Abstract:

Cystathionineβ-synthase (CBS)overexpression is related to the proliferation and migration of human coloncancers. Targeted therapy thatinhibits CBS has achieved promising effectsin colon cancer treatments, butno selective inhibitor of CBS is available. In our previous study,a natural biflavonoid compound,sikokianinC,was identified as a potent and selective inhibitor of CBS. However, the mode of action of this compoundand its antitumor efficacyin vivoremain unknown. In the present study, we have demonstrated thatsikokianin C selectivelyinhibits CBS activity in a competitive manner, and the five key residues involved inthe binding of sikokianin C to the substrate channel ofCBS protein were identified via a combination ofmolecular docking and site-directed mutagenesis. Additionally, we analyzed the antitumor efficacy ofsikokianin C against human colon cancer cellsin vitroandin vivo. Sikokianin C greatly suppressed the proliferationof HT29 colon cancer cells with an IC50value of 1.6μM, and CBS is the target of sikokianin C inmammalian cells, as evidenced by CBS knockdown analyses. Moreover, sikokianin C induced the apoptosisof HT29 cancer cells in a dose dependent manner. Treating mice with sikokianin C dramatically reducedthe tumor volume and the weight of the colon cancer xenograftin vivo. These results indicate that the selectiveCBS inhibitor sikokianin C can potentially be used for the treatment of colon cancer.