EOHSI/NIEHS Seminar Series – Fall 2015
Matthew Redinbo, Ph.D.
Kenan Distinguished Professor of Chemistry
Biochemistry and Microbiology
University of North Carolina
“Alleviating chemotherapy-induced GI toxicity
by selectively targeting the microbiome”
October 16, 2015 – 12:00 PM
Rutgers University – Busch Campus
EOHSI – Conference Room C
170 Frelinghuysen Road, Piscataway NJ 08854
Summary: The dose-limiting toxicity of the anticancer drug irinotecan is acute, delayed GI injury leading to intense diarrhea. The molecular mechanism of this toxicity is related the inactivation of the drug and its reactivation in the mammalian GI. Like many therapeutics, irinotecan is inactivated by glucuronidation, which links a monosaccharide to this potent antineoplastic compound. The drug-glucuronide is then sent to the GI for elimination. However, sugar scavenging glucuronidase enzymes encoded by the GI microbiota efficiently remove the glucuronide sugar, reactivating the drug in the intestinal lumen and producing the GI damage associated with this, and many other therapeutics.
We sought to alleviate the toxicity of irinotecan by focusing on the microbiota as a source of drug targets. We hypothesized that selective, potent and non-lethal inhibitors of microbial beta-glucuronidase enzymes would eliminate drug reactivation in the GI, and reduce GI toxicity and diarrhea. We identified by high-throughput screening several potent bacterial beta-glucuronidase inhibitors, established both structurally and functionally that they are specific only for microbial enzymes and not the mammalian orthologues. We also showed that these compounds were non-lethal to both bacterial and mammalian cells. Finally, we demonstrated that they significantly alleviate irinotecan-induced GI toxicity in mice. We have since extended this work to the non-steroidal anti-inflammatory drugs that cause small intestinal ulcerations by the same mechanism.