LINEAR AND CYCLIC-PEPTIDES AS SUBSTRATES AND MODULATORS OF P-GLYCOPROTEIN - PEPTIDE BINDING AND EFFECTS ON DRUG TRANSPORT AND ACCUMULATION

One cause of multidrug resistance (MDR) in human cancers is the overex pression of the P-glycoprotein multidrug transporter, a member of the ABC superfamily of membrane proteins. Natural products and chemotherap eutic drugs are pumped out of the cell by P-glycoprotein in an ATP-dep endent fashion. There is growing evidence that many hydrophobic peptid es are also P-glycoprotein substrates. With the use of a fluorescence- quenching assay, we have shown that some linear and cyclic hydrophobic peptides interact with P-glycoprotein, whereas others do not. The mea sured values of the quenching constant, K-q, for interaction of peptid es with P-glycoprotein ranged from 200 nM for cyclosporine A to 138 mu M for the tripeptide N-acetyl-leucyl-leucyl-norleucinal. Peptides tha t interacted with P-glycoprotein in the fluorescence assay also blocke d colchicine transport into plasma membrane vesicles from MDR cells. T he values of D-m, the peptide concentration causing 50 % inhibition of drug uptake, were highly correlated with the values of K-q, over thre e orders of magnitude. The P-glycoprotein ATPase stimulation/inhibitio n profile of the peptides was not helpful in making a quantitative ass essment of the ability of a peptide to interact with P-glycoprotein or to block drug transport. Some hydrophobic peptides were able to resto re accumulation in MDR cells of the chemotherapeutic drug daunorubicin and the fluorescent dye rhodamine 123 to the levels observed in the d rug-sensitive parent. Peptides that interacted with P-glycoprotein als o displayed a relatively low overall toxicity to intact MDR cells, and inhibited drug transport at concentrations below the toxic range. Hyd rophobic peptides should be given serious consideration for developmen t as clinical chemosensitizing agents.