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Modulating Activity of ABC Transporters in Blood Brain Barrier Cells in Culture

The blood‐brain barrier (BBB) is a physical and dynamic barrier that separates the central nervous system from the circulatory system in order to protect the brain from harmful endogenous and exogenous chemicals. The capillary endothelial cells that form the BBB are firmly sealed via tight junctions and express relatively high amounts of ATP‐binding cassette efflux transporters like P‐glycoprotein (P‐gp) and the breast cancer resistant protein (BCRP) to protect the brain from entry of potentially harmful chemicals. While protective to the brain under normal circumstances, this high level of expression of these proteins at the BBB are problematic when attempting to treat diseases of the brain like neurodegenerative diseases or brain cancers since P‐gp and BCRP impede entry of therapeutic drugs into the brain. Previously, we have computationally identified several drug‐like molecules that inhibit or modulate P‐gp and/or BCRP activities. The cell line, hCMEC/d3, was used in our studies as a model for the BBB. Using qPCR, we confirmed a higher level of expression of both P‐gp and BCRP in hCMEC/d3 cells when compared to non‐cancerous HFL‐1 cells. When hCMEC/d3 cells were treated with the P‐gp and BCRP inhibitors, accumulation of the P‐gp substrate rhodamine‐123 as well as the P‐gp and BCRP substrates, mitoxantrone and daunorubicin, was observed. We conclude that our newly discovered P‐gp and BCRP inhibitors may make good leads for the development of co‐therapeutics to inhibit and/or modulate the activity of P‐gp and BCRP in the BBB and facilitate therapeutic drug uptake through the BBB and into the brain.