Oxidative Stress-Regulated Lentiviral TK/GCV Gene Therapy for Lung Cancer Treatment
Oxidative Stress-Regulated Lentiviral TK/GCV Gene Therapy for Lung Cancer Treatment
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DOI：
10.1158/0008-5472.can-12-1166
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发表时间：
2012-12-01
期刊：
影响因子：
11.2
通讯作者：
Levonen, Anna-Liisa
中科院分区：
文献类型：
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作者：
Leinonen, Hanna M.;Ruotsalainen, Anna-Kaisa;Levonen, Anna-Liisa
核因子红系相关因子2(Nrf2)是一种转录因子，调节对细胞的各种毒性伤害的保护，包括细胞毒性癌症化疗药物。许多肺癌细胞含有Nrf2或其抑制物Keap1的突变，导致Nrf2的永久激活和化疗耐药。在这项研究中，我们试图通过使用表达单纯疱疹病毒胸苷激酶(HSV-TK/GCV)的慢病毒(LV)载体，在抗氧化反应元件(ARE)的调控下，检验这一属性是否可以用于癌症自杀基因治疗。ARE是结合Nrf2的顺式作用增强子序列。在NRF2结构性过表达的人肺腺癌细胞中，发现在基础条件下ARE活性很高。在这种情况下，ARE-HSV-TK比由结构性活性启动子驱动HSV-TK表达的载体更有效。在小鼠肺癌移植瘤模型中，与LV-PGK-TK/GCV相比，LV-Are-TK/GCV自杀基因治疗在缩小肿瘤体积方面是有效的。我们的结论是，Are调控的HSV-TK/GCV治疗为在具有高Are活性的细胞中进行自杀癌基因治疗提供了一种有前景的方法，允许更大程度的针对这些细胞的治疗靶向。巨蟹座；72(23)；6227-35。(C)2012年AACR。
Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells. Cancer Res; 72(23); 6227-35. (C) 2012 AACR.