Abstract
Objective:
Bazhen Decoction (BZD) is a common adjuvant therapy drug for colorectal cancer (CRC), although its anti-tumor mechanism is unknown. This study aims to explore the core components, key targets, and potential mechanisms of BZD treatment for CRC.
Methods:
The Traditional Chinese Medicine Systems Pharmacology (TCMSP) was employed to acquire the BZD's active ingredient and targets. Meanwhile, the Drugbank, Therapeutic Target Database (TTD), DisGeNET, and GeneCards databases were used to retrieve pertinent targets for CRC. The Venn plot was used to obtain intersection targets. Cytoscape software was used to construct an "herb-ingredient-target" network and identify core targets. GO and KEGG pathway enrichment analyses were conducted using R language software. Molecular docking of key ingredients and core targets of drugs was accomplished using PyMol and Autodock Vina software. Cell and animal research confirmed Bazhen Decoction efficacy and mechanism in treating colorectal cancer.
Results:
BZD comprises 173 effective active ingredients. Using four databases, 761 targets related to CRC were identified. The intersection of BZD and CRC yielded 98 targets, which were utilized to construct the "herb-ingredient-target" network. The four key effector components with the most targets were quercetin, kaempferol, licochalcone A, and naringenin. Protein-protein interaction (PPI) analysis revealed that the core targets of BZD in treating CRC were AKT1, MYC, CASP3, ESR1, EGFR, HIF-1A, VEGFR, JUN, INS, and STAT3. The findings from molecular docking suggest that the core ingredient exhibits favorable binding potential with the core target. Furthermore, the GO and KEGG enrichment analysis demonstrates that BZD can modulate multiple signaling pathways related to CRC, like the T cell receptor, PI3K-Akt, apoptosis, P53, and VEGF signaling pathway. In vitro, studies have shown that BZD dose-dependently inhibits colon cancer cell growth and invasion and promotes apoptosis. Animal experiments have shown that BZD treatment can reverse abnormal expression of PI3K, AKT, MYC, EGFR, HIF-1A, VEGFR, JUN, STAT3, CASP3, and TP53 genes. BZD also increases the ratio of CD4+ T cells to CD8+ T cells in the spleen and tumor tissues, boosting IFN-γ expression, essential for anti-tumor immunity. Furthermore, BZD has the potential to downregulate the PD-1 expression on T cell surfaces, indicating its ability to effectively restore T cell function by inhibiting immune checkpoints. The results of HE staining suggest that BZD exhibits favorable safety profiles.
Conclusion:
BZD treats CRC through multiple components, targets, and metabolic pathways. BZD can reverse the abnormal expression of genes such as PI3K, AKT, MYC, EGFR, HIF-1A, VEGFR, JUN, STAT3, CASP3, and TP53, and suppresses the progression of colorectal cancer by regulating signaling pathways such as PI3K-AKT, P53, and VEGF. Furthermore, BZD can increase the number of T cells and promote T cell activation in tumor-bearing mice, enhancing the immune function against colorectal cancer. Among them, quercetin, kaempferol, licochalcone A, naringenin, and formaronetin are more highly predictive components related to the T cell activation in colorectal cancer mice. This study is of great significance for the development of novel anti-cancer drugs. It highlights the importance of network pharmacology-based approaches in studying complex traditional Chinese medicine formulations.