Abstract 1043: Efficacy and mechanistic insights of Shengyang Qushi Decoction in managing surufatinib-associated diarrhea

Abstract Background: Surufatinib, a novel TKI targeting VEGFRs, FGFR1, and CSF1R, treats advanced neuroendocrine tumors but often causes diarrhea, which impairs patients’ health and anti-tumor efficacy. We’ve successfully established a rat model of surufatinib-induced diarrhea. This study aims to investigate Shengyang Qushi Decoction's mechanism in treating this diarrhea, focusing on intestinal mucosal barrier and inflammation, for clinical application. Methods: Sixty male rats were randomly assigned to five groups after a 3-day acclimation period: control, model, low-dose decoction (12g/kg), high-dose decoction (24g/kg), and positive control (Loperamide 0.36mg/kg) group. Except for the control group, all received oral administration of surufatinib at a dose of 110 mg/kg, followed by corresponding treatment after 12 hours. We monitored body weight, general condition and assessed diarrhea. Histological changes in the colon were evaluated. ELISA measured plasma diamine oxidase (DAO) and D-lactate levels, as well as serum inflammatory cytokines (TNF-α, IL-1β, IL-6). Western blotting assessed the expression of tight junction proteins, inflammatory cytokines (TNF-α, IL-1β), and key proteins in the NF-κB pathway (IKK-α, IκB-α, NF-κB p65) in colon tissue. Results: Rats in the high-dose decoction group had slower weight gain than the control but more than other groups, with improved physical appearance and activity levels, and food and water intake similar to the control. Diarrhea rates were 50%, 17%, and 42% in the low-dose decoction, high-dose decoction, and positive control groups, respectively. Hematoxylin-eosin staining revealed intact colonic structure in the control group with orderly mucosal epithelia and no abnormalities. In the high-dose decoction group showed intact colon mucosa with minimal inflammation and no congestion or edema. DAO levels were not significantly different among groups, but D-lactate levels were significantly higher in the model group (P < 0.01), and decreased after intervention, most notably in the high-dose decoction group. After drug intervention, the colonic tight junction proteins increased, most notably in the high-dose decoction group (P < 0.01 vs. model). Serum TNF-α, IL-1β, and IL-6 levels declined, with the high-dose decoction group showing the greatest reduction (P < 0.01). And the colon’s TNF-α and IL-1β proteins followed the same trend (P < 0.01). Western blotting showed reduced expression of phosphorylated NF-κB pathway proteins (p-IKK-α, p-IκB-α, p-p65) after intervention, with the high-dose decoction group showing the greatest decrease (P < 0.01). Conclusions: Animal experiments confirm Shengyang Qushi Decoction's efficacy in treating surufatinib-induced diarrhea. It mitigates colonic tight junction damage, reduces mucosal permeability, inhibits NF-κB signaling pathway activation, and alleviates colonic inflammation. Citation Format: Huangying Tan, Shaobo Hu. Efficacy and mechanistic insights of Shengyang Qushi Decoction in managing surufatinib-associated diarrhea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1043.