Ginsenosides facilitate the anti-cancer efficacy of cyclophosphamide via modulating intestinal bacteria and alleviating intestinal mucositis in mammary carcinoma mice

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Background: Ginsenosides has been reported to facilitate the chemotherapy of cyclophosphamide (CTX), but the underlying mechanism is still elusive. Here, ICR mice bearing subcutaneous 4T1 tumor (mouse mammary carcinoma cells) were used to investigate the enhanced chemotherapeutic effects and underlying the mechanism of concurrent administration of ginsenosides and CTX. Results: Combinational treatment with ginsenosides in mice enhanced the anti-cancer efficacy of CTX as observed by elevated tumor growth inhibition rate, prolonged survival rate, decreased tumor burden and increased apoptosis in tumor tissues. The mechanism underlying the enhancing effects involved the elevation of the anti-cancer immunity, which manifested as accelerating anti-cancer cytokines (IL-2, IL-6, IL-17, TNF-α and INF-γ) that was further ascribed to the ginsenosides-induced generation of intestinal probiotics including Bifidobacterium, Akkermansia and Lactobacillus. Moreover, through activating Nrf2 and inhibiting NFκB pathways, ginsenosides reversed CTX-induced intestinal mucositis by maintaining normal intestinal permeability and junction proteins function. Conclusion: Ginsenosides ameliorate CTX-induced intestinal mucositis and promote anti-cancer immunity via maintaining intestinal homeostasis, consequently enhancing the anti-cancer efficacy of CTX.