Interaction of bioactive hydrophobic peptides with the human multidrug transporter.
In this report we demonstrate that various biologically active hydrophobic peptide derivatives, e.g., proteinase inhibitors, chemoattractants, ionophores, enkephalins, and immunosuppressants, stimulate a membrane ATPase activity associated with the human multidrug transporter (MDR1). The stimulation of the MDR1-ATPase by these agents does not correlate with their known biochemical or pharmacological activities but rather with their hydrophobicity. The peptides that show high-affinity interaction with the MDR1-ATPase also interfere strongly with fluorescent dye extrusion catalyzed by the multidrug transporter in intact cells and some have been shown to reverse drug resistance in cultured cells. These data suggest that several hydrophobic peptides behave as substrates of the multidrug transporter and may be used to modulate the chemotherapy resistance of tumor cells.
Sarkadi
B
B
National Institute of Haematology, Blood Transfusion and Immunology, Budapest, Hungary.
Müller
M
M
Homolya
L
L
Holló
Z
Z
Seprödi
J
J
Germann
U A
UA
Gottesman
M M
MM
Price
E M
EM
Boucher
R C
RC
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004351:Drug Resistance; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009036:Moths; D010455:Peptides / Q000378:metabolism*; D013050:Spectrometry, Fluorescence
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D010455:Peptides; D000251:Adenosine Triphosphatases