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

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.

Dachaihu decoction inhibits hypernutrition-induced liver metastasis from colorectal cancer by maintaining the gut vascular barrier

“…C-BAs interact with intestinal barrier cells including intestinal epithelial cells and the endothelium and disrupt this fundamental barrier, which can lead to the systemic entry of harmful entities, such as intestinal microbes and their metabolites, and initiation of tumor-promoting inflammation. 43 , 48 We demonstrated the effect of individual C-BAs in damaging the vascular barrier in HUVECs and found that GCDCA was the most potent BA in permeabilizing the HUVEC monolayer barrier, followed by TCA and TCDCA, with the least effects seen for GCA. DCHD treatment reversed HUVEC barrier disruption induced by GCDCA and increased the expression of TJ proteins.…”

Research progress of intestinal microbiota in targeted therapy and immunotherapy of colorectal cancer

“…Previous studies have shown that CEACAM1 and TIGIT inhibitors can be used as potential adjuvant drugs for CRC [17] . At present, some small molecule drugs under clinical trial are screened, such as azelnidipine and liothyronine [18] . A recent study has shown that Sodium New Houttuyfonate (SNH) significantly inhibits the progression of CRC by targeting F. nucleatum's membrane-associated protein FadA, leading to FadA polymerization, membrane rupture, and penetration, which blocks the tumor-promoting activity of F. nucleatum and F. nucleatum-associated cancer-driven inflammation, protecting the intestinal barrier [19] .…”

“…Based on this finding, Song et al considered neutralizing or modulating LPS produced by gut microbes as a potential treatment for colorectal cancer. Therefore, they suggest that genetically engineered bacteria that secrete LPS traps or PmB produced by Bacillus polymyxa are promising therapeutic approaches to kill Gram-negative bacillus instead of Activating Wnt/β-catenin signaling pathway [14] ; Activating NF-κB signaling pathway and upregulating miR-21 [15] ; Activating MyD88 signaling pathway [16] Small molecule compound inhibitors: Azelnidipine and liothyronine [18] . Sodium New Houttuyfonate (SNH) [18] .…”

Evaluation of Fusobacterium nucleatum Enoyl-ACP Reductase (FabK) as a Narrow-Spectrum Drug Target

“…nucleatum may promote the progression and metastasis of cancers has spurred research aimed at identifying antivirulence and antimicrobial agents to eradicate F. nucleatum from tumor environments. − The advantage of eliminating F. nucleatum was demonstrated in a study by Bullman et al, wherein mice treated with the antimicrobial metronidazole exhibited a decrease in F.…”