NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells.
NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells.
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DOI：
10.1016/j.ctarc.2021.100340
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发表时间：
2021
影响因子：
--
通讯作者：
Keniry M
中科院分区：
文献类型：
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作者：
Vazquez N;Lopez A;Cuello V;Persans M;Schuenzel E;Innis-Whitehouse W;Keniry M
癌细胞几乎普遍地通过关键信号传导组分和/或表观遗传机制的突变而具有组成型活性磷脂酰肌醇-3激酶（PI 3 K）途径活性。PI 3 K通路抑制剂的分数目前正在调查作为推定的化疗药物。然而，由PI 3 K通路抑制诱导的反馈和干细胞机制可导致治疗功效降低。为了解决治疗障碍，我们检查了JAKi是否会在PI 3 K通路抑制的情况下降低干基因表达以改善治疗功效。我们用NVP-BEZ 235（双重PI 3 K和mTOR抑制剂）与Janus激酶抑制剂JAKi组合靶向胶质母细胞瘤（GBM）和基底样乳腺癌（BBC）细胞系中的PI 3 K通路。我们检查了用NVP-BEZ 235和/或JAKi处理的细胞中的生长、基因表达和凋亡。生长和恢复测定显示，与单独的NVP-BEZ 235处理相比，用NVP-BEZ 235/JAKi双重处理没有显著影响。基因表达和流式细胞仪显示，单和双处理诱导细胞凋亡。在双重NVP-BEZ 235/JAKi处理样品中保留了干细胞基因表达。未来的体内研究可能会进一步了解NVP-BEZ 235/JAKi联合治疗对GBM和BBC的影响。
Cancer cells almost universally harbor constitutively active Phosphatidylinositol-3 Kinase (PI3K) Pathway activity via mutation of key signaling components and/or epigenetic mechanisms. Scores of PI3K Pathway inhibitors are currently under investigation as putative chemotherapeutics. However, feedback and stem cell mechanisms induced by PI3K Pathway inhibition can lead to reduced treatment efficacy. To address therapeutic barriers, we examined whether JAKi would reduce stem gene expression in a setting of PI3K Pathway inhibition in order to improve treatment efficacy. We targeted the PI3K Pathway with NVP-BEZ235 (dual PI3K and mTOR inhibitor) in combination with the Janus Kinase inhibitor JAKi in glioblastoma (GBM) and basal-like breast cancer (BBC) cell lines. We examined growth, gene expression, and apoptosis in cells treated with NVP-BEZ235 and/or JAKi. Growth and recovery assays showed no significant impact of dual treatment with NVP-BEZ235/JAKi compared to NVP-BEZ235 treatment alone. Gene expression and flow cytometry revealed that single and dual treatments induced apoptosis. Stem gene expression was retained in dual NVP-BEZ235/JAKi treatment samples. Future in vivo studies may give further insight into the impact of combined NVP-BEZ235/JAKi treatment in GBM and BBC.