Alleviating cancer drug toxicity by inhibiting a bacterial enzyme

Science. 2010 Nov 5;330(6005):831-5. doi: 10.1126/science.1191175.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / metabolism
  • Antineoplastic Agents, Phytogenic / toxicity*
  • Bacteria, Anaerobic / drug effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / metabolism
  • Camptothecin / toxicity
  • Cell Line, Tumor
  • Colon / drug effects
  • Colon / microbiology
  • Colon / pathology
  • Crystallography, X-Ray
  • Diarrhea / prevention & control
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / enzymology
  • Escherichia coli Proteins / antagonists & inhibitors
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / isolation & purification
  • Escherichia coli Proteins / metabolism
  • Female
  • Glucuronidase / antagonists & inhibitors*
  • Glucuronidase / chemistry
  • Glucuronidase / isolation & purification
  • Glucuronidase / metabolism
  • Glucuronidase / pharmacology*
  • Humans
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • Irinotecan
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Prodrugs / metabolism
  • Prodrugs / toxicity
  • Protein Conformation

Substances

  • Antineoplastic Agents, Phytogenic
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Prodrugs
  • SN38-Glu
  • Irinotecan
  • Glucuronidase
  • Camptothecin

Associated data

  • PDB/3K46
  • PDB/3K4A
  • PDB/3K4D
  • PDB/3LPF
  • PDB/3LPG