Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma.
Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma.
复制标题
DOI：
10.1158/1541-7786.mcr-17-0413
复制
发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Persson AI
中科院分区：
文献类型：
--
作者：
Ilkhanizadeh S;Sabelström H;Miroshnikova YA;Frantz A;Zhu W;Idilli A;Lakins JN;Schmidt C;Quigley DA;Fenster T;Yuan E;Trzeciak JR;Saxena S;Lindberg OR;Mouw JK;Burdick JA;Magnitsky S;Berger MS;Phillips JJ;Arosio D;Sun D;Weaver VM;Weiss WA;Persson AI
间质流体压力（IFP）是实体瘤（包括侵袭性原发性脑肿瘤多形性胶质母细胞瘤（GBM））中药物摄取的屏障。目前尚不清楚流体动力学如何影响肿瘤进展以及是否可以作为治疗目标。为了解决这个问题，开发了一种新的基于遥测的方法来测量GBM异种移植物进展期间IFP的变化。抗分泌因子（AF）是一种内源性蛋白质，在动物和患者中显示出抗分泌作用。在这里，AF蛋白的内源性诱导或AF肽的外源性给药降低了IFP并增加了GBM异种移植物中的药物摄取。AF抑制GBM细胞的细胞体积调节，这种作用在体外由钠-钾-氯化物共转运蛋白1（SLC 12 A2/NKCC 1）抑制剂布美他尼表型模拟。结果，AF诱导GBM模型中的细胞凋亡并增加存活率。在体外，AF减少GBM细胞增殖的能力通过布美他尼和NKKC 1敲低进行表型模拟。接下来，评估AF使GBM细胞对烷化剂替莫唑胺（GBM患者的标准护理）敏感的能力。重要的是，AF诱导和替莫唑胺治疗的组合阻断了GBM异种移植物的再生长。因此，AF介导的细胞体积调节抑制代表了增加药物摄取和改善GBM结果的新策略。
Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma multiforme (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays anti-secretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopied in vitro by the sodium-potassium-chloride co-transporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models. In vitro, the ability AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKKC1 knockdown. Next, AF’s ability to sensitize GBM cells to the alkylating agent temozolomide, standard of care in GBM patients, was evaluated. Importantly, combination of AF induction and temozolomide treatment blocked regrowth in GBM xenografts. Thus, AF-mediated inhibition of cell volume regulation represents a novel strategy to increase drug uptake and improve outcome in GBM.