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

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 resultan...

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Autores principales: Bhatt, Aadra P., Pellock, Samuel J., Biernat, Kristen A., Walton, William G., Wallace, Bret D., Creekmore, Benjamin C., Letertre, Marine M., Swann, Jonathan R., Wilson, Ian D., Roques, Jose R., Darr, David B., Bailey, Sean T., Montgomery, Stephanie A., Roach, Jeffrey M., Azcarate-Peril, M. Andrea, Sartor, R. Balfour, Gharaibeh, Raad Z., Bultman, Scott J., Redinbo, Matthew R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132129/
https://www.ncbi.nlm.nih.gov/pubmed/32170007
http://dx.doi.org/10.1073/pnas.1918095117
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author Bhatt, Aadra P.
Pellock, Samuel J.
Biernat, Kristen A.
Walton, William G.
Wallace, Bret D.
Creekmore, Benjamin C.
Letertre, Marine M.
Swann, Jonathan R.
Wilson, Ian D.
Roques, Jose R.
Darr, David B.
Bailey, Sean T.
Montgomery, Stephanie A.
Roach, Jeffrey M.
Azcarate-Peril, M. Andrea
Sartor, R. Balfour
Gharaibeh, Raad Z.
Bultman, Scott J.
Redinbo, Matthew R.
author_facet Bhatt, Aadra P.
Pellock, Samuel J.
Biernat, Kristen A.
Walton, William G.
Wallace, Bret D.
Creekmore, Benjamin C.
Letertre, Marine M.
Swann, Jonathan R.
Wilson, Ian D.
Roques, Jose R.
Darr, David B.
Bailey, Sean T.
Montgomery, Stephanie A.
Roach, Jeffrey M.
Azcarate-Peril, M. Andrea
Sartor, R. Balfour
Gharaibeh, Raad Z.
Bultman, Scott J.
Redinbo, Matthew R.
author_sort Bhatt, Aadra P.
collection PubMed
description 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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spelling pubmed-71321292020-04-09 Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy Bhatt, Aadra P. Pellock, Samuel J. Biernat, Kristen A. Walton, William G. Wallace, Bret D. Creekmore, Benjamin C. Letertre, Marine M. Swann, Jonathan R. Wilson, Ian D. Roques, Jose R. Darr, David B. Bailey, Sean T. Montgomery, Stephanie A. Roach, Jeffrey M. Azcarate-Peril, M. Andrea Sartor, R. Balfour Gharaibeh, Raad Z. Bultman, Scott J. Redinbo, Matthew R. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2020-03-31 2020-03-13 /pmc/articles/PMC7132129/ /pubmed/32170007 http://dx.doi.org/10.1073/pnas.1918095117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Bhatt, Aadra P.
Pellock, Samuel J.
Biernat, Kristen A.
Walton, William G.
Wallace, Bret D.
Creekmore, Benjamin C.
Letertre, Marine M.
Swann, Jonathan R.
Wilson, Ian D.
Roques, Jose R.
Darr, David B.
Bailey, Sean T.
Montgomery, Stephanie A.
Roach, Jeffrey M.
Azcarate-Peril, M. Andrea
Sartor, R. Balfour
Gharaibeh, Raad Z.
Bultman, Scott J.
Redinbo, Matthew R.
Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy
title Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy
title_full Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy
title_fullStr Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy
title_full_unstemmed Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy
title_short Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy
title_sort targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132129/
https://www.ncbi.nlm.nih.gov/pubmed/32170007
http://dx.doi.org/10.1073/pnas.1918095117
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