A demethylating agent enhances chemosensitivity to vinblastine in a xenograft model of renal cell carcinoma
A demethylating agent enhances chemosensitivity to vinblastine in a xenograft model of renal cell carcinoma
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DOI：
10.3892/ijo.2011.999
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发表时间：
2011-06-01
影响因子：
5.2
通讯作者：
Ueno, Koichi
中科院分区：
文献类型：
--
作者：
Iwata, Hiroki;Sato, Hiromi;Ueno, Koichi
肾细胞癌（RCC）对化疗耐药的部分原因是P-糖蛋白的过度表达。据报道，在肾细胞癌中，启动子区的高甲基化使几个肿瘤抑制基因沉默。我们最近报道，长春碱（VBL）的体外细胞毒性增强预处理与去甲基化剂，5-氮杂-2 '-脱氧胞苷（Aza），在RCC细胞系，Caki-1。在这项研究中，我们研究了Aza和VBL在Caki-1异种移植模型和其他RCC细胞系中的联合作用。在异种移植模型中，与对照组相比，联合治疗组的肿瘤体积和重量显著抑制，并且B1中的P-糖蛋白、Bcl-2和cycll的表达降低。因此，这种联合作用可能是通过细胞内VBL的积累以及细胞凋亡和细胞周期阻滞的增强来介导的。此外，VBL的细胞毒性在体外增强三个RCC细胞系Aza处理。这些结果表明，阿扎胞苷和VBL联合治疗对RCC有效。
Renal cell carcinoma (RCC) is resistant to chemotherapy partly due to the overexpression of the P-glycoprotein. Several tumor suppressor genes have been reported to be silenced by hypermethylation of the promoter region in RCC. We recently reported that the in vitro cytotoxicity of vinblastine (VBL) was enhanced by pre-treatment with the demethylating agent, 5-aza-2'-deoxycytidine (Aza), in the RCC cell line, Caki-1. In this study, we investigated the combined effect of Aza and VBL in a Caki-1 xenograft model and in other RCC cell lines in vitro. In the xenograft model, tumor volume and weight were significantly suppressed in the co-treatment group, compared to the control, and the expressions of P-glycoprotein, Bcl-2 and cycl in B1 were reduced. Thus, this combined effect could be mediated by the accumulation of intracellular VBL and the enhancement of apoptosis and cell cycle arrest. Moreover, the cytotoxicity of VBL was enhanced in vitro in three RCC cell lines by Aza treatment. These findings suggest that the combination treatment with Aza and VBL is effective against RCC.