Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

Abstract

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11–induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

“…The dichotomization of the analytes associated with blood‐ and gut‐related safety events are consistent with reports of differential metabolism occurring in the plasma and in the gut. In particular, it has been reported that SN‐38G can be converted back to SN‐38 in the gut via microflora, but this mechanism is absent in the plasma 22, 23. Because SN‐38G in the plasma is observed at an ∼10‐times higher concentration than SN‐38, the conversion in the gut may result in higher SN‐38 concentrations in the gut compared with the plasma.…”

PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy

“…Second, glucuronide conjugates can be transported to the intestines via biliary excretion. To diminish this effect, several methods have been used, including depletion of intestinal microbes by antibiotics (30,31) and inhibition of bacterial bG by chemical inhibitors (32,33). Therefore, we treated mice with antibiotics or a bG inhibitor before 124 I-TrapG injection.…”

How to Determine the Role of the Microbiome in Drug Disposition

“…Multiple lines of evidence point to a gut-liver axis in which both the microbiome and liver influence each other through biliary excretion and recycling, signaling, and regulation of gene expression (Tripathi et al, 2018). In addition, increasing evidence points to the gut-liver axis' importance to drug excretion; for example, the anti-cancer drug irinotecan (Wallace et al, 2010) and the Alzheimer's drug tacrine (Yip et al, 2018), both of which will be discussed later.…”

“…A seminal example of this approach comes from the study of the side effects presented in a subset of patients taking irinotecan's bioactive compound, SN-38, a widely-used chemotherapeutic for colorectal cancer. SN-38 undergoes glucuronidation in the liver resulting in SN-38G which is excreted to the intestine where it is acted upon by β-glucuronidases that revert the metabolite to SN-38, and, as a result, causes severe diarrhea (Wallace et al, 2010). The link between patient quantified by Guthrie and colleagues.…”