Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783517384782381056 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7132129 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bhattaadrap targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT pellocksamuelj targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT biernatkristena targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT waltonwilliamg targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT wallacebretd targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT creekmorebenjaminc targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT letertremarinem targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT swannjonathanr targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT wilsoniand targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT roquesjoser targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT darrdavidb targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT baileyseant targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT montgomerystephaniea targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT roachjeffreym targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT azcarateperilmandrea targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT sartorrbalfour targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT gharaibehraadz targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT bultmanscottj targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy AT redinbomatthewr targetedinhibitionofgutbacterialbglucuronidaseactivityenhancesanticancerdrugefficacy |