https://orcid.org/0000-0001-5794-4975
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Abstract
Purpose
Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition.
Methods
Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings.
Results
By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay.
Conclusion
Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.
Graphical Abstract
Abbreviations
BP, biological process; CI, cinobufotalin injection; Cino, cinobufagin; GO, Gene ontology; Ing, ingredients; IC50, half maximal inhibitory concentration; KD, the equilibrium dissociation constant; Ka, association rate constant; KEGG, Kyoto Encyclopedia of Genes and Genomes; OS, overall survival; P4, cell cycle pathway; SPR, surface plasmon resonance; TCM, traditional Chinese medicine; TACE, transcatheter arterial chemoembolization.
Data Sharing Statement
The data used to support the findings of this study are available from the corresponding author (Ming Zhou) on request.
Ethics Statement
The requirement for ethical review for the use of public database data was specifically exempted by the authorization of the Ethics Committee of Central South University. The animal study was approved by the Institutional Animal Care and Use Committee (IACUC) of central south university (No. KTZXM-202204200002, Changsha, China). The study was conducted in accordance with the local legislation and institutional requirements.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.