Lamellarin O, a pyrrole alkaloid from an Australian marine sponge, Ianthella sp., reverses BCRP mediated drug resistance in cancer cells
- PMID: 24979269
- PMCID: PMC4113800
- DOI: 10.3390/md12073818
Lamellarin O, a pyrrole alkaloid from an Australian marine sponge, Ianthella sp., reverses BCRP mediated drug resistance in cancer cells
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.
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References
-
- Hegedus C., Ozvegy-Laczka C., Apati A., Magocsi M., Nemet K., Orfi L., Keri G., Katona M., Takats Z., Varadi A., et al. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: Implications for altered anti-cancer effects and pharmacological properties. Br. J. Pharmacol. 2009;158:1153–1164. doi: 10.1111/j.1476-5381.2009.00383.x. - DOI - PMC - PubMed
-
- Cole S.P.C., Bhardwaj G., Gerlach J.H., Mackie J.E., Grant C.E., Almquist K.C., Stewart A.J., Kurz E.U., Duncan A.M.V., Deeley R.G. Overexpression of a transporter gene in a multidrug-resistant human lung-cancer cell-line. Science. 1992;258:1650–1654. - PubMed
-
- Szakacs G., Paterson J.K., Ludwig J.A., Booth-Genthe C., Gottesman M.M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 2006;5:219–234. - PubMed
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