HDAC inhibitor valproic acid enhances tumor cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model
HDAC inhibitor valproic acid enhances tumor cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model
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DOI：
10.1002/ijc.24700
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发表时间：
2010-02-01
影响因子：
6.4
通讯作者：
Mulherkar, Rita
中科院分区：
文献类型：
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作者：
Kothari, Vishal;Joshi, Ganesh;Mulherkar, Rita
安全性、有效性和增强的转基因表达是使用任何载体进行基因治疗时的主要关注点。临床上广泛使用的载体之一。试验是腺病毒，它提供了一种安全的方式来传递治疗基因。然而，由于大多数肿瘤细胞表达低的科萨基和腺病毒受体，腺病毒在体内的转导效率差。类似地，转基因表达保持较低，可能是因为在真核细胞中感染后腺病毒基因组的染色质化，这是由组蛋白脱乙酰酶（HDAC）介导的效应。使用携带单纯疱疹胸苷激酶（HSVtk）和GFP基因的重组腺病毒（Ad-HSVtk），我们证明HDAC抑制剂丙戊酸可以引起宿主细胞上CAR表达的增加，从而增强Ad-HSVtk感染性。它还导致转基因（HSVtk和GFP）表达的增加。这反过来又导致更昔洛韦在体外以及在异种移植裸鼠模型中体内治疗后HNSCC细胞的细胞杀伤增加。
Safety, efficacy and enhanced transgene expression are the primary concerns while using any vector for gene therapy. One of the widely used vectors in clinical. trials is adenovirus which provides a safe way to deliver the therapeutic gene. However, adenovirus has poor transduction efficiency in vivo since most tumor cells express low coxsackie and adenovirus receptors. Similarly transgene expression remains low, possibly because of the chromatization of adenoviral genome upon infection in eukaryotic cells, an effect mediated by histone deacetylases (HDACs). Using a recombinant adenovirus (Ad-HSVtk) carrying the herpes simplex thymidine kinase (HSVtk) and GFP genes we demonstrate that HDAC inhibitor valproic acid can bring about an increase in CAR expression on host cells and thereby enhanced Ad-HSVtk infectivity. It also resulted in an increase in transgene (HSVtk and GFP) expression. This, in turn, resulted in increased cell kill of HNSCC cells, following ganciclovir treatment in vitro as well as in vivo in a xenograft nude mouse model.