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

Marine Drugs

卷:12

Yun-Kai Zhang¹  Tanaji T. Talele¹  Zhe-Sheng Chen¹  Xue Xiao²  Xiao-Cong Huang²  Angela A. Salim²  Robert J. Capon² 

[1] Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences,St. John's University, Queens, NY 11439, USA;

[2] Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia;

关键词: ABC transporter;    multidrug resistance;    cancer;    P-glycoprotein;    BCRP;    MRP1;    lamellarin O;    marine natural products;   

DOI  :  10.3390/md12073818

来源: DOAJ

【 摘 要 】

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 byin silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore.

【 授权许可】

Unknown