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Lamellarin O, a pyrrole alkaloid from an Australian marine sponge, Ianthella sp., reverses BCRP mediated drug resistance in cancer cells.
- Source :
-
Marine drugs [Mar Drugs] 2014 Jun 27; Vol. 12 (7), pp. 3818-37. Date of Electronic Publication: 2014 Jun 27. - Publication Year :
- 2014
-
Abstract
- ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this molecular target nevertheless remains a promising strategy for addressing and potentially overcoming MDR. In a search for new classes of inhibitor, we used fluorescent accumulation and efflux assays supported by cell flow cytometry and MDR reversal assays, against a panel of sensitive and MDR human cancer cell lines, to evaluate the marine sponge co-metabolites 1-12 as inhibitors of P-gp, BCRP or MRP1 initiated MDR. These studies identified and characterized lamellarin O (11) as a selective inhibitor of BCRP mediated drug efflux. A structure-activity relationship analysis inclusive of the natural products 1-12 and the synthetic analogues 13-19, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters physiology
Animals
Australia
Doxorubicin pharmacology
Drug Resistance, Multiple
Fluoresceins metabolism
Humans
Mitoxantrone metabolism
Molecular Docking Simulation
Multidrug Resistance-Associated Proteins physiology
Neoplasm Proteins physiology
Structure-Activity Relationship
ATP-Binding Cassette Transporters antagonists & inhibitors
Coumarins pharmacology
Drug Resistance, Neoplasm drug effects
Heterocyclic Compounds, 4 or More Rings pharmacology
Isoquinolines pharmacology
Neoplasm Proteins antagonists & inhibitors
Porifera metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1660-3397
- Volume :
- 12
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Marine drugs
- Publication Type :
- Academic Journal
- Accession number :
- 24979269
- Full Text :
- https://doi.org/10.3390/md12073818