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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2014
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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. |
format | Online Article Text |
id | pubmed-4113800 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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