Repurposing cyclovirobuxine D as a novel inhibitor of colorectal cancer progression via modulating the CCT3/YAP axis

Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusions and Implications 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.