Old drug new use - Amoxapine and its metabolites as potent bacterial β-glucuronidase inhibitors for alleviating cancer drug toxicity

Ren Kong, Timothy Liu, Xiaoping Zhu, Syed Ahmad, Alfred L. Williams, Alexandria T. Phan, Hong Zhao, John E. Scott, Li An Yeh, Stephen T.C. Wong

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Purpose: Irinotecan (CPT-11) induced diarrhea occurs frequently in patients with cancer and limits its usage. Bacteria β-glucuronidase (GUS) enzymes in intestines convert the nontoxic metabolite of CPT-11, SN-38G, to toxic SN-38, and finally lead to damage of intestinal epithelial cells and diarrhea. We previously reported amoxapine as a potent GUS inhibitor in vitro. To further understand the molecular mechanism of amoxapine and its potential for treatment of CPT-11-induced diarrhea, we studied the binding modes of amoxapine and its metabolites by docking and molecular dynamics simulation, and tested the in vivo efficacy on mice in combination with CPT-11. Experimental Design: The binding of amoxapine, its metabolites, 7-hydroxyamoxapine and 8-hydro-xyamoxapine, and a control drug loxapine with GUS was explored by computational protocols. The in vitro potencies of metabolites were measured by Escherichia coli GUS enzyme and cell-based assay. Low-dosage daily oral administration was designed to use along with CPT-11 to treat tumor-bearing mice. Results: Computational modeling results indicated that amoxapine and its metabolites bound in the active site of GUS and satisfied critical pharmacophore features: aromatic features near bacterial loop residue F365' and hydrogen bond toward E413. Amoxapine and its metabolites were demonstrated as potent in vitro. Administration of low dosages of amoxapine with CPT-11 in mice achieved significant suppression of diarrhea and reduced tumor growth. Conclusions: Amoxapine has great clinical potential to be rapidly translated to human subjects for irinotecan-induced diarrhea.

Original languageEnglish (US)
Pages (from-to)3521-3530
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number13
DOIs
StatePublished - Jul 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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