Augmentation of antitumor effects of p53 Gene therapy by combination with HDAC inhibitor
Augmentation of antitumor effects of p53 Gene therapy by combination with HDAC inhibitor
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DOI：
10.4161/cbt.4.4.1620
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发表时间：
2005-02
影响因子：
3.6
通讯作者：
R. Takimoto;J. Kato;T. Terui;K. Takada;G. Kuroiwa;Jing Wu;H. Ohnuma;D. Takahari;M. Kobune;Y. Sato;T. Takayama;T. Matsunaga;Yoshiro Niistu
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作者：
R. Takimoto;J. Kato;T. Terui;K. Takada;G. Kuroiwa;Jing Wu;H. Ohnuma;D. Takahari;M. Kobune;Y. Sato;T. Takayama;T. Matsunaga;Yoshiro Niistu
我们先前已经证明，HDAC抑制剂(HDACi)通过320和373个赖氨酸残基的乙酰化激活p53分子，上调PIG3和NOXA的表达，并诱导表达野生型和伪野生型p53基因的癌细胞凋亡(Terui T.，等人，癌症研究63,8948-8954,2003)。也有报道称，经HDACi治疗后，柯萨奇病毒受体的表达和随后腺病毒在癌细胞中的转染率都得到了提高。本研究进一步探讨携带野生型P53基因的腺病毒载体(Ad-P53)联合丁酸钠(SB)对人胃癌细胞(Kato-III)和人肝癌细胞(Huh7)裸鼠移植瘤的联合治疗作用。我们首先证实了SB处理可增加加藤-III细胞中柯萨奇腺病毒受体的表达，并伴随着转基因(X-GAL)表达的增加。然后，我们将Ad-P53注射到Kato-III和HuH7皮下肿瘤中，并联合腹腔注射SB，发现其对肿瘤的生长抑制作用明显高于单独治疗。在接受这种联合治疗的5只小鼠中，有3只肿瘤完全消退，而单独治疗则没有观察到肿瘤消退。联合治疗的肿瘤比单一治疗的肿瘤显示出更多的TUNEL阳性细胞。此外，联合治疗的肿瘤比单独治疗的肿瘤坏死性改变更明显，这与CD34染色显示的肿瘤血管密度在联合治疗的肿瘤中比单独使用p53基因或SB治疗的肿瘤更差的观察结果是一致的。这一发现进一步支持了这一发现，即BAI-1(脑特异性血管生成抑制因子-1)是一种血管形成抑制因子，在转Ad-P53的Kato-III和Huh7细胞中被SB诱导。因此，Sb被证明是P53基因治疗癌症的有效增强剂。
We have previously shown that the HDAC inhibitors (HDACI) activate the p53 molecule through acetylation of 320 and 373 lysine residues, up-regulate PIG3 and NOXA and induce apoptosis in cancer cells expressing wild and pseudo-wild type p53 genes (Terui T., et al., Cancer Res. 63, 8948-8954, 2003). It has also been reported that expression of the Coxackie edenovirus receptor and subsequent transfection efficiency of the adenovirus in cancer cells were enhanced by HDACI treatment. In this study, we extended these observations to explore the combination effect of adenoviral vector carrying wild type p53 (Ad-p53) gene therapy with a HDACI, sodium butyrate (SB), on xenografted human gastric cancer cells (KATO-III) and hepatocellular carcinoma cells (HuH7) in nude mice. We first confirmed an increased expression of Coxackie Adenovirus receptors with an associated increment of transgene (X-gal) expression by SB treatment in KATO-III cells. We then injected Ad-p53 into subcutaneous tumors of KATO-III and HuH7 combined with intraperitoneal administration of SB and found a significantly higher growth suppressive effect than single treatments of each. Even a complete regression of tumors was observed in three of five mice treated with this combination while with single treatment no tumor regression was observed. Tumors treated with the combination showed higher numbers of TUNEL positive cells than those treated with a single modality. Moreover, necrotic changes were more evident in tumors treated with the combination than separately, a compatible finding to the observation that vascularity revealed by CD34 staining was poorer in tumors treated with the combination than those treated with p53 gene or SB alone. This was further supported by the finding that BAI-1 (brain specific angiogenesis inihibitor-1), an inhibitor of vascularization, was induced by SB treatment in KATO-III and HuH7 cells transfected with Ad-p53. Thus SB was shown to be an efficient potentiator of p53 gene therapy for cancer.