在米非司酮诱导的生长抑制中的作用，将不同组织亚型和遗传背景的人卵巢癌细胞暴露于存在或不存在PI3K抑制剂LY294002的情况下的米非司酮细胞抑制剂量。卵巢癌细胞中Akt的激活，以其在Ser473上的磷酸化为标志，不被细胞抑制浓度的米非司酮所改变，但被LY294002处理后被阻断。米非司酮/LY294002联合用药，而不是单独用药，通过基因组DNA断裂和caspase-3的裂解，以及伴随而来的抗凋亡蛋白Bcl2和XIAP的下调，证明了联合使用米非司酮和LY294002可以通过凋亡杀死卵巢癌细胞。从药理学的角度来看，当使用中剂量分析算法评估细胞生长抑制时，米非司酮和LY294002之间的相互作用是协同的。米非司酮/LY294004在二维细胞培养中所引起的致命性是在有组织的三维球体中概括的。这项研究表明，米非司酮和LY294002单独使用时会导致细胞生长停滞；但当它们联合使用时，会导致死亡。
We have previously shown that the antiprogestin and 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 as a consequence of the persistent activity 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. The activation of Akt in ovarian cancer cells, as marked by its phosphorylation on Ser473, was not modified by cytostatic concentrations of mifepristone, but it was blocked upon 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 antiapoptotic 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 2-dimensional cell cultures was recapitulated in organized, 3-dimensional spheroids. This study demonstrates that mifepristone and LY294002 when used individually cause cell growth arrest; yet, when combined, they cause lethality.