通过组蛋白去乙酰化酶和 PI3K/AKT/mTOR 信号靶向子宫内膜间质肉瘤细胞的作用。

Effects of targeting endometrial stromal sarcoma cells via histone deacetylase and PI3K/AKT/mTOR signaling.

机构信息

Institute of Pathology, Medical University of Graz, Graz, Austria.

Institute of Pathology, Medical University of Graz, Graz, Austria Department of Pathology, Hospital of the Sisters of Charity Linz, Linz, Austria.

出版信息

Anticancer Res. 2014 Jun;34(6):2883-97.

PMID:24922651

Abstract

AIM

Endometrial stromal sarcoma (ESS) is a rare gynecological mesenchymal malignancy with only few therapeutic options. This study aimed to investigate the efficacy of the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA) combined with inhibitors of the phosphoinositid-3-Kinase (PI3K) pathway in ESS therapy.

MATERIALS AND METHODS

The effects of SAHA combined with inhibitor of PI3K (LY294002, LY), mammalian target of rapamycin mTOR (rapamycin), and their combination on cell growth and the PI3K pathway in two ESS cell lines (ESS-1 and MES-SA) and one non-neoplastic cell line HESC, were investigated.

RESULTS

SAHA reduced growth of the three cell lines by inhibiting protein kinase B AKT and mTOR/p70S6K cascade activation. SAHA combined with LY or rapamycin, or both, synergistically reduced p-p70S6K and p-4E-BP1 levels. SAHA combined with LY and rapamycin led to the strongest growth inhibition and slowest growth recovery among the combination treatments.

CONCLUSION

SAHA combined with inhibition of PI3K and mTOR could represent an efficient therapy option for patients with ESS.

摘要

目的

子宫内膜间质肉瘤（ESS）是一种罕见的妇科间充质恶性肿瘤，治疗选择有限。本研究旨在探讨组蛋白去乙酰化酶（HDAC）抑制剂 suberanilohydroxamic acid（SAHA）联合磷酸肌醇-3-激酶（PI3K）通路抑制剂在 ESS 治疗中的疗效。

材料和方法

研究了 SAHA 联合 PI3K 抑制剂（LY294002，LY）、哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂（rapamycin）及其联合用药对两种 ESS 细胞系（ESS-1 和 MES-SA）和一种非肿瘤细胞系 HESC 的细胞生长和 PI3K 通路的影响。

结果

SAHA 通过抑制蛋白激酶 B AKT 和 mTOR/p70S6K 级联激活来抑制三种细胞系的生长。SAHA 联合 LY 或 rapamycin，或两者联合，协同降低 p-p70S6K 和 p-4E-BP1 水平。SAHA 联合 LY 和 rapamycin 导致联合治疗中生长抑制最强，生长恢复最慢。