The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells
The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells
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DOI：
10.1016/j.jocn.2016.10.042
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发表时间：
2017-02-01
影响因子：
2
通讯作者：
Robins, H. Ian
中科院分区：
文献类型：
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作者：
Clark, Paul A.;Gaal, Jordan T.;Robins, H. Ian
最近一项新诊断的胶质母细胞瘤（GBM）的3期研究表明，在联合放疗/TMZ后，替莫唑胺（TMZ）中添加肿瘤治疗野（TTFields）可显著延长生存期和无进展生存期。初步数据表明，甲基化和未甲基化的O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子状态都有好处。然而，迄今为止，尚未有研究来解决TTFields和TMZ的潜在相互作用。因此，使用患者源性GBM干细胞样细胞（GSC），包括表达MGMT（TMZ耐药：12.1和22 GSC）和不表达MGMT（TMZ敏感：33和114 GSC）细胞系，在体外研究了TTFields和TMZ的作用。使用细胞增殖和球体形成测定构建剂量-反应曲线。结果表明，与不表达MGMT（33个GSC：IC 50 = 1.5 μ M; 114个GSC：IC 50 = 5.2 μ M）的细胞系相比，表达MGMT（12.1个GSC：IC 50 = 160 μ M; 22个GSC：IC 50 = 44 μ M）的细胞系的TMZ抗性增加>= 10倍。TTFields在所有试验剂量（50-500 kHz）下均抑制12.1 GSC增殖，最佳频率为200 kHz。在200 kHz下，TTFields以相当的水平抑制两种MGMT GSC亚型的增殖和肿瘤球形成（12.1 GSC：分别为74 +/- 2.9%和38 +/-3.2%; 22 GSC：分别为61 +/- 11%和38 +/-2.6%; 33 GSC：分别为56 +/- 9.5%和60 +/-7.1%; 114 GSC：79 +/- 3.5%和41 +/-4.3%）。TTFields（200 kHz）和TMZ联合使用显示出叠加的抗肿瘤作用，TTFields在两种细胞类型中的疗效相同（即，+/- MGMT表达），对TMZ抗性没有影响。这是首次证明TTFields对癌症干细胞的影响。这些研究的扩展可能具有临床意义。(C)2016爱思唯尔有限公司版权所有
A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22 GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114 GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a >= 10-fold increase in TMZ resistance of MGMT-expressing (12.1 GSCs: IC50 = 160 mu M; 22 GSCs: IC50 = 44 mu M) compared to MGMT non-expressing (33 GSCs: IC50 = 1.5 mu M; 114 GSCs: IC50 = 5.2 mu M) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500 kHz) with an optimal frequency of 200 kHz. At 200 kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1 GSC: 74 +/- 2.9% and 38 +/- 3.2%, respectively; 22 GSC: 61 +/- 11% and 38 +/- 2.6%, respectively; 33 GSC: 56 +/- 9.5% and 60 +/- 7.1%, respectively; 114 GSC: 79 +/- 3.5% and 41 +/- 4.3%, respectively). In combination, TTFields (200 kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., +/- MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications. (C) 2016 Elsevier Ltd. All rights reserved.