Phosphatidylinositol 3-kinase (PI3Kα)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells.
Phosphatidylinositol 3-kinase (PI3Kα)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells.
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DOI：
10.18632/oncotarget.20385
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发表时间：
2017-09-29
期刊：
影响因子：
--
通讯作者：
Orditura M
中科院分区：
文献类型：
--
作者：
Morgillo F;Della Corte CM;Diana A;Mauro CD;Ciaramella V;Barra G;Belli V;Franzese E;Bianco R;Maiello E;de Vita F;Ciardiello F;Orditura M
磷脂酰肌醇3-激酶（PI 3 Ks）通路通常在乳腺癌患者中发生改变，但其作用仍不清楚。突变型PI 3 K α选择性抑制剂Taselisib和AKT抑制剂ipatasertib目前正在与紫杉醇或激素疗法联合治疗乳腺癌的临床试验中进行研究。本研究的目的是评估PI 3 K或AKT抑制是否可以防止对化疗的耐药性并增强其疗效。通过MTT（3，（4，5-二甲基噻唑-2）2，5-溴化联苯四唑）和细胞凋亡集落形成试验（流式细胞术分析），在体外评价ipatasertib和他塞利昔布联合长春瑞滨或紫杉醇或艾日布林对人乳腺癌细胞（具有不同的激素受体、HER 2和PI 3 Ka突变表达谱）细胞存活的疗效。我们还通过蛋白质印迹分析研究了联合治疗对下游细胞内信号传导的影响，并通过迁移试验研究了联合治疗对转移特性的影响。最后，我们通过免疫荧光分析了细胞骨架的变化。观察到ipatasertib或taselisib联合抗微管化疗在抗增殖、促凋亡和抗转移作用方面的显著协同作用。联合治疗可完全抑制PI 3 K和MAPK通路下游蛋白的活化，影响Survivin的表达。联合治疗完全打乱了人类乳腺癌细胞的细胞骨架，生存素从细胞质到细胞核的当代离域，从而表明这种组合的潜在机制。靶向PI 3 K可以增强抗微管药物在人乳腺癌细胞中的功效。
The Phosphatidylinositol 3-kinase (PI3Ks) pathway is commonly altereted in breast cancer patients, but its role is still unclear. Taselisib, a mutant PI3Kα selective inhibitor, and ipatasertib, an AKT inhibitor, are currently under investigation in clinical trials in combination with paclitaxel or hormonal therapies in breast cancer. The aim of this study was to evaluate if PI3K or AKT inhibition can prevent resistance to chemotherapy and potentiate its efficacy. The efficacy of combined treatment of ipatasertib and taselisib plus vinorelbine or paclitaxel or eribulin was evaluated in vitro on human breast cancer cells (with different expression profile of hormonal receptors, HER2, and of PI3Ka mutation) on cell survival by using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and colony forming assays on cell apoptosis by flow-cytometry analysis. We also investigated the effect of combined treatment on downstream intracellular signaling, by western blot analysis, and on metastatic properties, by migration assays. Finally, we analyzed changes in cell cytoskeleton by immunofluorescence. A significant synergism of ipatasertib or taselisib plus anti-microtubule chemotherapy in terms of anti-proliferative, pro-apoptotic and anti-metastatic effect was observed. The combined treatment completely inhibited the activation of proteins downstream of PI3K and MAPK pathways and affected the expression of survivin. Combined treatments completely disorganized the cytoskeleton in human breast cancer cells, with contemporary delocalization of survivin from cytoplasm to nucleus, thus suggesting a potential mechanism for this combination. Targeting PI3K may enhance the efficacy of anti-microtubule drugs in human breast cancer cells.
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影响因子：
3.8
作者：
Twelves, Chris;Cortes, Javier;Vahdat, Linda;Olivo, Martin;He, Yi;Kaufman, Peter A.;Awada, Ahmad
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9.2
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作者：
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