Exploring the mechanism and key active components of Gegen Qinlian decoction combined with XELOX in the treatment of ulcerative colitis-associated colorectal cancer based on network pharmacology and multi-omics analysis

Abstract

Ulcerative colitis (UC) is an autoimmune disease with a steady increase in global prevalence and long-term susceptibility to colorectal cancer (CRC). CRC is often treated with XELOX regimen (oxaliplatin and capecitabine), which is limited by the high toxicity, many adverse reactions and intolerance of patients, thus often leading to termination of chemotherapy. Traditional Chinese medicine is effective in improving patients' clinical symptoms. Gegen Qinlian decoction (GQD) is frequently utilized in the management of UC and has the potential to treat CRC. Whereas, there are few studies on GQD in the treatment of UC-associated CRC, and the therapeutic mechanism of GQD combined with XELOX has not been fully reported. Herein, HPLC-Q-TOF-MS/MS technique was used to analyze the main chemical components of GQD. Network pharmacology was performed to unveil the critical genes and components of GQD against UC and UC-associated CRC. The detection of TNF-α, IL-1β, IL-6, VEGF, SOD, MDA and immune factors revealed that GQD played a key role in improving immune function, reducing inflammation and resisting oxidative stress. 16S rDNA sequencing technology results showed that GQD could maintain gastrointestinal homeostasis by increasing beneficial bacteria and decreasing harmful bacteria. Then, metabolomics based on HPLC-Q-TOF-MS/MS found that the combination of GQD and XELOX could significantly restore the disturbance of metabolites. Particularly, the compound-reaction-gene-enzyme network was first constructed to realize the combination of network pharmacology and metabolomics. The results showed that GQD may assist XELOX to play a synergistic anti-tumor role by regulating the key enzymes ALOX15, CYP1B1 and PTGS2 in unsaturated fatty acid metabolism. Finally, the mechanism was verified by western blot, and the key pharmacodynamic components were found by molecular docking. Overall, the current study offered fresh perspectives on both the prevention and treatment of UC to CRC as well as fresh concepts for the therapeutic application of GQD with XELOX to lessen the side effects of chemotherapy and enhance patients' quality of life.