Anti-tumor activity of dual inhibition of phosphatidylinositol 3-kinase and MDM2 against clear cell ovarian carcinoma
Anti-tumor activity of dual inhibition of phosphatidylinositol 3-kinase and MDM2 against clear cell ovarian carcinoma
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DOI：
10.1016/j.ygyno.2019.08.028
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发表时间：
2019-11-01
影响因子：
4.7
通讯作者：
Fujii, Tomoyuki
中科院分区：
文献类型：
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作者：
Makii, Chinami;Ikeda, Yuji;Fujii, Tomoyuki
简介：PI3K信号通路作为透明细胞卵巢癌（CCOC）的分子靶点受到关注。MDM2是PI3K通路中AKT的效应器之一，与p53结合并降解p53。在本研究中，我们旨在阐明PIK3CA和MDM2表达的预后意义，以及双重抑制P13K途径和MDM2的潜在治疗作用。材料和方法：采用芯片技术检测75份CCOC的cDNA表达。用DS-7423 （pan-PI3K和mTOR双抑制剂）和RG7112 （MDM2抑制剂）对CCOC细胞株进行MTT法、western blotting和流式细胞术检测细胞增殖、MDM2相关蛋白表达水平和凋亡情况。DS-7423 （3mg /kg）和/或RG7112 （50mg /kg）每天口服，持续三周，使用肿瘤异种移植物和免疫组织化学方法评估抗肿瘤效果。结果：PIK3CA和MDM2均高表达的肿瘤在71个CC005的表达序列中预后明显差（P= 0.013）。RG7112通过DS-7423和MDM2双重抑制PI3K通路，在4株无TP53突变的CCOC细胞株中显示协同抗增殖作用。与单独使用任何一种药物相比，联合治疗更强地诱导促凋亡蛋白（PUMA和cleaved PARP），并增加亚G1群和凋亡细胞。联合治疗显著降低小鼠肿瘤体积(P
Introduction: PI3K pathway signaling has received attention as a molecular target in clear cell ovarian carcinoma (CCOC). MDM2 is one of the AKT effectors in the PI3K pathway, which binds to and degrades p53. In this study, we aimed to clarify the prognostic significance of PIK3CA and MDM2 expression, and potential therapeutic effect of a dual inhibition of the P13K pathway and MDM2.Materials and methods: cDNA expression was evaluated by using microarray data using 75 samples of CCOC. DS-7423 (dual inhibitor of pan-PI3K and mTOR) and RG7112 (MDM2 inhibitor) were used on CCOC cell lines to evaluate cell proliferation, expression level of MDM2 related proteins, and apoptosis by MTT assay, western blotting, and flow cytometry. DS-7423 (3 mg/kg) and/or RG7112 (50 mg/kg) were orally administrated every day for three weeks, and the anti-tumor effect was evaluated using tumor xenografts, along with immunohistochemistry.Results: Tumors with high expression of both PIK3CA and MDM2 showed significantly worse prognosis in expression array of 71 CC005 (P= 0.013). Dual inhibition of the PI3K pathway by DS-7423 and MDM2 by RG7112 showed synergistic anti-proliferative effect in 4 CCOC cell lines without TP53 mutations. The combination therapy more robustly induced pro-apoptotic proteins (PUMA and cleaved PARP) with increase of sub G1 population and apoptotic cells, compared with either single agent alone. The combination therapy significantly reduced tumor volume in mice (P