Yang Xiaoqin, Zhang Heng, He Chenglin, Wang Di, Li Jingjing, Fu Chaomei, Wang Yitao, Wu Yihan, Zhang Jinming
State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Hong Kong, SAR, China.
J Ethnopharmacol. 2025 Mar 26;344:119538. doi: 10.1016/j.jep.2025.119538. Epub 2025 Feb 27.
Although several traditional Chinese medicine formulas have demonstrated remarkable outcomes in suppressing the severe gastrointestinal toxicity induced by irinotecan (CPT-11), few studies have investigated whether enhanced anti-cancer efficacy and reduced intestinal toxicity can be achieved through co-administration. CPT-11, as a first-line drug for treating colorectal cancer, has the side effect of intestinal toxicity. Previous studies have primarily focused on using traditional Chinese medicine to alleviate diarrhea caused by CPT-11. The combination of the classic Chinese medicine prescription Gegen Qinlian decoction (GQD) extract and CPT-11 can significantly reduce its intestinal toxicity. However, the mechanism by which it enhances anti-cancer effects remains to be elucidated.
To investigate the combined effects of GQD and CPT-11 on colorectal cancer progression and intestinal toxicity.
The CT-26 xenograft tumor-bearing mouse model was established to evaluate the synergistic antitumor effects of GQD extract and CPT-11. Tumor size and tumor tissue changes were assessed, and flow cytometry was employed to analyze immune cell populations, thereby evaluating the impact of the combined treatment on tumor growth inhibition and immune modulation. Under anaerobic glycolysis conditions, glucose uptake and cell viability of CT26 cells were measured, and Western blotting analysis was used to determine the protein expression of PKM2 and GAPDH in tumors, assessing the metabolic impact of GQD extract on cancer cells. Flow cytometry was also used to assess the polarization of macrophages in colon tissue, and ELISA was employed to measure cytokine levels in colon tissue, evaluating the protective effect of GQD extract on the colon.
The combination of GQD extract and CPT-11 significantly increased tumor growth suppression and decreased intestinal toxicity in the mouse model. The anti-cancer synergy was reduced Treg cell immunosuppression and increased CD4 and CD8 T cell populations. GQD extract regulated glucose uptake and cell viability in CT-26 cells under anaerobic glycolysis, potentially disrupting cancer cell glycolysis. GQD also alleviated intestinal toxicity by modulating cytokine levels and promoting macrophage polarization from M1 to M2 in colon tissues.
The study indicates that GQD extract improves CPT-11 efficacy in treating colorectal cancer and provides insights into the synergistic effects of TCM formulas in cancer treatment.
尽管几种中药配方在抑制伊立替康（CPT - 11）引起的严重胃肠道毒性方面已显示出显著效果，但很少有研究探讨联合用药是否能提高抗癌疗效并降低肠道毒性。CPT - 11作为治疗结直肠癌的一线药物，具有肠道毒性副作用。先前的研究主要集中于使用中药缓解CPT - 11引起的腹泻。经典中药方剂葛根芩连汤（GQD）提取物与CPT - 11联合使用可显著降低其肠道毒性。然而，其增强抗癌作用的机制仍有待阐明。
探讨GQD与CPT - 11联合应用对结直肠癌进展和肠道毒性的综合影响。
建立CT - 26荷瘤异种移植小鼠模型，以评估GQD提取物与CPT - 11的协同抗肿瘤作用。评估肿瘤大小和肿瘤组织变化，并采用流式细胞术分析免疫细胞群体，从而评估联合治疗对肿瘤生长抑制和免疫调节的影响。在无氧糖酵解条件下，测量CT26细胞的葡萄糖摄取和细胞活力，并使用蛋白质印迹分析来确定肿瘤中PKM2和GAPDH的蛋白表达，评估GQD提取物对癌细胞的代谢影响。流式细胞术还用于评估结肠组织中巨噬细胞的极化，酶联免疫吸附测定法（ELISA）用于测量结肠组织中的细胞因子水平，评估GQD提取物对结肠的保护作用。
在小鼠模型中，GQD提取物与CPT - 11联合使用显著增强了肿瘤生长抑制作用并降低了肠道毒性。抗癌协同作用表现为Treg细胞免疫抑制作用降低，CD4和CD8 T细胞群体增加。GQD提取物在无氧糖酵解条件下调节CT - 26细胞的葡萄糖摄取和细胞活力，可能干扰癌细胞的糖酵解。GQD还通过调节细胞因子水平和促进结肠组织中巨噬细胞从M1向M2极化来减轻肠道毒性。
该研究表明GQD提取物可提高CPT - 11治疗结直肠癌的疗效，并为中药配方在癌症治疗中的协同作用提供了见解。
