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

Autor:	Bhatt AP; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290.; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555.; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555., Pellock SJ; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290., Biernat KA; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290., Walton WG; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290., Wallace BD; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290., Creekmore BC; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290., Letertre MM; Computational and Systems Medicine, Department of Surgery & Cancer, Imperial College London, SW7 2AZ London, United Kingdom., Swann JR; Computational and Systems Medicine, Department of Surgery & Cancer, Imperial College London, SW7 2AZ London, United Kingdom., Wilson ID; Computational and Systems Medicine, Department of Surgery & Cancer, Imperial College London, SW7 2AZ London, United Kingdom., Roques JR; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Darr DB; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Bailey ST; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Montgomery SA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525., Roach JM; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555.; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555., Azcarate-Peril MA; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555.; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555., Sartor RB; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555.; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7555.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599., Gharaibeh RZ; Department of Medicine, Division of Gastroenterology, University of Florida, Gainesville, FL 32610., Bultman SJ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7264., Redinbo MR; Department of Biochemistry, Integrated Program for Biological and Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290; redinbo@unc.edu.; Department of Biophysics, Integrated Program for Biological and Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Mar 31; Vol. 117 (13), pp. 7374-7381. Date of Electronic Publication: 2020 Mar 13.
DOI:	10.1073/pnas.1918095117
Abstrakt:	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. Competing Interests: Competing interest statement: M.R.R. is the Scientific Founder of Symberix, Inc., which is developing drugs targeting the human microbiome. B.D.W., who is currently an employee of Symberix, Inc., conducted the work presented here as a graduate student at the University of North Carolina at Chapel Hill. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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