Abnormal chloride conductance in multidrug resistant HL60/AR cells.
Chloride channel currents were measured in drug sensitive parental HL60 and multidrug resistant (MDR) subline HL60/AR cells, using a whole cell patch-clamp technique. In addition, the in vitro effects of 4,4' diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), a Cl- channel blocker, on intracellular accumulation and sensitivity to daunorubicin and intracellular pH (pH(i)) in HL60 cells were examined. Baseline DIDS blockable Cl- currents were consistently lower in HL60/AR cells (0.9 pA/pF) as compared to HL60 cells (7.0 pA/pF). Similarly cAMP-activated Cl- currents were minimal in HL60/AR cells (0.2 pA/pF) as compared to HL60 cells (8 pA/pF). In vitro treatment of drug sensitive HL60 cells with DIDS resulted in concentration-dependent decreased accumulation and increased resistance to daunorubicin and decreased pH(i). These data show that altered Cl- permeability is associated with MDR and suggest that Cl- channels may play a role in MDR.
Gollapudi
S
S
Division of Basic and Clinical Immunology, University of California, Irvine 92717.
McDonald
T
T
Gardner
P
P
Kang
N
N
Gupta
S
S
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism / Q000493:pharmacokinetics; D000242:Cyclic AMP / Q000494:pharmacology; D003630:Daunorubicin / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism*; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D004317:Doxorubicin; D000242:Cyclic AMP; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D003630:Daunorubicin