Sodium New Houttuyfonate Inhibits Cancer-Promoting Fusobacterium nucleatum (Fn) to Reduce Colorectal Cancer Progression.
Sodium New Houttuyfonate Inhibits Cancer-Promoting Fusobacterium nucleatum (Fn) to Reduce Colorectal Cancer Progression.
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结直肠癌（CRC）是世界范围内第三大常见恶性肿瘤和第二大致命癌症。最近的研究发现，革兰氏阴性厌氧细菌具核梭杆菌（Fn），常见于人类口腔和肠道，和CRC的发展之间的密切关系。目前，没有针对CRC治疗的特异性抗微生物疗法。由于现有抗生素治疗的抗生素过敏、副作用和耐药性，迫切需要靶向特定CRC促进细菌的新一代抗菌治疗。在这项研究中，我们正在寻找草药，并发现新的鱼腥草素钠（SNH），来自植物鱼腥草，显示出强大的抗菌活性Fn对宿主细胞的毒性很小。重要的是，SNH抑制Fn诱导的炎症和Fn促进的CRC生长。SNH具有较强的抗Fn活性，为临床治疗结直肠癌提供了重要的基础。结直肠癌（CRC）是世界范围内发病率和死亡率的主要原因。最近的研究表明，常见的厌氧菌具核梭杆菌（Fn）与大肠癌的发生、转移和耐药性密切相关。然而，没有针对CRC治疗的特异性抗微生物疗法。草药治疗疾病历史悠久，疗效显著，正引起人们的广泛关注。在这项研究中，我们测试了六种常见的植物化学物质对Fn的抗菌活性，以及抗Fn植物化学物质是否可以调节与Fn相关的CRC发展。在这些抗菌剂中，我们发现SNH在体外和体内对癌细胞和正常细胞显示出最高的抗菌活性和很小的细胞毒性。在机制上，SNH可以靶向膜相关的FadA，导致FadA寡聚化、膜片段化和透化。更重要的是，SNH阻断了Fn的促肿瘤活性和Fn相关的癌症驱动的炎症，从而改善了Fn损伤的肠道屏障。SNH降低了接种Fn的CRC细胞衍生小鼠异种移植物中的Fn负荷，并显著抑制CRC进展。我们的数据表明，SNH可用于抑制Fn和CRC的癌症驱动的炎症的抗菌治疗。我们的研究结果为未来以肠道微生物为靶点的CRC临床治疗提供了重要基础。
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. 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.
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影响因子：
16.6
作者：
Arthur, Janelle C.;Gharaibeh, Raad Z.;Muehlbauer, Marcus;Perez-Chanona, Ernesto;Uronis, Joshua M.;McCafferty, Jonathan;Fodor, Anthony A.;Jobin, Christian
通讯作者：
Jobin, Christian
DOI：
10.1186/s13046-020-01677-w
发表时间：
2020-09-29
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Guo P;Tian Z;Kong X;Yang L;Shan X;Dong B;Ding X;Jing X;Jiang C;Jiang N;Yu Y
通讯作者：
Yu Y
影响因子：
5.2
作者：
Kim JY;He F;Karin M
通讯作者：
Karin M
影响因子：
37.3
作者：
Parekh HS;Liu G;Wei MQ
通讯作者：
Wei MQ
影响因子：
5.2
作者：
Andrews, JM
通讯作者：
Andrews, JM