ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
Old drug new use--amoxapine and its metabolites as potent bacterial β-glucuronidase inhibitors for alleviating cancer drug toxicity.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 87 citations in OpenAlex.
- A Comprehensive Review on Irinotecan-Induced Delayed Diarrhea: From Mechanisms to Therapeutic Options.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Microbiome-Modulating Strategies in Anticancer Therapy: A Review of Current Evidence and Recommendations for Further Treatment Improvement.Probiotics and antimicrobial proteins · 2026Review
- Review
- Managing Irinotecan-Induced Diarrhea: A Comprehensive Review of Therapeutic Interventions in Cancer Treatment.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Rifaximin alleviates irinotecan-induced diarrhea in mice model.Annals of medicine · 2024Article
- Targeted inhibition of Gus-expressingActa pharmaceutica Sinica. B · 2024Article
- Potential of Synbiotics and Probiotics as Chemopreventive Agent.Probiotics and antimicrobial proteins · 2024Review
- Microbiome and cancer: from mechanistic implications in disease progression and treatment to development of novel antitumoral strategies.Frontiers in immunology · 2024Review
- Drug-microbiota interactions: an emerging priority for precision medicine.Signal transduction and targeted therapy · 2023Review
- A New Paradigm in the Relationship between Gut Microbiota and Breast Cancer: β-glucuronidase Enzyme Identified as Potential Therapeutic Target.Pathogens (Basel, Switzerland) · 2023Review
- How Can the Microbiome Induce Carcinogenesis and Modulate Drug Resistance in Cancer Therapy?International journal of molecular sciences · 2023Review
- Targeting the human gut microbiome with small-molecule inhibitors.Nature reviews. Chemistry · 2023Review
- Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer.World journal of gastroenterology · 2023Review
- Pharmacomicrobiomics in Pediatric Oncology: The Complex Interplay between Commonly Used Drugs and Gut Microbiome.International journal of molecular sciences · 2022Review
- The role of gut microbial β-glucuronidase in drug disposition and development.Drug discovery today · 2022Review
- Carbohydrate-active enzymes (CAZymes) in the gut microbiome.Nature reviews. Microbiology · 2022Review
- Review
- Converging multi-modality datasets to build efficient drug repositioning pipelines against Alzheimer's disease and related dementias.Medical review (2021) · 2022Article
- Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma.Frontiers in immunology · 2022Article
- Artificial intelligence unifies knowledge and actions in drug repositioning.Emerging topics in life sciences · 2021Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
purposeIrinotecan (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
designThe 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.
resultsComputational 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.
conclusionsAmoxapine has great clinical potential to be rapidly translated to human subjects for irinotecan-induced diarrhea.
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