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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / antagonists & inhibitors*
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ATP-Binding Cassette Transporters / physiology
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Animals
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Australia
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Coumarins / pharmacology*
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Doxorubicin / pharmacology
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm / drug effects*
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Fluoresceins / metabolism
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Humans
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Isoquinolines / pharmacology*
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Mitoxantrone / metabolism
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Molecular Docking Simulation
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Multidrug Resistance-Associated Proteins / physiology
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / physiology
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Porifera / metabolism*
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Structure-Activity Relationship
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Coumarins
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Fluoresceins
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Heterocyclic Compounds, 4 or More Rings
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Isoquinolines
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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lamellarin O
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Doxorubicin
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Mitoxantrone
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fluorexon
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multidrug resistance-associated protein 1