Microbial Glucuronidase Inhibition Reduces Severity of Diclofenac-Induced Anastomotic Leak in Rats

Yauw, Simon T.K.; Arron, Melissa; Lomme, Roger M. L. M.; Broek, Petra van den; Greupink, Rick; Bhatt, Aadra P.; Redinbo, Matthew R.; Goor, Harry van

doi:10.1089/sur.2017.245

Cited by 22 publications

(22 citation statements)

References 41 publications

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“…Beyond irinotecan, the intestinal toxicity of NSAIDs, which are also glucuronidated and reactivated by GUS enzymes in the gut, has also been alleviated using targeted microbial GUS inhibitors administered to male and female mice (10,11,34). Inh1 has been shown in rats to reduce nonsteroidal antiinflammatory drug (NSAID)-induced intestinal anastomotic leakage (35). Kong et al (36) have replicated our findings with Inhibitor 1 and have shown that the tricyclic antidepressant amoxapine is a bacterial GUS inhibitor.…”

Section: Discussionsupporting

confidence: 61%

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

Bhatt

Pellock

Biernat

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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150

104

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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 immunedeficient 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. microbiome | chemotherapy | cancer | gastrointestinal toxicity I rinotecan (CPT-11) is essential for treating colorectal and pancreatic cancers and is frequently administered as a mixture with 5-fluorouracil and/or oxaliplatin. Ongoing clinical trials seek to extend irinotecan to other forms of cancer. However, irinotecan causes both myelosuppression and gastrointestinal (GI) side effects, including mucositis and late-onset diarrhea, which are often dose limiting: 88% of irinotecan patients develop diarrhea, with 30% experiencing acute grade 3 to 4 diarrhea (1-3). This toxicity is frequently refractory to antimotility drugs. Thus, treating irinotecaninduced diarrhea is a significant clinical need (4, 5).The irinotecan prodrug is activated in vivo to SN38, a potent topoisomerase I inhibitor (6) that retards the growth of rapidly proliferating cells in tumors and the intestinal epithelium, which renews every 5 d. SN38 is detoxified through the addition of glucuronic acid (GlcA) to form SN38-G, a compound marked for elimination via the GI tract. Gut commensal bacterial β-glucuronidase (GUS) proteins remove GlcA from SN38-G. Reactivated SN38 inflicts epithelial damage, resulting in bleeding diarrhea and acute weight loss in animal models (7). We reduced irinotecan-induced gut toxicity using inhibitors that selectively, nonlethally, and potently block the actions of gut bacterial GUS enzymes (8,9). The utility of GUS inhibition also extends to drugs be...

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Section: Discussionsupporting

confidence: 61%

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

Bhatt

Pellock

Biernat

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

150

104

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“…However, an attempt to reduce the inhibitor's serum exposure for increased GI residence by replacing ethoxy unit with hydroxyl or morpholinyl groups led to inferior pharmacological profile compared to parent compound 151 [226]. Further, compound 152 exerted 2-fold reduction in the severity of diclofenacinduced anastomotic leakage, without affecting drug's plasma concentration in Wistar rats receiving 0.8 mg of the inhibitor and 3 mg/kg of diclofenac [227]. In contrast, rats receiving diclofenac only suffered severe leakage thus suggesting the inhibitor's potential clinical utility to improve anastomotic healing.…”

Section: Coumarins and Azacoumarinsmentioning

confidence: 99%

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Awolade

Cele

Kerru

et al. 2020

European Journal of Medicinal Chemistry

107

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BiomarkerEnzyme inhibition Molecular target Structure activity relationship a b s t r a c tThe emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, b-glucuronidase (bGLU) e a lysosomal acid hydrolase responsible for the catalytic deconjugation of b-D-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of bGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of bGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved bGLU inhibitory potency and the development of new therapeutic agents in consequential.

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“…Second, an in-depth evaluation of the level of microbial BGUS inhibition (feces) by UNC10201652 needs to be performed in the MMTV-PyMT mice to determine the extent to which inhibition of all relevant BGUS enzymes occurs at the chosen dose (20 µM/day). It is important to note that this dose was chosen based on prior observations that BGUS inhibition at this dose are effective in vivo across several mouse models [27,28,31,35]. In this context, evaluation of the intestinal and breast microbiota in terms of any major changes in species/class/phyla using 16S or other metagenomic sequencing needs to be carried out.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibitor 1 was found to have no effect on plasma levels of diclofenac in mice [31]. Finally, in 2018, it was shown that Inhibitor 1 blocks anastomotic leakage after intestinal resection in rats given diclofenac [35]. Thus, a potent and specific BGUS inhibitor that does not kill microbial cells has been shown to be effective in blocking several negative outcomes with drugs or surgical…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Microbial Beta-Glucuronidase Does Not Prevent Breast Carcinogenesis in the Polyoma Middle T Mouse

Beck

Ervin

et al. 2019

Preprint

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Purpose: To demonstrate whether inhibition of intestinal microbial beta (b)-glucuronidase (BGUS) abrogates tumor formation in a MMTV-PyMT mouse breast cancer model. Methods: Female MMTV-PyMT heterozygote mice (4 weeks old) were randomized to oral gavage with vehicle or UNC10201652 (20 µg/day), a microbial BGUS inhibitor, for 9 weeks. The entire animal carcass was assessed for tumor deposits by histology and immunohistochemical staining for tumor (Ki67, PCNA) and breast specific (ER, PR, Cyclin D1, aSMA, Integrin b1) markers. Results: The MMTV-PyMT breast pathology in our study simulates prior published reports of tumor incidence and aggressiveness. There was no significant difference in the tumor histology, number of tumors (lesions), and patterns of spread of tumors in the UNC10201652 versus the vehicle treated mice. Similarly, there were no significant differences in the semi-quantitative scores for expression of ER, PR, Ki67, PCNA, or Integrin b1. There were also no major differences seen in qualitative screening of Cyclin D1 and aSMA. Conclusions:MMTV-PyMT mice administered UNC10201652, when compared to vehicle treated mice, show a similar abundance of breast tumor (and tumor initiating) lesions ranging from hyperplasia to frank carcinoma. There is a trend, however small, that the incidence of hyperplastic and adenomas may be decreased in UNC10201652 treated mice. Further refined dosing strategies in MMTV-PyMT are planned to clarify its biological significance. To our knowledge this is the first report of use of any BGUS inhibitor in chemoprevention of breast tumors using a genetic model simulating human breast cancer.

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Microbial Glucuronidase Inhibition Reduces Severity of Diclofenac-Induced Anastomotic Leak in Rats

Abstract: Microbial glucuronidase inhibitor reduces diclofenac-induced anastomotic leakage severity, which suggests a harmful effect of diclofenac metabolite reactivation in the gut. This finding improves the understanding of the pathogenesis of anastomotic leakage.

Cited by 22 publications

References 41 publications

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

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

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Inhibition of Microbial Beta-Glucuronidase Does Not Prevent Breast Carcinogenesis in the Polyoma Middle T Mouse

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