Details

Autor(en) / Beteiligte

• REN KONG
• LIU, Timothy
• XIAOPING ZHU
• AHMAD, Syed
• WILLIAMS, Alfred L
• PHAN, Alexandria T
• HONG ZHAO
• SCOTT, John E
• YEH, Li-An
• WONG, Stephen T. C

Titel

Old Drug New Use―Amoxapine and Its Metabolites as Potent Bacterial β-Glucuronidase Inhibitors for Alleviating Cancer Drug Toxicity

Ist Teil von

• Clinical cancer research, 2014-07, Vol.20 (13), p.3521-3530

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. Amoxapine has great clinical potential to be rapidly translated to human subjects for irinotecan-induced diarrhea.