Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs
Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs
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DOI：
10.1158/1535-7163.mct-16-0176
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发表时间：
2016-11-01
影响因子：
5.7
通讯作者：
Nikolova, Teodora
中科院分区：
文献类型：
--
作者：
Berte, Nancy;Piee-Staffa, Andrea;Nikolova, Teodora
恶性胶质瘤表现出高水平的内在和获得性耐药，预后不良。胶质母细胞瘤的一线和二线治疗药物是烷化剂，包括氯乙基化亚硝基脲（CNU）、洛莫司汀、尼莫司汀、福莫司汀和卡莫司汀。这些药物靶向肿瘤DNA，形成O-6-氯乙基鸟嘌呤加合物和二级DNA链间交联（ICL）。这些交联被认为会转化为DNA双链断裂，从而触发细胞死亡途径。在这里，我们表明，洛莫司汀（CCNU）与中等毒性剂量诱导ICLs在胶质母细胞瘤细胞，抑制DNA复制叉运动，并引发DSB和染色体畸变的形成。由于同源重组（HR）参与了对CNU应答形成的DSB的修复，因此我们阐明了HR的药理学抑制剂是否可能对这些终点产生影响并增强杀伤作用。我们表明，Rad 51抑制剂RI-1和B 02大大改善DSB，染色体变化，以及凋亡和坏死的水平。我们还表明，MRE 11的抑制剂，mirin，它阻止了MRN复合物的形成，从而识别DSB，对这些终点也有敏化作用。在胶质瘤异种移植模型中，Rad 51抑制剂RI-1明显增强CCNU对肿瘤生长的作用。数据表明，HR的药理学抑制，例如通过RI-1，是增强CNU抗癌作用的合理策略。(C)2016年AACR。
Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First-and second-line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNU) lomustine, nimustine, fotemustine, and carmustine. These agents target the tumor DNA, forming O-6-chloroethylguanine adducts and secondary DNA interstrand cross-links (ICL). These cross-links are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement, and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacologic inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes, and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggest that pharmacologic inhibition of HR, for example by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs. (C) 2016 AACR.