Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models
Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models
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DOI：
10.1158/1535-7163.mct-07-0395
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发表时间：
2008-04
影响因子：
5.7
通讯作者：
Y. Sasaki;H. Negishi;M. Idogawa;Hiromu Suzuki;H. Mita;M. Toyota;Y. Shinomura;K. Imai;T. Tokino-T
中科院分区：
文献类型：
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作者：
Y. Sasaki;H. Negishi;M. Idogawa;Hiromu Suzuki;H. Mita;M. Toyota;Y. Shinomura;K. Imai;T. Tokino-T
在各种癌症类型中，野生型p53基因的治疗性替代已被追求为潜在的基因治疗策略;然而，一些癌症模型在体内和体外对p53具有抗性。因此，克服p53介导的细胞凋亡的耐药性是提高p53基因治疗效果的重要途径。组蛋白去乙酰化酶抑制剂是一类新型的化疗药物，能够逆转转化细胞的恶性表型。据报道，一种天然组蛋白去乙酰化酶抑制剂FK 228部分由于上调柯萨奇病毒腺病毒受体表达而增强腺病毒感染。在这项研究中，进行了临床前实验，以建立在未来的临床试验中，腺病毒介导的p53家族基因转移和FK 228预处理相结合的机制原理。FK 228预处理通过增强Ad-p53的转导增强人癌细胞的凋亡。FK 228还诱导p53蛋白的过度乙酰化，并特异性增强p53介导的Noxa表达。此外，FK 228和Ad-p53的组合诱导Bax易位到线粒体。小分子干扰RNA双敲低Bax和Noxa的表达可拮抗Ad-p53和FK 228诱导凋亡的协同作用。在人类癌症异种移植模型中，FK 228显著增加了p53和p63基因治疗的疗效。这些结果为联合p53基因治疗和FK 228预处理治疗癌症提供了强有力的理论基础。[Mol癌症治疗2008;7（4）：779-87]
Therapeutic replacement of the wild-type p53 gene has been pursued as a potential gene therapy strategy in a variety of cancer types; however, some cancer models are resistant to p53 in vivo and in vitro. Therefore, to improve p53 gene therapy, it is important to overcome the resistance to p53-mediated apoptosis. Histone deacetylase inhibitors are a novel class of chemotherapeutic agents that are able to reverse the malignant phenotype of transformed cells. A natural histone deacetylase inhibitor, FK228, is reported to enhance adenovirus infection due in part to the up-regulation of coxsackievirus adenovirus receptor expression. In this study, preclinical experiments were done to establish a mechanistic rationale for the combination of adenovirus-mediated p53 family gene transfer and FK228 pretreatment in future clinical trials. Pretreatment with FK228 enhanced apoptosis in human cancer cells through enhanced transduction of Ad-p53. FK228 also induced hyperacetylation of the p53 protein and specifically enhanced p53-mediated Noxa expression. Additionally, the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria. The double knockdown of Bax and Noxa expression by small interfering RNA antagonized the synergistic effect of Ad-p53 and FK228 on apoptosis induction. In human cancer xenograft models, FK228 significantly increased the therapeutic effectiveness of p53 as well as p63 gene therapy. These results provide a strong rationale for combining p53 gene therapy and FK228 pretreatment in cancer therapy. [Mol Cancer Ther 2008;7(4):779–87]