The effect of ion channel blockers, immunosuppressive agents, and other drugs on the activity of the multi-drug transporter.
The MDRI protein is an energy-dependent transport protein responsible for the multi-drug resistance seen in many tumors. A variety of drugs have been shown to inhibit the function of this pump, including compounds known to block various ion channels. The mouse lymphoma cell line L5178Y has been transduced with the human mdrI gene. Using this cell line, we have tested a number of compounds to determine whether there is a correlation between the ability to block a specific type of ion channel, or shift membrane potential, and the ability to act as an MDR-reversing agent using the fluorescent substrates Rhodamine 123 and daunorubicin as test compounds. Our results show no apparent correlation between the ability to block a specific ion channel and reversal of MDR transport ability. We have found active MDR inhibitors in compounds that affect K+, Na+, Ca++, H+, but not Cl- channels. Our data suggest that Cl- channel activity may be distinct from MDR activity. Several immunosuppressive compounds and analogs were also tested and found to be active reversing agents. Measurements suggest a significant difference in resting membrane potential between the L5178YvMDR line and the L5178Y parental cell line used in these experiments. No correlation was found between the ability of drugs to alter membrane potential and to inhibit MDR transport activity. Our results suggest that MDR transport function may be independent of the physiological movement of ions and show that a wide variety of compounds can inhibit MDR transport.
Weaver
J L
JL
Division of Research and Testing, Food and Drug Administration, Washington, DC 20204.
Szabo
G
G
Pine
P S
PS
Gottesman
M M
MM
Goldenberg
S
S
Aszalos
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000595:Amino Acid Sequence; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003630:Daunorubicin / Q000378:metabolism / Q000493:pharmacokinetics; D004351:Drug Resistance; D004988:Ethers, Cyclic / Q000494:pharmacology; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D006863:Hydrogen-Ion Concentration; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000737:chemistry; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism*; D007940:Leukemia L5178 / Q000188:drug therapy / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D011188:Potassium; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001572:Benzofurans; D002352:Carrier Proteins; D004988:Ethers, Cyclic; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D007473:Ion Channels; D008562:Membrane Glycoproteins; D015221:Potassium Channels; D012235:Rhodamines; C073886:potassium-binding benzofuran isophthalate; D020112:Rhodamine 123; D011188:Potassium; D003630:Daunorubicin