Niu Weining, Chen Fei, Wang Jun, Qian Jing, Yan Shasha
School of Life Sciences , Northwestern Polytechnical University , Xi'an , 710072 , China . Email:
Medchemcomm. 2017 Nov 16;9(1):113-120. doi: 10.1039/c7md00484b. eCollection 2018 Jan 1.
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 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 a combination of molecular docking and site-directed mutagenesis. Additionally, we analyzed the antitumor efficacy of sikokianin C against human colon cancer cells and . Sikokianin C greatly suppressed the proliferation of HT29 colon cancer cells with an IC 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 . These results indicate that the selective CBS inhibitor sikokianin C can potentially be used for the treatment of colon cancer.
胱硫醚β-合酶（CBS）的过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有前景的效果，但目前尚无CBS的选择性抑制剂。在我们之前的研究中，一种天然双黄酮化合物，西科蒽宁C，被鉴定为一种有效且选择性的CBS抑制剂。然而，该化合物的作用模式及其抗肿瘤疗效仍不清楚。在本研究中，我们证明了西科蒽宁C以竞争性方式选择性抑制CBS活性，并通过分子对接和定点诱变相结合的方法确定了西科蒽宁C与CBS蛋白底物通道结合所涉及的五个关键残基。此外，我们分析了西科蒽宁C对人结肠癌细胞的抗肿瘤疗效。西科蒽宁C以1.6μM的IC值极大地抑制了HT29结肠癌细胞的增殖，CBS敲低分析证明CBS是西科蒽宁C在哺乳动物细胞中的靶点。此外，西科蒽宁C以剂量依赖性方式诱导HT29癌细胞凋亡。用西科蒽宁C治疗小鼠可显著降低结肠癌异种移植瘤的体积和重量。这些结果表明，选择性CBS抑制剂西科蒽宁C有可能用于结肠癌的治疗。
