Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Cancer Biol Ther. 2013 May;14(5):450-7. doi: 10.4161/cbt.24423.
Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G₀/G₁ phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation.
许多研究已经提供了令人信服的证据，证明 hERG 是人类癌症的重要诊断和预后因素，也是抗肿瘤治疗的有用靶点。我们之前的研究还表明，通过 shRNA 干扰敲低 herg 基因表达可抑制神经母细胞瘤细胞在体外和体内的生长。在实验中，研究了一种新型 4-氨基哌啶类似物 ZC88 对 hERG 钾通道的作用，并观察了其在体外和体内的抗肿瘤活性。结果表明，ZC88 可浓度依赖性地阻断在非洲爪蟾卵母细胞中表达的 hERG1 和 hERG1b 通道。ZC88 在几种肿瘤细胞系中表现出显著的增殖抑制活性，hERG 表达较高的肿瘤细胞对 ZC88 更为敏感。在 ZC88 的存在下，肿瘤细胞的有丝分裂进程明显受到抑制，细胞被阻滞在 G₀/G₁ 期。ZC88 在不影响心脏 QT 间期的情况下，在裸鼠中显著抑制肿瘤生长。ZC88 的抗肿瘤作用至少部分与其阻断 hERG 通道有关，这表明 hERG 钾通道在肿瘤细胞增殖中发挥积极作用。
