Antitumor effect of sikokianin C, a selective cystathionine β-synthase inhibitor, against human colon cancer in vitro and in vivo†,RSC Medicinal Chemistry

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Antitumor effect of sikokianin C, a selective cystathionine β-synthase inhibitor, against human colon cancer in vitro and in vivo†
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-11-16 00:00:00 , DOI: 10.1039/c7md00484b
Weining Niu ₁ , Fei Chen ₁ , Jun Wang ₁ , Jing Qian ₁ , Shasha Yan ₁

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Cystathionine β-synthase (CBS) overexpression is related to the proliferation and migration of human colon cancers. Targeted therapy that inhibits CBS has achieved promising effects in colon cancer treatments, but no selective inhibitor of CBS is available. In our previous study, a natural biflavonoid compound, sikokianin C, was identified as a potent and selective inhibitor of CBS. However, the mode of action of this compound and its antitumor efficacy in vivo remain unknown. In the present study, we have demonstrated that sikokianin C selectively inhibits CBS activity in a competitive manner, and the five key residues involved in the binding of sikokianin C to the substrate channel of CBS protein were identified via a combination of molecular docking and site-directed mutagenesis. Additionally, we analyzed the antitumor efficacy of sikokianin C against human colon cancer cells in vitro and in vivo. Sikokianin C greatly suppressed the proliferation of HT29 colon cancer cells with an IC₅₀ value of 1.6 μM, and CBS is the target of sikokianin C in mammalian cells, as evidenced by CBS knockdown analyses. Moreover, sikokianin C induced the apoptosis of HT29 cancer cells in a dose dependent manner. Treating mice with sikokianin C dramatically reduced the tumor volume and the weight of the colon cancer xenograft in vivo. These results indicate that the selective CBS inhibitor sikokianin C can potentially be used for the treatment of colon cancer.

中文翻译：

sikokianin C（一种选择性胱硫醚 β-合酶抑制剂）在体外和体内对人类结肠癌的抗肿瘤作用†

胱硫醚β-合酶（CBS）过度表达与人类结肠癌的增殖和迁移有关。抑制CBS的靶向治疗在结肠癌治疗中取得了良好的效果，但目前还没有选择性的CBS抑制剂。在我们之前的研究中，一种天然双黄酮化合物，sikokianin C，被鉴定为一种有效的、选择性的 CBS 抑制剂。然而，该化合物的作用方式及其体内抗肿瘤功效仍然未知。在本研究中，我们证明了sikokianin C以竞争性方式选择性抑制CBS活性，并通过分子对接和位点结合鉴定了参与sikokianin C与CBS蛋白底物通道结合的五个关键残基。定向诱变。此外，我们还分析了麦草素 C在体外和体内对人结肠癌细胞的抗肿瘤功效。Sikokianin C 极大地抑制了 HT29 结肠癌细胞的增殖，IC ₅₀值为 1.6 μM，并且 CBS 是哺乳动物细胞中 Sikokianin C 的靶标，CBS 敲低分析证明了这一点。此外，sikokianin C 以剂量依赖性方式诱导 HT29 癌细胞凋亡。用sikokianin C治疗小鼠可显着减少体内结肠癌异种移植物的肿瘤体积和重量。这些结果表明选择性 CBS 抑制剂 sikokianin C 有可能用于治疗结肠癌。

更新日期：2017-11-16

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