Reversal of P-glycoprotein-mediated multidrug resistance by cholesterol derived from low density lipoprotein in a vinblastine-resistant human lymphoblastic leukemia cell line.
Biochem Cell Biol. 2007 Oct;85(5):638-46. PMID: 17901905
School of Pharmacy, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, NL A1B 3V6, [corrected] Canada.
P-glycoprotein (P-gp) is believed to be one of the most common causes of multidrug resistance (MDR) in chemotherapy. Studies have shown that the biosynthesis of cholesterol and cholesterol esters interfere with the function of P-gp. Since low density lipoprotein (LDL) carries a large amount of cholesterol, we investigated the effect of cholesterol derived from LDL on a line of human lymphoblastic leukemia MDR cells, CEM/VLB. Our results demonstrated that, in addition to increased cytotoxicity, the uptake of vinblastine in CEM/VLB cells increased, and LDL subsequently increased the intracellular vinblastine concentrations retained by CEM/VLB cells. The cholesterol levels in the membrane of the MDR cells were restored, while LDL significantly decreased the P-gp-associated ATPase activity. Current studies have shown that LDL leads to the resensitization of CEM/VLB cells to cytotoxic agents, likely through the restoration of cholesterol and reduction of P-gp-associated ATPase in the cell membrane.