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Mar. Drugs 2014, 12(7), 3818-3837; https://doi.org/10.3390/md12073818

Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells

1
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia
2
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 29 May 2014 / Revised: 13 June 2014 / Accepted: 16 June 2014 / Published: 27 June 2014
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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 112 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 112 and the synthetic analogues 1319, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore. View Full-Text
Keywords: ABC transporter; multidrug resistance; cancer; P-glycoprotein; BCRP; MRP1; lamellarin O; marine natural products ABC transporter; multidrug resistance; cancer; P-glycoprotein; BCRP; MRP1; lamellarin O; marine natural products
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Huang, X.-C.; Xiao, X.; Zhang, Y.-K.; Talele, T.T.; Salim, A.A.; Chen, Z.-S.; Capon, R.J. Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells. Mar. Drugs 2014, 12, 3818-3837.

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