Статья

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Aadra P. BhattCenter for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555;Samuel J. PellockDepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290;Kristen A. BiernatDepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290;William G. WaltonDepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290;Bret D. WallaceDepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290;Benjamin C. CreekmoreDepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290;Marine P. M. LetertreComputational and Systems Medicine, Department of Surgery & Cancer, Imperial College London, SW7 2AZ London, United Kingdom;Jonathan R. SwannComputational and Systems Medicine, Department of Surgery & Cancer, Imperial College London, SW7 2AZ London, United Kingdom;Ian D. WilsonComputational and Systems Medicine, Department of Surgery & Cancer, Imperial College London, SW7 2AZ London, United Kingdom;Jose RoquesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;David B. DarrLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;Sean T. BaileyLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;Stephanie A. MontgomeryDepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525;Jeffrey RoachCenter for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555;M. Andrea Azcárate-PerilCenter for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555;R. Balfour SartorCenter for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555;Raad Z. GharaibehDepartment of Medicine, Division of Gastroenterology, University of Florida, Gainesville, FL 32610;Scott J. BultmanDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7264;Matthew R. RedinboDepartment of Biochemistry, Integrated Program for Biological and Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290;

2020en

ABI

Аннотация

Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.

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Идентификаторы

DOI: 10.1073/pnas.1918095117

Цитирования и источники

Цитирований: 2Использованных источников: 0

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