Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging.
Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging.
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通过荧光共振能量转移成像，PI3K/MTOR和MEK抑制（SAR245409和Pimasertib）组合的协同抗肿瘤作用（SAR245409和Pimasertib）在粘液卵巢癌细胞中。
DOI：
10.18632/oncotarget.8807
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发表时间：
2016-05-17
期刊：
影响因子：
--
通讯作者：
Fujii T
中科院分区：
文献类型：
--
作者：
Inaba K;Oda K;Aoki K;Sone K;Ikeda Y;Miyasaka A;Kashiyama T;Fukuda T;Makii C;Arimoto T;Wada-Hiraike O;Kawana K;Yano T;Osuga Y;Fujii T
本研究的目的是阐明卵巢粘液癌（OMC）细胞中PI 3 K/mTOR和MAPK通路的双重抑制的协同作用，使用荧光共振能量转移（FRET）成像。我们将6种OMC细胞系暴露于PI 3 K/mTOR抑制剂（voxtalisib，SAR 245409）和/或MEK抑制剂（pimasertib），并使用Chou-Talalay方法评价协同效应。然后，通过延时FRET成像计算S6 K（PI 3 K途径）和ERK（MAPK途径）激酶活性，以及它们各自的增殖或细胞毒性作用。pimasertib（30 nM）与SAR 245409联合给药可协同抑制所有6种OMC细胞系的细胞生长（联合指数：0.03-0.5）并诱导细胞凋亡。FRET成像结果表明，ERK抑制诱导的抗增殖和凋亡的剂量依赖性的方式在MCAS和OAW 42细胞。然而，S6 K抑制抑制增殖的阈值方式在两个细胞系中，虽然凋亡仅诱导OAW 42细胞。这些结果表明，组合的PI 3 K/mTOR和MEK抑制在OMC细胞中表现出协同抗肿瘤作用，并且FRET成像可用于分析活细胞中的激酶活性并阐明其细胞抑制和细胞毒性作用。
The aim of this study was to clarify the synergistic effects of dual inhibition of the PI3K/mTOR and MAPK pathways in ovarian mucinous carcinoma (OMC) cells, using fluorescence resonance energy transfer (FRET) imaging. We exposed 6 OMC cell lines to a PI3K/mTOR inhibitor (voxtalisib, SAR245409) and/or a MEK inhibitor (pimasertib), and evaluated synergistic effects using the Chou–Talalay method. Then, S6K (PI3K pathway) and ERK (MAPK pathway) kinase activities, and their individual proliferative or cytotoxic effects were calculated by time-lapse FRET imaging. In combination with SAR245409, pimasertib (30 nM) synergistically inhibited cell growth (combination indexes: 0.03–0.5) and induced apoptosis in all 6 OMC cell lines. FRET-imaging results demonstrated that ERK inhibition induced both anti-proliferation and apoptosis in a dose-dependent manner in both MCAS and OAW42 cells. However, S6K inhibition suppressed proliferation in a threshold manner in both cell lines, although apoptosis was only induced in OAW42 cells. These results demonstrated that combined PI3K/mTOR and MEK inhibition exhibited synergistic antitumor effects in OMC cells and that FRET imaging is useful for analyzing kinase activities in live cells and elucidating their cytostatic and cytotoxic effects.
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