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.
Highlights
Cancer is the leading cause of death and represents a large diverse group of diseases, of which some can spread to other sites of the body and result in systemic metastasis
This study demonstrated that ianthellidones 1–8 and lamellarins 9–10 and 12 were non-cytotoxic towards SW620 and SW620 Ad300 (IC50 > 30 μM), while lamellarin O (11) exhibited comparable and moderate cytotoxicity towards both SW620 (IC50 22.0 μM) and SW620 Ad300 (IC50 22.3 μM) (Supplementary Table S1), with the maximal concentration for >80% survival of SW620 and SW620 Ad300 cells being 15 μM
This study indicates that 11 is a promising breast cancer resistant protein (BCRP) inhibitor, with the potential to increase uptake and decrease efflux of cancer chemotherapeutics in BCRP over-expressing cells
Summary
Cancer is the leading cause of death and represents a large diverse group of diseases, of which some can spread to other sites of the body and result in systemic metastasis. The over-expression of three ATP binding cassette (ABC) transporters, P-glycoprotein (P-gp) [1,2], breast cancer resistant protein (BCRP) [3] and/or multi-drug resistance protein 1 (MRP1) [4], have been correlated with many occurrences of MDR. Three generations of P-gp inhibitors have been developed [5], none have proved to be clinically useful Despite these disappointing results, the need to discover clinically effective inhibitors remains as compelling as ever [6], with marine natural products representing an attractive source of bioactive chemical diversity
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