Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells
Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells
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DOI：
10.1016/j.canlet.2015.07.013
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发表时间：
2015-10-10
期刊：
影响因子：
9.7
通讯作者：
Rameshwar, Pranela
中科院分区：
文献类型：
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作者：
Munoz, Jessian L.;Walker, Nykia D.;Rameshwar, Pranela
化疗耐药可通过P-糖蛋白(P-gp)发生，P-gp是一种依赖于12-跨膜ATP的药物外排泵。胶质母细胞瘤(GBM)存活率低，对其一线药物替莫唑胺(TMZ)具有均匀的获得性化疗耐药。尽管付出了很多努力，但克服TMZ耐药性仍然是一项挑战。我们报道了通过增加P-gp基因mdr1的转录自主诱导TMZ抗性。本研究探讨了P-gp和TMZ如何相互作用获得抗性。利用阿霉素耐药的DC3F细胞(DC3F/ADX)的实验模型，我们发现P-gp的增加导致了TMZ的耐药。TMZ浓度的增加与钙黄素竞争P-gp，导致DC3F/ADX细胞外排减少。三种不同的P-gp抑制剂通过增加Caspase3的活性，逆转了两种不同的GBM细胞对TMZ的耐药性。分子模拟预测结合部位是P-gp的胞内区域，并确定了TMZ外流的特定氨基酸和能量动力学。综上所述，我们证实了P-gp靶向TMZ，TMZ是GBM中TMZ抗性的关键调节因子。这项研究为TMZ与其他P-gp底物竞争的有效性提供了见解，从而为联合靶向治疗打开了大门。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
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.