Identification of the ENT1 Antagonists Dipyridamole and Dilazep as Amplifiers of Oncolytic Herpes Simplex Virus-1 Replication
Identification of the ENT1 Antagonists Dipyridamole and Dilazep as Amplifiers of Oncolytic Herpes Simplex Virus-1 Replication
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DOI：
10.1158/0008-5472.can-10-0155
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Martuza, Robert L.
中科院分区：
文献类型：
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作者：
Passer, Brent J.;Cheema, Tooba;Martuza, Robert L.
溶瘤性单纯疱疹病毒-1 （oHSV）载体在肿瘤细胞中选择性复制，通过溶瘤杀死肿瘤细胞，同时保留正常细胞。oHSV载体的缺点之一是它们的复制和扩散到邻近的癌细胞有限。在这里，我们报告了高通量化学文库筛选的结果，以鉴定增强oHSV G47 Delta复制的小分子化合物。在筛选的2640种生物活性物质中，鉴定了6种化合物，并随后验证了它们对G47 Delta复制的增强作用。其中两种化合物，双嘧达莫和地拉西普，通过有效和直接抑制平衡核苷转运体-1 （ENT1）来干扰核苷酸代谢。双嘧达莫和地拉西普促进的复制扩增依赖于HSV核糖核苷酸还原酶大亚基ICP6的突变。我们的研究结果表明，ENT1拮抗剂通过增加细胞核糖核苷活性来增加oHSV在肿瘤细胞中的复制。癌症Res;70 (10);3890 - 5。(c) 2010年aacr。
Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47 Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47 Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity. Cancer Res; 70(10); 3890-5. (C) 2010 AACR.