ArticleBlood2013
The constitutive androstane receptor is a novel therapeutic target facilitating cyclophosphamide-based treatment of hematopoietic malignancies.
Article in Blood, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 44 citations in OpenAlex.
- Mitigating cyclophosphamide-induced hepatorenal toxicity: Linalool's role in modulating oxidative stress, inflammation, and apoptosis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies.Journal of medicinal chemistry · 2025Article
- Prodrugs in Oncology: Bioactivation and Impact on Therapeutic Efficacy and Toxicity.International journal of molecular sciences · 2025Review
- Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review.Cells · 2024Review
- Clinical Relevance of the Constitutive Androstane Receptor.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment.JCI insight · 2022Article
- CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function.Scientific reports · 2022Article
- Article
- Alogliptin: a novel approach against cyclophosphamide-induced hepatic injury via modulating SIRT1/FoxO1 pathway.Toxicology research · 2020Article
- Ser100-Phosphorylated RORMolecular pharmacology · 2020Article
- Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies.European journal of medicinal chemistry · 2019Article
- DL5050, a Selective Agonist for the Human Constitutive Androstane Receptor.ACS medicinal chemistry letters · 2019Article
- Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases.International journal of molecular sciences · 2018Review
- Molecular Basis of Metabolism-Mediated Conversion of PK11195 from an Antagonist to an Agonist of the Constitutive Androstane Receptor.Molecular pharmacology · 2017Article
- Insights into CYP2B6-mediated drug-drug interactions.Acta pharmaceutica Sinica. B · 2016Review
- Small-molecule modulators of PXR and CAR.Biochimica et biophysica acta · 2016Review
- Antiproliferation of berberine is mediated by epigenetic modification of constitutive androstane receptor (CAR) metabolic pathway in hepatoma cells.Scientific reports · 2016Article
- Activation of the Constitutive Androstane Receptor Increases the Therapeutic Index of CHOP in Lymphoma Treatment.Molecular cancer therapeutics · 2016Article
- Transcriptional Regulation of CYP2B6 Expression by Hepatocyte Nuclear Factor 3β in Human Liver Cells.PloS one · 2016Article
- Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid.Scientific reports · 2015Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Cyclophosphamide (CPA) is one of the most widely used chemotherapeutic prodrugs that undergoes hepatic bioactivation mediated predominantly by cytochrome P450 (CYP) 2B6. Given that the CYP2B6 gene is primarily regulated by the constitutive androstane receptor (CAR, NR1I3), we hypothesize that selective activation of CAR can enhance systemic exposure of the pharmacologically active 4-hydroxycyclophosamide (4-OH-CPA), with improved efficacy of CPA-based chemotherapy. In this study, we have developed a unique human primary hepatocyte (HPH)-leukemia cell coculture model; the chemotherapeutic effects of CPA on leukemia cells can be directly investigated in vitro in a cellular environment where hepatic metabolism was well maintained. Our results demonstrated that activation of CAR preferentially induces the expression of CYP2B6 over CYP3A4 in HPHs, although endogenous expression of these enzymes in leukemia cells remains negligible. Importantly, coadministration of CPA with a human CAR activator led to significantly enhanced cytotoxicity in leukemia cells by inducing the apoptosis pathways, without concomitant increase in the off-target hepatotoxicity. Associated with the enhanced antitumor activity, a time and concentration-dependent increase in 4-OH-CPA formation was observed in the coculture system. Together, our findings offer proof of concept that CAR as a novel molecular target can facilitate CPA-based chemotherapy by selectively promoting its bioactivation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.