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

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...

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Autores principales: Huang, Xiao-Cong, Xiao, Xue, Zhang, Yun-Kai, Talele, Tanaji T., Salim, Angela A., Chen, Zhe-Sheng, Capon, Robert J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113800/
https://www.ncbi.nlm.nih.gov/pubmed/24979269
http://dx.doi.org/10.3390/md12073818
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author Huang, Xiao-Cong
Xiao, Xue
Zhang, Yun-Kai
Talele, Tanaji T.
Salim, Angela A.
Chen, Zhe-Sheng
Capon, Robert J.
author_facet Huang, Xiao-Cong
Xiao, Xue
Zhang, Yun-Kai
Talele, Tanaji T.
Salim, Angela A.
Chen, Zhe-Sheng
Capon, Robert J.
author_sort Huang, Xiao-Cong
collection PubMed
description 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.
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spelling pubmed-41138002014-07-29 Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells Huang, Xiao-Cong Xiao, Xue Zhang, Yun-Kai Talele, Tanaji T. Salim, Angela A. Chen, Zhe-Sheng Capon, Robert J. Mar Drugs Article 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. MDPI 2014-06-27 /pmc/articles/PMC4113800/ /pubmed/24979269 http://dx.doi.org/10.3390/md12073818 Text en © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Huang, Xiao-Cong
Xiao, Xue
Zhang, Yun-Kai
Talele, Tanaji T.
Salim, Angela A.
Chen, Zhe-Sheng
Capon, Robert J.
Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells
title Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells
title_full Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells
title_fullStr Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells
title_full_unstemmed Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells
title_short Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells
title_sort lamellarin o, a pyrrole alkaloid from an australian marine sponge, ianthella sp., reverses bcrp mediated drug resistance in cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113800/
https://www.ncbi.nlm.nih.gov/pubmed/24979269
http://dx.doi.org/10.3390/md12073818
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