Zhao Wei, Feng Shasha, Wang Jian, Zhang Zhenshuai, Chen Lu, Jiang Li, Li Ming, Wang Tianxiao
School of Pharmacy, Henan University, Kaifeng, Henan, China.
Front Pharmacol. 2024 May 17;15:1404532. doi: 10.3389/fphar.2024.1404532. eCollection 2024.
Cancer targeted therapy is essential to minimize damage to normal cells and improve treatment outcomes. The elevated activity of Cystathionine beta-synthase (CBS), an enzyme responsible for producing endogenous hydrogen sulfide (HS), plays a significant role in promoting tumor growth, invasiveness, and metastatic potential. Consequently, the selective inhibition of CBS could represent a promising therapeutic strategy for cancer. Currently, there is much interest in combining paclitaxel with other drugs for cancer treatment. This study aimed to investigate the efficacy of combining benserazide, a CBS inhibitor, with paclitaxel in treating tumors. Firstly, we demonstrated CBS is indeed involved in the progression of multiple cancers. Then it was observed that the total binding free energy between the protein and the small molecule is -98.241 kJ/mol. The release of HS in the group treated with 100 μM benserazide was reduced by approximately 90% compared to the negative control, and the thermal denaturation curve of the complex protein shifted to the right, suggesting that benserazide binds to and blocks the CBS protein. Next, it was found that compared to paclitaxel monotherapy, the combination of benserazide with paclitaxel demonstrated stronger antitumor activity in KYSE450, A549, and HCT8 cells, accompanied by reduced cell viability, cell migration and invasion, as well as diminished angiogenic and lymphangiogenic capabilities. studies showed that the combined administration of benserazide and paclitaxel significantly reduced the volume and weight of axillary lymph nodes in comparison to the control group and single administration group. Further mechanistic studies revealed that the combination of benserazide and paclitaxel significantly suppressed the S-sulfhydration of SIRT1 protein, thereby inhibiting the expression of SIRT1 protein and activating SIRT1 downstream Notch1/Hes1 signaling pathway in KYSE450, A549, and HCT8 cells. Meanwhile, we observed that benserazide combined with paclitaxel induced a more significant downregulation of HIF-1α, VEGF-A, VEGF-C, and VEGF-D proteins expression levels in KYSE450, A549, and HCT8 cells compared to paclitaxel alone. These findings indicated that benserazide enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and down-regulating HIF-1α/VEGF signaling pathway. This study suggests that benserazide may have potential as a chemosensitizer in cancer treatment.
癌症靶向治疗对于将对正常细胞的损害降至最低并改善治疗效果至关重要。胱硫醚β-合酶（CBS）活性升高，该酶负责产生内源性硫化氢（HS），在促进肿瘤生长、侵袭性和转移潜能方面发挥着重要作用。因此，选择性抑制CBS可能是一种有前景的癌症治疗策略。目前，人们对将紫杉醇与其他药物联合用于癌症治疗很感兴趣。本研究旨在探讨CBS抑制剂苄丝肼与紫杉醇联合治疗肿瘤的疗效。首先，我们证明了CBS确实参与了多种癌症的进展。然后观察到蛋白质与小分子之间的总结合自由能为-98.241 kJ/mol。与阴性对照相比，用100μM苄丝肼处理的组中HS的释放减少了约90%，复合蛋白的热变性曲线向右移动，表明苄丝肼与CBS蛋白结合并阻断了它。接下来，发现与紫杉醇单药治疗相比，苄丝肼与紫杉醇联合在KYSE450、A549和HCT8细胞中表现出更强的抗肿瘤活性，同时细胞活力、细胞迁移和侵袭减少，血管生成和淋巴管生成能力也减弱。研究表明，与对照组和单药治疗组相比，苄丝肼和紫杉醇联合给药显著降低了腋窝淋巴结的体积和重量。进一步的机制研究表明，苄丝肼和紫杉醇联合显著抑制了SIRT1蛋白的S-硫醇化，从而抑制了SIRT1蛋白的表达，并激活了KYSE450、A549和HCT8细胞中SIRT1下游的Notch1/Hes1信号通路。同时，我们观察到与单独使用紫杉醇相比，苄丝肼与紫杉醇联合在KYSE450、A549和HCT8细胞中诱导HIF-1α、VEGF-A、VEGF-C和VEGF-D蛋白表达水平更显著地下调。这些发现表明，苄丝肼通过抑制SIRT1的S-硫醇化和下调HIF-1α/VEGF信号通路增强了紫杉醇的抗癌作用。本研究表明，苄丝肼在癌症治疗中可能具有作为化学增敏剂的潜力。
