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首页> 外文期刊>Cancer letters >Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells
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Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells

机译：替替莫唑啉代竞争于p-糖蛋白，并有助于胶质母细胞瘤细胞中的化学抑制剂

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摘要

Chemotherapeutic resistance can occur by P-glycoprotein (P-gp), a 12-transmembrane ATP-dependent drug efflux pump. Glioblastoma (GBM) has poor survival rate and uniformly acquired chemoresistance to its frontline agent, Temozolomide (TMZ). Despite much effort, overcoming TMZ resistance remains a challenge. We reported on autonomous induction of TMZ resistance by increased transcription MDR1, the gene for P-gp. This study investigated how P-gp and TMZ interact to gain resistance. Using an experimental model of Adriamycin-resistant DC3F cells (DC3F/Adx), we showed that increased P-gp caused TMZ resistance. Increasing concentrations of TMZ competed with Calcein for P-gp, resulting in reduced efflux in the DC3F/Adx cells. Three different inhibitors of P-gp reversed the resistance to TMZ in two different GBM cell lines, by increasing active Caspase 3. Molecular modeling predicted the binding sites to be the intracellular region of P-gp and also identified specific amino acids and kinetics of energy for the efflux of TMZ. Taken together, we confirmed P-gp targeting of TMZ, a crucial regulator of TMZ resistance in GBM. This study provides insights on the effectiveness by which TMZ competes with other P-gp substrates, thereby opening the door for combined targeted therapies. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
机译：通过P-糖蛋白（P-GP），12种跨膜ATP依赖性药水泵可能发生化疗抗性。胶质母细胞瘤（GBM）的存活率差，并均匀地获得其前线代理，替莫唑胺（TMZ）的化学化。尽管有很多努力，但克服了TMZ抵抗仍然是一个挑战。通过增加转录MDR1，P-GP基因报道了TMZ抗性的自主诱导。本研究研究了P-GP和TMZ如何相互作用以获得阻力。使用抗亚霉素抗性DC3F细胞的实验模型（DC3F / ADX），我们显示增加的P-GP导致TMZ抗性。增加浓度的TMZ竞争P-GP的Calcein，导致DC3F / ADX细胞中的渗出减少。 P-GP的三种不同抑制剂在两种不同的GBM细胞系中扭转了TMZ的抗性，通过增加活性胱天蛋白酶3.分子模拟预测到P-GP的细胞内区域，并确定了特定的氨基酸和能量动力学对于TMZ的流出。一起服用，我们确认了TMZ的P-GP靶向，GBM中TMZ抗性的关键调节因子。本研究提供了对TMZ与其他P-GP基板竞争的有效性的见解，从而为组合靶向疗法开门。 （c）2015 Elsevier Ireland Ltd.保留所有权利。

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