The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.
The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.
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DOI：
10.1111/bjh.12498
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发表时间：
2013-10
影响因子：
6.5
通讯作者：
Hsi ED
中科院分区：
文献类型：
--
作者：
Bodo J;Zhao X;Sharma A;Hill BT;Portell CA;Lannutti BJ;Almasan A;Hsi ED
先前，我们发现抑制蛋白激酶Cβ (PKCβ)/AKT通路增加了组蛋白去乙酰化酶抑制剂（HDI）诱导的淋巴瘤细胞凋亡的参与。在本研究中，我们研究了δ异构体特异性磷脂酰肌苷3-激酶（PI3K）抑制剂GS-1101与HDI、panobinostat （LBH589）和亚酰苯胺羟肟酸（SAHA）联合诱导的细胞毒性和细胞死亡机制。HDI、LBH589和GS-1101同时作用于淋巴瘤细胞系、原发性非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）细胞。通过使用不同浓度的LBH589和GS-1101，正式研究了LBH589/GS-1101组合的相互作用。在所有被试细胞系和原代NHL和CLL细胞中，联合治疗对增殖产生协同抑制作用，并显示出协同诱导凋亡的作用。本研究表明，干扰PI3K信号可显著增加hdi介导的恶性造血细胞凋亡，可能通过AKT依赖性或AKT非依赖性机制实现。此外，在PI3K抑制剂处理的细胞中观察到的hdi相关凋亡的增加似乎与细胞外信号调节激酶（ERK）信号通路的破坏有关。本研究为临床检测PI3K抑制剂与HDI的联合使用提供了强有力的依据。
Previously, we showed that inhibition of the protein kinase C β (PKCβ)/AKT pathway augments engagement of the histone deacetylase inhibitor (HDI)-induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform-specific phosphatidylinositide 3-kinase (PI3K) inhibitor, GS-1101, in combination with the HDI, panobinostat (LBH589) and suberoylanilide hydroxamic acid (SAHA). Lymphoma cell lines and primary Non-Hodgkin Lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) cells were simultaneously treated with the HDI, LBH589 and GS-1101. An interaction of the LBH589/GS-1101 combination was formally examined by using various concentrations of LBH589 and GS-1101. Combined treatment resulted in a synergistic inhibition of proliferation and showed synergistic effect on apoptotic induction in all tested cell lines and primary NHL and CLL cells. This study indicates that interference with PI3K signalling dramatically increases HDI-mediated apoptosis in malignant haematopoietic cells, possibly through both AKT-dependent or AKT- independent mechanisms. Moreover, the increase in HDI-related apoptosis observed in PI3K inhibitor-treated cells appears to be related to the disruption of the extracellular signal-regulated kinase (ERK) signalling pathway. This study provides a strong rational for testing the combination of PI3K inhibitors and HDI in the clinic.
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影响因子：
56.9
作者：
XIA, ZG;DICKENS, M;GREENBERG, ME
通讯作者：
GREENBERG, ME
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.8
作者：
Dias, N;Bailly, C
通讯作者：
Bailly, C
DOI：
10.1016/s0169-328x(98)00036-9
发表时间：
1998-05-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Espinos, E;Weber, MJ
通讯作者：
Weber, MJ
影响因子：
4.8
作者：
Nesterov, A;Lu, XJ;Kraft, AS
通讯作者：
Kraft, AS