CHU Clermont-Ferrand, CHU Estaing, Chirurgie Gynécologique, Clermont-Ferrand, France.
Clermont Université, Université d'Auvergne, ISIT UMR6284, Clermont-Ferrand, France.
Sci Rep. 2017 Feb 20;7:42939. doi: 10.1038/srep42939.
Endometriosis is a common gynecological disorder responsible for infertility and pelvic pain. A complete cure for patients with endometriosis awaits new targets and strategies. Here we show that U0126 (a MEK inhibitor) and MK2206 (an AKT inhibitor) synergistically inhibit cell growth of deep endometriotic stromal cells (DES) grown on polyacrylamide gel substrates (PGS) of varying stiffness (2 or 30 kilopascal [kPa]) or plastic in vitro. No significant differences in cell proliferation were observed among DES, endometrial stromal cells of patients with endometriosis (EES) from the proliferative phase (P), EES-S (secretory phase) and EES-M (menstrual phase) compared to cells grown on a substrate of the same stiffness at both higher (U0126 [30 μM] and MK2206 [9 μM]) and lower (U0126 [15 μM] and MK2206 [4.5 μM]) combined doses. However, cell re-growth of DES after drug discontinuation was higher than that of EES-P and EES-S when cells were grown on rigid substrates at both combined doses. Combination U0126 and MK2206 treatment is more effective than each drug alone in cell growth inhibition of DES. However, further studies are required to investigate the mechanisms underlying high cell survival and proliferation after drug discontinuation for developing target therapies that prevent recurrence.
子宫内膜异位症是一种常见的妇科疾病，可导致不孕和盆腔疼痛。目前仍缺乏根治子宫内膜异位症患者的方法，需要寻找新的治疗靶点和策略。我们发现 U0126（MEK 抑制剂）和 MK2206（AKT 抑制剂）联合应用可协同抑制在不同硬度（2 或 30 千帕斯卡）聚丙稀酰胺凝胶基底或塑料上生长的深部子宫内膜间质细胞（DES）的体外增殖。DES、增殖期子宫内膜间质细胞（EES）、分泌期 EES（EES-S）和月经期 EES（EES-M）与在相同硬度基底上培养的细胞相比，在高浓度（U0126[30μM]和 MK2206[9μM]）和低浓度（U0126[15μM]和 MK2206[4.5μM]）联合用药时，细胞增殖无显著差异。然而，与 EES-P 和 EES-S 相比，DES 在药物停止使用后在刚性基底上的再增殖率更高，无论是在高浓度还是低浓度联合用药时。与单药治疗相比，U0126 和 MK2206 联合用药在抑制 DES 细胞生长方面更有效。然而，为了开发预防疾病复发的靶向治疗方法，还需要进一步研究药物停止使用后细胞高存活率和增殖的机制。
