Overcoming temozolomide resistance in glioblastoma via dual inhibition of NAD+ biosynthesis and base excision repair.
Overcoming temozolomide resistance in glioblastoma via dual inhibition of NAD+ biosynthesis and base excision repair.
复制标题
通过双重抑制NAD+生物合成和碱基切除修复，克服胶质母细胞瘤中替莫唑胺的耐药性。
DOI：
10.1158/0008-5472.can-10-3213
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Sobol RW
中科院分区：
文献类型：
--
作者：
Goellner EM;Grimme B;Brown AR;Lin YC;Wang XH;Sugrue KF;Mitchell L;Trivedi RN;Tang JB;Sobol RW
多形性胶质母细胞瘤（GBM）是一种破坏性脑肿瘤，预后不良，中位生存时间短。标准治疗包括放疗和使用 DNA 烷化剂替莫唑胺 (TMZ) 的化疗。然而，由于修复蛋白 O6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 表达升高或错配修复 (MMR) 途径缺陷，大部分肿瘤对 TMZ 诱导的 DNA 损伤 O6-甲基鸟嘌呤 (O6-MeG) 的细胞毒性作用具有抵抗力。尽管大多数 TMZ 诱导的损伤（N7-甲基鸟嘌呤和 N3-甲基腺嘌呤）都是碱基切除修复 (BER) 底物，但这些 DNA 损伤也很容易修复。然而，阻断 BER 可以增强对 TMZ 的反应，因此 BER 通路已成为逆转 TMZ 耐药性的一个有吸引力的目标。我们的实验室最近报告说，抑制 BER 会导致修复中间体的积累，从而通过聚（ADP-核糖）聚合酶的过度激活诱导能量消耗介导的细胞死亡。根据我们的观察，TMZ 通过 BER 抑制诱导的细胞死亡取决于 NAD+ 的可用性，我们假设联合 BER 和 NAD+ 生物合成抑制将比单独的 BER 抑制更大地增加 TMZ 在胶质母细胞瘤细胞系中的功效。重要的是，我们发现 BER 和 NAD+ 生物合成抑制的组合显着使 MGMT 表达升高的神经胶质瘤细胞和 MMR 缺陷的神经胶质瘤细胞变得敏感，这两种基因型通常与 TMZ 耐药相关。这两种相互作用途径（DNA 修复和 NAD+ 生物合成）的双重靶向可能被证明是治疗耐药性和复发性 GBM 患者的有效治疗组合。
Glioblastoma multiforme (GBM) is a devastating brain tumor with poor prognosis and low median survival time. Standard treatment includes radiation and chemotherapy with the DNA alkylating agent temozolomide (TMZ). However, a large percentage of tumors are resistant to the cytotoxic effects of the TMZ-induced DNA lesion O6-methylguanine (O6-MeG) due to elevated expression of the repair protein O6-methylguanine-DNA methyltransferase (MGMT) or a defect in the mismatch repair (MMR) pathway. Although a majority of the TMZ induced lesions (N7-methylguanine and N3-methyladenine) are base excision repair (BER) substrates, these DNA lesions are also readily repaired. However, blocking BER can enhance response to TMZ and therefore the BER pathway has emerged as an attractive target for reversing TMZ resistance. Our lab has recently reported that inhibition of BER leads to the accumulation of repair intermediates that induce energy depletion-mediated cell death via hyperactivation of poly(ADP-ribose) polymerase. Based on our observation that TMZ-induced cell death via BER inhibition is dependent on the availability of NAD+, we have hypothesized that combined BER and NAD+ biosynthesis inhibition will increase TMZ efficacy in glioblastoma cell lines greater than BER inhibition alone. Importantly, we find that the combination of BER and NAD+ biosynthesis inhibition significantly sensitizes glioma cells with elevated expression of MGMT and those deficient in MMR, two genotypes normally associated with TMZ resistance. Dual targeting of these two interacting pathways (DNA repair and NAD+ biosynthesis) may prove to be an effective treatment combination for patients with resistant and recurrent GBM.