The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota.
The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota.
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DOI：
10.1016/j.celrep.2022.111625
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发表时间：
2022-11-15
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影响因子：
8.8
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具核梭杆菌（Fn）是结直肠癌（CRC）组织中的优势细菌物种，其与癌症进展和较差的患者预后相关。在针对Fn CRC分离物的1，846种生物活性化合物的小分子抑制剂筛选之后，我们发现15%的抑制剂是包括氟嘧啶的抑制剂。这些发现的验证表明，5-氟尿嘧啶（5-FU）是一种一线CRC化疗药物，是Fn CRC分离株的有效抑制剂。我们还鉴定了对5-FU耐药的肿瘤内微生物群成员，包括大肠杆菌。此外，CRC E.大肠杆菌分离物可以修饰5-FU并减轻5-FU对其他敏感的Fn和人CRC上皮细胞的毒性。最后，我们证明了离体患者CRC肿瘤微生物群在5-FU暴露后发生群落破坏，并有可能耗尽5-FU水平，降低局部药物疗效。总之，这些观察结果支持进一步研究CRC肿瘤内微生物群在患者对化疗反应中的作用。LaCourse等人表明，与结直肠癌相关的细菌具核梭杆菌（Fusobacterium nucleatum）被化学治疗剂5-氟尿嘧啶抑制，表明5-氟尿嘧啶功效可能部分归因于其抗微生物活性。特定的肿瘤内微生物群成员将5-氟尿嘧啶修饰成无毒形式，拯救具核梭杆菌和癌上皮细胞生长。
Fusobacterium nucleatum (Fn) is a dominant bacterial species in colorectal cancer (CRC) tissue that is associated with cancer progression and poorer patient prognosis. Following a small-molecule inhibitor screen of 1,846 bioactive compounds against a Fn CRC isolate, we find that 15% of inhibitors are antineoplastic agents including fluoropyrimidines. Validation of these findings reveals that 5-fluorouracil (5-FU), a first-line CRC chemotherapeutic, is a potent inhibitor of Fn CRC isolates. We also identify members of the intratumoral microbiota, including Escherichia coli, that are resistant to 5-FU. Further, CRC E. coli isolates can modify 5-FU and relieve 5-FU toxicity toward otherwise-sensitive Fn and human CRC epithelial cells. Lastly, we demonstrate that ex vivo patient CRC tumor microbiota undergo community disruption after 5-FU exposure and have the potential to deplete 5-FU levels, reducing local drug efficacy. Together, these observations argue for further investigation into the role of the CRC intratumoral microbiota in patient response to chemotherapy. LaCourse et al. show that Fusobacterium nucleatum, a bacterium associated with colorectal cancer, is inhibited by the chemotherapeutic 5-fluorouracil, suggesting that 5-fluorouracil efficacy may in part be due to its antimicrobial activity. Specific intratumoral microbiota members modify 5-fluorouracil into a nontoxic form, rescuing Fusobacterium nucleatum and cancer epithelial cell growth.