Abstract
Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of β-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial β-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 μM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells.
Highlights
Irinotecan inhibits cell proliferation and is used for the primary treatment of colorectal cancer
[4,5-f]quinoline[19], and bis(2-ethylhexyl)phthalate and its derivatives[12]. These toxic compounds can promote tumor formation[20,21], they can be metabolized by UDP-glucuronosyltransferase to produce harmless glucuronide conjugates
Redinbo and coworkers were the first to report a selective inhibitor (ASN03273363) for gut bacterial GUSs (Ki = 0.16 μM for Escherichia coli GUS, EcGUS) that does not inhibit human GUS (HsGUS)
Summary
Irinotecan inhibits cell proliferation and is used for the primary treatment of colorectal cancer. Several food-derived toxic compounds are released back into the bloodstream by these GUSs, such as amygdalin (found in apricots, peaches, bitter almonds, plums)18, 2-amino-3-methylimidazo [4,5-f]quinoline (genotoxic/carcinogenic compound formed in meat and fish during cooking)[19], and bis(2-ethylhexyl)phthalate and its derivatives (plasticizers)[12] These toxic compounds can promote tumor formation[20,21], they can be metabolized by UDP-glucuronosyltransferase to produce harmless glucuronide conjugates. Several approaches have been proposed to suppress the irinotecan-induced intestinal toxicity, including enhanced the delivery of SN-38 to tumor[22], adjusted the releasing rate of SN3823, and reduced the immune response[24,25] Another promising approach was to develop specific inhibitor of intestinal bacterial GUSs9,26,27. The HsGUS and EcGUS structures differ in loop 3, which is one of eight loops near the active site
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