Old drug new use--amoxapine and its metabolites as potent bacterial β-glucuronidase inhibitors for alleviating cancer drug toxicity. Clin Cancer Res 2014 Jul 01;20(13):3521-30
Date
05/02/2014Pubmed ID
24780296Pubmed Central ID
PMC4079752DOI
10.1158/1078-0432.CCR-14-0395Scopus ID
2-s2.0-84903837906 (requires institutional sign-in at Scopus site) 84 CitationsAbstract
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-hydroxyamoxapine, 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.
Author List
Kong R, Liu T, Zhu X, Ahmad S, Williams AL, Phan AT, Zhao H, Scott JE, Yeh LA, Wong STAuthor
Alexandria T. Phan MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AmoxapineAnimals
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Camptothecin
Cell Line, Tumor
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Activation
Female
Glycoproteins
Mice
Molecular Conformation
Molecular Docking Simulation
Molecular Dynamics Simulation
Neoplasms
Protective Agents
Protein Binding
Xenograft Model Antitumor Assays
