The use of histone deacetylase inhibitor FK228 and DNA hypomethylation agent 5-azacytidine in human bladder cancer therapy
The use of histone deacetylase inhibitor FK228 and DNA hypomethylation agent 5-azacytidine in human bladder cancer therapy
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DOI：
10.1002/ijc.22405
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发表时间：
2007-04-15
影响因子：
6.4
通讯作者：
Hsieh, Jer-Tsong
中科院分区：
文献类型：
--
作者：
Karam, Jose A.;Fan, Jinhai;Hsieh, Jer-Tsong
转移性移行细胞癌（TCC）患者的长期无病生存率仍然相当低。需要新的化疗药物来降低TCC的发病率和死亡率。在这项研究中，我们评估了几种表观遗传修饰剂在膀胱癌治疗中的应用。组蛋白去乙酰化酶抑制剂（FK228， TSA）和DNA低甲基化剂（5-氮杂胞苷）采用体外细胞活力、细胞周期分析和western blot等方法检测其作用机制。还设计了药物联合实验，以研究这些药物的任何附加或协同作用。此外，采用两个膀胱癌异种移植模型（一个皮下和一个原位）来评估这些药物在体内的治疗效果。三种药物对5种不同的TCC细胞系表现出不同的生长抑制作用，并呈剂量和时间依赖性。除了阻滞G2/M细胞周期外，FK228在诱导凋亡方面比其他两种单一药物更有效，并且FK228和5-Aza联合使用进一步增强了这种作用。p21的诱导与FK228或TSA密切相关，而与5-Aza无关，5-Aza是通过p53非依赖性途径介导的。与体外结果一致，FK228在皮下和原位异种移植模型中均表现出显著的体内Tcc肿瘤生长抑制作用。FK228是一种有效的TCC体内化疗药物，副作用极小。通过p53非依赖性途径介导的p21水平升高是FK228作用机制的标志。(c) 2007 Wiley-Liss, Inc。
The long-term disease-free survival in patients with metastatic transitional cell carcinoma (TCC) is still considerably low. Novel chemotherapeutic agents are needed to decrease the morbidity and mortality of TCC. In this study, we have evaluated several epigenetic modifiers for their therapeutic application in bladder cancer. Both histone deacetylase inhibitors (FK228, TSA) and DNA hypomethylating agent (5-Azacytidine) were tested using in vitro assays such as cell viability, cell cycle analysis and western blot to determine their mechanisms of action. Drug combination experiments were also designed to study any additive or synergistic effects of these agents. In addition, two bladder cancer xenograft models (one subcutaneous and one orthotopic) were employed to assess the therapeutic efficacy of these agents in vivo. Three agents exhibited various growth inhibitory effects on 5 different TCC cell lines in a dose- and time-dependent manner. In addition to G2/M cell cycle arrest, FK228 is more potent in inducting apoptosis than the two other single agents, and combination of both FK228 and 5-Aza further enhances this effect. p21 induction is closely associated with FK228 or TSA but not 5-Aza, which is mediated via p53-independent pathway. Consistent with in vitro results, FK228 exhibited a significant in vivo growth inhibition of Tcc tumor in both subcutaneous and orthotopic xenograft models. FK228 is a potent chemotherapeutic agent for TCC in vivo with minimal undesirable side effects. The elevated p21 level mediated via p53 independent pathway is a hallmark of FK228 mechanism of action. (c) 2007 Wiley-Liss, Inc.