State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
School of Integrated Chinese and Western Medicine, Anhui University of Traditional Chinese Medicine, Hefei, China.
Br J Pharmacol. 2024 Nov;181(21):4348-4368. doi: 10.1111/bph.16494. Epub 2024 Jul 11.
Colorectal cancer (CRC) ranks second in mortality worldwide and requires effective and affordable remedies. Cyclovirobuxine D (CVB-D) is the main effective component of Huangyangning tablet, an approved traditional patent medicine, which is mainly used for cardiovascular treatment. As a multibioactive natural compound, CVB-D possesses underlying anticancer activities.
Cell viability and clone-forming ability were determined in human CRC lines. Western blot, immunofluorescence assay, transmission electron microscopy and senescence-associated β-galactosidase (SA-β-Gal) staining were utilized to investigate cell autophagy and senescence. The molecular mechanisms were explored by virtual prediction and experimental validation. Patient-derived xenograft (PDX), dextran sulfate sodium salt (DSS), and azomethane (AOM)/DSS mouse models were employed for in vivo studies.
CVB-D inhibited the growth and development of advanced CRC cells / mice by inducing autophagic and senescent activities through the chaperonin containing TCP1 subunit 3 (CCT3)/yes-associated protein (YAP) axis. CVB-D acted as a promising inhibitor of CCT3 by interacting with its ATP site. In PDX tumours, CVB-D showed potential therapeutic effects by targeting CCT3. Treatment with CVB-D alleviated the mouse model of colitis induced by DSS and attenuated AOM/DSS-induced formation of adenomatous polyps by its action on CCT3.
Our study has provided a scientific basis for the suggestion that CVB-D may be recognized as a prospective drug candidate for the therapy of CRC in patients.
结直肠癌（CRC）在全球死亡率中排名第二，需要有效的、负担得起的治疗方法。环维黄杨星 D（CVB-D）是黄杨宁片的主要有效成分，黄杨宁片是一种已批准的传统专利药物，主要用于心血管治疗。作为一种多生物活性天然化合物，CVB-D 具有潜在的抗癌活性。
用人 CRC 细胞系测定细胞活力和克隆形成能力。采用 Western blot、免疫荧光检测、透射电镜和衰老相关β-半乳糖苷酶（SA-β-Gal）染色来研究细胞自噬和衰老。通过虚拟预测和实验验证来探讨分子机制。采用患者来源的异种移植（PDX）、葡聚糖硫酸钠盐（DSS）和偶氮甲烷（AOM）/DSS 小鼠模型进行体内研究。
CVB-D 通过 CCT3/Yes 相关蛋白（YAP）轴诱导自噬和衰老活性，抑制晚期 CRC 细胞/小鼠的生长和发展。CVB-D 通过与 CCT3 的 ATP 结合位点相互作用，作为 CCT3 的一种有前途的抑制剂。在 PDX 肿瘤中，CVB-D 通过靶向 CCT3 显示出潜在的治疗效果。CVB-D 治疗可减轻 DSS 诱导的结肠炎小鼠模型的病情，并通过其对 CCT3 的作用减轻 AOM/DSS 诱导的腺瘤性息肉形成。
我们的研究为 CVB-D 可能被认为是 CRC 患者治疗的潜在候选药物提供了科学依据。
