The multidrug transporter ABCG2 (BCRP) is inhibited by plant‐derived cannabinoids
Open accessAbstract
Background and purpose: Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P‐glycoprotein in vitro . Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and Δ 9 ‐tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. Experimental approach: Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. Key results: CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over‐expressing cell line. The THC metabolite, (−)‐11‐nor‐9‐carboxy‐Δ 9 ‐THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub‐toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. Conclusions and implications: Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2‐mediated multidrug‐resistant phenotype in vitro . This finding may have implications for the co‐administration of cannabinoids with pharmaceuticals that are ABCG2 substrates. British Journal of Pharmacology (2007) 152 , 815–824; doi: 10.1038/sj.bjp.0707467 ; published online 1 October 2007
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Preclinical studies have reported that cannabinoids may also bind membrane transporters including breast cancer resistance protein and P-gp, which can, theoretically, impact the effect of other medications.
“Preclinical studies have reported that cannabinoids may also bind membrane transporters including breast cancer resistance protein111 and P-gp,112,113 which can, theoretically, impact the effect of other medications.”
From Clinical Practice Guidelines for Cannabis and Cannabinoid-Based Medicines in the Management of Chronic Pain and Co-Occurring Conditions (2024) · cites this paper as [111]
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- Authors
- Holland, M. L., Lau, D. T. T., Allen, J. D., & Arnold, J. C.
- Affiliations
- The University of Sydney (AU)
- Centenary Institute (AU)
- Corresponding author
- Arnold, J C
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2007-11
- Volume
- 152
- Issue
- 5
- Pages
- 815-824
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC2190019
- OpenAlex
- W1571533074
- Cited by
- 150
- References
- 38
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 8 · 2023: 14 · 2022: 14 · 2021: 11 · 2020: 13 · 2019: 11 · 2018: 9 · 2017: 5 · 2016: 14 · 2015: 6 · 2014: 3 · 2013: 10 · 2012: 6
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- ABCG2, multidrug transporter, cannabinol, cannabidiol, delta-9-tetrahydrocannabinol, multidrug resistance, chemosensitization, mitoxantrone, topotecan, cannabinoid receptors, vanilloid receptor, drug-drug interactions
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Adenosine Triphosphatases, Animals, Cannabinoids, Cell Line, Cell Survival, Dose-Response Relationship, Drug, Flow Cytometry, Humans, Mitoxantrone, Neoplasm Proteins, Plant Extracts, Sulfasalazine, Dronabinol, Immunoblotting, ATP-Binding Cassette Transporters, Topotecan, Inhibitory Concentration 50, Reverse Transcriptase Polymerase Chain Reaction, Receptor, Cannabinoid, CB1, Cell Line, Tumor, TRPV Cation Channels, Mice
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