Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

By B. Wallace, Hongwei Wang, Kimberly T. Lane, John E. Scott, J. Orans, J. Koo, M. Venkatesh, C. Jobin, L. Yeh, S. Mani and 1 more. Science, 2010

996 citations recorded by the source corpus.

Blocking Interfering Microbes Irinotecan is a widely used anticancer pro-drug that is converted in the liver into the active form, but when it gets into the gut, the normally benign microbial flora can convert it into the toxic form, which kills the rapidly multiplying gut epithelium as it would kill rapidly dividing tumor cells, and thus causes diarrhea. Wallace et al. (p. 831; see the Perspective by Patel and Kaufmann) used high-throughput screening to identify inhibitors that target the offending bacterial enzyme, β-glucuronidase, without killing the bacteria or affecting orthologous mammalian enzymes. Crystal structures revealed the molecular basis of selectivity, and in vivo studies showed that an inhibitor protected mice from irinotecan-induced toxicity. Targeting an enzyme in human microbial symbiotes might prevent a chemotherapeutic side effect. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9a6f14f1cac021bddc6e7f5d3cc0f3e4f7d0f0a0

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Citations in the corpus

Microbiome and Malignancy (2011, background): “Responses to particular chemotherapeutic agents have been linked to specific gut microbiome metabolic activities (Wallace et al., 2010).”
Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. (2016, neutral): “…found to be a competitive antagonist of the CD28-B7 interaction in that it effectively blocks costimulation at the T-cell-APC interface and thus abrogates activation of T cell responses (Krummel and Immunity 44, June 21, 2016 ª 2016 Elsevier Inc. 1255 Allison, 1995; Walunas et al., 1994).”
Human Gut Microbiota and Gastrointestinal Cancer (2018, background): “Gut microbiota mediate the toxicity of irinotecan (CPT-11) chemotherapy that can induce the loss of intestinal barrier function [229].”
The microbiome and cancer (2018, background): “Irinotecan metabolism is an example where bacterial β-glucuronidase activity induces more severe side effects, including dose-limiting diarrhea, in some patients by reactivating the drug in the colon [84].”
Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. (2012, background): “The presence of microbes that convert luminal compounds into potential carcinogens also puts one at increased risk for cancer and can lead to adverse responses to chemotherapeutic agents (Wallace et al., 2010).”
Gut microbiome-host interactions in health and disease (2011, background): “Potent bacterial β-glucuronidase inhibitors have been identified by high-throughput screening and been shown to have no effect on the orthologous mammalian enzyme [92].”
Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism (2019, background): “Overall, these data suggest that AFMT could be a promising tool compound for the study of bacterial L-dopa metabolism (56) and highlight the promise of developing L-dopa–based combination therapies containing drugs that target both host and gut microbial decarboxylation.”
Mechanisms and consequences of intestinal dysbiosis (2017, background): “This modification is reversed in the gut through the action of bacterial glucuronidases, which re-activate the drug and increase intestinal toxicity [99].”
Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine (2017, background): “Earlier studies on the association between bacteria and cancer have focused primarily on exploring (i) the role of bacteria in tumor pathogenesis, (ii) the potential of gut bacteria to modulate anti-tumor immune responses (18, 19), and (iii) the contribution of bacterial metabolism to the adverse ef”