Affiliation:
1. Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45229, USA
Abstract
Background:
Irinotecan is widely used to treat various types of solid and metastatic cancer. It is an ester
prodrug and its hydrolytic metabolite (SN-38) exerts potent anticancer activity. Irinotecan is hydrolyzed primarily by
carboxylesterase-2 (CES2), a hydrolase abundantly present in the intestine such as the duodenum. We have identified
several potent and covalent CES2 inhibitors such as remdesivir and sofosbuvir. Remdesivir is the first small molecule
drug approved for COVID-19, whereas sofosbuvir is a paradigm-shift medicine for hepatitis C viral infection.
Irinotecan is generally well-tolerated but associated with severe/life-threatening diarrhea due to intestinal accumulation
of SN-38.
Objective:
This study was to test the hypothesis that remdesivir and sofosbuvir protect against irinotecan-induced
epithelial injury associated with gastrointestinal toxicity.
Methods:
To test this hypothesis, formation of organoids derived from mouse duodenal crypts, a robust cellular
model for intestinal regeneration, was induced in the presence or absence of irinotecan +/- pretreatment with a CES2
drug inhibitor.
Results:
Irinotecan profoundly inhibited the formation of intestinal organoids and the magnitude of the inhibition
was greater with female crypts than their male counterparts. Consistently, crypts from female mice had significantly
higher hydrolytic activity toward irinotecan. Critically, remdesivir and sofosbuvir both reduced irinotecan hydrolysis
and reversed irinotecan-reduced formation of organoids. Human duodenal samples robustly hydrolyzed irinotecan,
stable CES2 transfection induced cytotoxicity and the cytotoxicity was reduced by CES2 drug inhibitor.
Conclusion:
These findings establish a therapeutic rationale to reduce irinotecan-gastrointestinal injury and serve as
a cellular foundation to develop oral formulations of irinotecan with high safety.
Funder
National Institutes of Health
Publisher
Bentham Science Publishers Ltd.
Subject
Clinical Biochemistry,Pharmacology
Cited by
2 articles.
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