Sodium New Houttuyfonate Inhibits Cancer-Promoting Fusobacterium nucleatum (Fn) to Reduce Colorectal Cancer Progression

SIMPLE SUMMARY: Colorectal cancer (CRC) is the third most common malignancy and the second most deadly cancer worldwide. Recent studies have uncovered the close relationship between Gram-negative anaerobic bacterium Fusobacterium nucleatum (Fn), commonly found in the human oral cavity and gut, and CRC development. Currently, there is no specific antimicrobial therapy for CRC treatment. Due to the antibiotic allergy, side effects, and resistance of existing antibiotic therapy, a new generation of antimicrobial therapy targeting specific CRC-promoting bacteria is urgently needed. In this study, we were looking for herb medicines and found that sodium new houttuyfonate (SNH), derived from the plant Houttuynia cordata Thunb, showed potent antibacterial activity on Fn with little toxicity toward host cells. Importantly, SNH inhibited Fn-induced inflammation and CRC growth promoted by Fn. Our findings of SNH with potent anti-Fn activity are promising for CRC treatment and provide an important foundation for future antimicrobial therapy for clinical CRC treatment. ABSTRACT: Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide. Recent studies showed that the common anaerobe Fusobacterium nucleatum (Fn) is closely associated with a higher risk for carcinogenesis, metastasis, and chemoresistance of CRC. However, there is no specific antimicrobial therapy for CRC treatment. Herbal medicine has a long history of treating diseases with remarkable effects and is attracting extensive attention. In this study, we tested six common phytochemicals for their antimicrobial activities against Fn and whether anti-Fn phytochemicals can modulate CRC development associated with Fn. Among these antimicrobials, we found that SNH showed the highest antimicrobial activity and little cytotoxicity toward cancer cells and normal cells in vitro and in vivo. Mechanistically, SNH may target membrane-associated FadA, leading to FadA oligomerization, membrane fragmentation and permeabilization. More importantly, SNH blocked the tumor-promoting activity of Fn and Fn-associated cancer-driven inflammation, thus improving the intestinal barrier damaged by Fn. SNH reduced Fn load in the CRC-cells-derived mice xenografts with Fn inoculation and significantly inhibited CRC progression. Our data suggest that SNH could be used for an antimicrobial therapy that inhibits Fn and cancer-driven inflammation of CRC. Our results provide an important foundation for future gut microbiota-targeted clinical treatment of CRC.