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

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-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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 13 Pg. 3521-30 (Jul 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24780296 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• Glycoproteins
• Protective Agents
• beta-glucuronidase inhibitor
• 8-hydroxyamoxapine
• Irinotecan
• 7-hydroxyamoxapine
• Amoxapine
• Camptothecin

Topics

• Amoxapine (analogs & derivatives, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (toxicity)
• Antineoplastic Agents, Phytogenic (toxicity)
• Camptothecin (analogs & derivatives, toxicity)
• Cell Line, Tumor
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects)
• Female
• Glycoproteins (chemistry, pharmacology)
• Irinotecan
• Mice
• Molecular Conformation
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Neoplasms (drug therapy, mortality, pathology)
• Protective Agents (chemistry, pharmacology)
• Protein Binding
• Xenograft Model Antitumor Assays