Hypoxia enhances the replication of oncolytic herpes simplex virus in p53- breast cancer cells
Hypoxia enhances the replication of oncolytic herpes simplex virus in p53- breast cancer cells
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DOI：
10.4161/cc.8.14.8934
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发表时间：
2009-07-15
期刊：
影响因子：
4.3
通讯作者：
Britton, Alicia
中科院分区：
文献类型：
--
作者：
Fasullo, Michael;Burch, April D.;Britton, Alicia
低分化癌细胞对常规化疗是难治的。单纯疱疹病毒1型（HSV-1）衍生的溶瘤病毒对治疗是安全的，因为它们缺乏神经毒力基因ICP34.5。含有高MEK活性的癌细胞允许HSV-1衍生的溶瘤病毒R3616。考虑到缺氧增加MEK活性，我们确定了与常氧细胞相比，缺氧MDA-MB-231和MCF-7细胞是否更容许R3616。我们观察到MDA-MB-231低氧细胞中的滴度比常氧细胞高9倍（3.5 × 10 e6 pfu/4 × 10 e5 pfu/ml）;然而，低氧MCF-7细胞没有产生更高的R3616滴度。早期和晚期病毒感染的标志物与该结果一致：（1）在MDA-MB-231细胞中观察到病毒诱导的伴侣富集（VICE）结构域，以及（2）HSV-1糖蛋白C（gC），一种在感染后期产生的蛋白质，在缺氧的MDA-MB-231细胞中积累。因此，溶瘤R3616病毒可以靶向缺氧p53-乳腺癌细胞。
Hypoxic cancer cells are refractory to conventional chemotherapy. Herpes simplex virus type-1 (HSV-1)-derived oncolytic viruses are safe for therapy since they lack the neurovirulence gene ICP34.5. Cancer cells containing high MEK activity are permissive to the HSV-1-derived oncolytic virus, R3616. Considering that hypoxia increases MEK activity, we determined whether hypoxic MDA-MB-231 and MCF-7 cells were more permissive to R3616, compared to normoxic cells. We observed nine-fold higher (3.5 x 10e6 pfu/4 x 10e5 pfu/ml) titers in MDA-MB-231 hypoxic cells compared to normoxic; however, hypoxic MCF-7 cells did not yield higher R3616 titers. Markers for early and late viral infection were consistent with this result: (1) virus-induced chaperone-enriched (VICE) domains were observed in MDA-MB-231 cells, and (2) the HSV-1 glycoprotein C (gC), a protein produced late in infection, accumulated in hypoxic MDA-MB-231 cells. Thus, oncolytic R3616 virus may target hypoxic p53-breast cancer cells.