Valproic acid, a histone deacetylase inhibitor, is an antagonist for oncolytic adenoviral gene therapy
Valproic acid, a histone deacetylase inhibitor, is an antagonist for oncolytic adenoviral gene therapy
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DOI：
10.1016/j.ymthe.2006.07.009
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发表时间：
2006-12-01
影响因子：
12.4
通讯作者：
Rodriguez, Ronald
中科院分区：
文献类型：
--
作者：
Houti, Naseruddin;Chowdhury, Wasim;Rodriguez, Ronald
溶瘤腺病毒优先在肿瘤细胞中复制并裂解肿瘤细胞。然而，由于许多实体瘤中柯萨奇和腺病毒受体（CAR）表达水平较低，它们在癌症基因治疗中的应用变得复杂。组蛋白脱乙酰酶抑制剂 (HDACIs) 显着上调肿瘤细胞中的 CAR 表达，并具有额外的抗肿瘤活性。因此，HDACIs 与溶瘤腺病毒基因治疗相结合有明确的理由。我们提出证据表明HDAC1治疗显着抑制腺病毒复制、病毒爆发和肿瘤细胞杀伤。丙戊酸(VPA)是一种成熟的HDAC1，在病毒生命周期的后期抑制腺病毒复制。我们假设 VPA 诱导细胞周期调节蛋白 p21（WAF1/CIP1）可能是这种活性的部分原因。我们证明 p21(WAF1/CIP1) 的表达单独限制病毒复制并降低不同癌细胞模型中的病毒滴度。我们还证明，VPA 和复制腺病毒相互抑制彼此杀死细胞的能力，与 p21(WAF1/CIP1) 表达无关。这些结果不仅确定了p21(WAF1/CIP1)在腺病毒复制生物学中的重要性，而且还表明VPA(HDAC1)治疗将抑制而不是增强溶瘤腺病毒基因治疗。
Oncolytic adenoviruses preferentially replicate in and lyse tumor cells. However, their application to cancer gene therapy has been complicated by the low levels of coxsackie and adenovirus receptor (CAR) expressed in many solid tumors. Histone deacetylase inhibitors (HDACIs) significantly upregulate CAR expression in tumor cells and have additional antineoplastic activities. Therefore, there is a clear rationale for the combination of HDACIs and oncolytic adenoviral gene therapy. We present evidence that HDACl treatment significantly inhibits adenoviral replication, viral burst, and tumor cell kill. Valproic acid (VPA), a well-established HDACl, inhibits adenoviral replication late in the viral life cycle. We hypothesized that VPA induction of the cell-cycle-regulating protein p21(WAF1/CIP1) may be partly responsible for this activity. We demonstrate that p21(WAF1/CIP1) expression alone limits viral replication and decreases viral titers in different cancer cell models. We also demonstrate that VPA and replicating adenovirus mutually inhibit each other's ability to kill cells, independent of p21(WAF1/CIP1) expression. These results not only identify the importance of p21(WAF1/CIP1) in the biology of adenoviral replication, but also suggest that oncolytic adenoviral gene therapy will be inhibited rather than enhanced by VPA (HDACl) treatment.