Recently, we and other groups revealed that aberrant expression of Kv10.1 channel, a voltage-gated potassium ion channel, contributes to a variety of tumorigenesis process.Potent and selective inhibitor of Kv10.1 is urgently needed, both as pharmacological tools for studying the physiological functions of this enigmatic channel and as potential leads for development of anti-tumor drugs. In this study, Procyanidin B1, a natural compound extracted from the grape seed, was identified as a potent, specific inhibitor, which can inhibit the Kv10.1 channel in a concentration-dependent manner (IC50 = 10.38 ± 0.87 μM), but has negligible effects on other potassium channels, including Kir2.1, HERG or KCNQ1. It was demonstrated that Procyanidin B1 directly binds to Kv10.1 channel and inhibits its currents, without increasing intracellular Ca2+. Further, three amino acids, I550, T552, and Q557 in the C-linker domain of Kv10.1 were found critical for forming the binding pocket of Procyanidin B1 with Kv10.1 channel.In addition, Procyanidin B1 inhibits migration and proliferation of liver cancer cells (HuH-7 cells, HepG2 cells) through inhibiting the currents of Kv10.1, but not Kv10.1 negatively expressed cell lines. Next, we assayed the tumor suppressing effect of Procyanidin B1 on cell line-derived xenograft mouse model. Our data showed that 15 mg/kg Procyanidin B1 can significantly suppress the growth of the tumor (HepG2) with an inhibition rate of about 60.25%. Compared with cisplatin, Procyanidin B1 has no any side effect on the normal metabolismof the mice. The present work indicated that Procyanidin B1 is a proming liver cancer anti-tumor drug, and also confirmed that Kv10.1 can serve as a potential, tumor-specific drug target.

中文翻译：

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原花青素B1是Kv10.1通道的新型特异性抑制剂，可抑制肝癌的发展

最近，我们和其他研究小组发现，电压门控钾离子通道Kv10.1通道的异常表达有助于多种肿瘤发生过程。迫切需要有效和选择性的Kv10.1抑制剂，作为研究的药理学工具该神秘通道的生理功能，并可能成为开发抗肿瘤药物的潜在途径。在本研究中，从葡萄籽中提取的天然化合物原花青素B1被确定为有效的特异性抑制剂，可以以浓度依赖的方式抑制Kv10.1通道（IC50 = 10.38±0.87μM），但具有对其他钾离子通道（包括Kir2.1，HERG或KCNQ1）的影响可忽略不计。已证明原花青素B1直接结合Kv10.1通道并抑制其电流，而不会增加细胞内Ca2 +。进一步，发现在Kv10.1的C接头结构域中的三个氨基酸I550，T552和Q557对形成具有Kv10.1通道的原花青素B1的结合口袋至关重要。此外，原花青素B1抑制肝癌细胞的迁移和增殖。 （HuH-7细胞，HepG2细胞）通过抑制Kv10.1的电流，但不抑制Kv10.1阴性表达的细胞系。接下来，我们测定了原花青素B1对源自细胞系的异种移植小鼠模型的肿瘤抑制作用。我们的数据表明，15 mg / kg原花青素B1可以显着抑制肿瘤（HepG2）的生长，抑制率约为60.25％。与顺铂相比，原花青素B1对小鼠的正常代谢没有任何副作用。目前的工作表明原花青素B1是一种新兴的肝癌抗肿瘤药物，并且也证实了Kv10。