60-Hz electric fields inhibit protein kinase C activity and multidrug resistance gene (MDR1) up-regulation.
Sixty-hertz electric fields have been shown to affect biological systems in a variety of ways, but the mechanisms by which electric fields influence cell function remain uncertain. We have investigated the effects of electric fields on cellular protein kinase C (PKC) activity and on the regulation of the multidrug resistance gene (MDR1), which is responsible for a major form of drug resistance in cancer. We found that exposure of H9 human leukemia cells to 60-Hz sinusoidal electric fields (330 or 750 mV/cm for 60 min) resulted in significantly decreased PKC activity in the cytosolic fraction, whereas electric fields at higher (1250 and 3000 mV/cm) or lower (10 mV/cm) intensities had no effect on PKC activity. Exposure of these cells to electric fields (330 or 750 mV/cm for 17 h) inhibited up-regulation of MDR1 expression by treatment with 25 microM 1-beta-D-arabinofuranosylcytosine (AraC). Again, lower or higher field strengths had little or no effect on the levels of AraC-induced MDR1 mRNA. Similarly, exposure of intact cells to staurosporine (100 nM), a potent PKC inhibitor, significantly reduced cytosolic PKC activity, but not that of the particulate fraction. Staurosporine also prevented AraC-induced MDR1 overexpression. These data show that intermediate-strength electric fields inhibit cytosolic PKC and suggest that electric fields and pharmacological inhibitors of PKC, such as staurosporine, affect cytosolic PKC activity and AraC-induced MDR1 overexpression through related mechanisms. Our findings also suggest the possible utility of 60-Hz electric fields for modulating multidrug resistance in tumor cells.
Walter
R J
RJ
Department of Surgery, Cook County Hospital, Chicago, Illinois 60612, USA.
Shtil
A A
AA
Roninson
I B
IB
Holian
O
O
D003561:Cytarabine / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D018432:Drug Resistance, Multiple; D004560:Electricity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D019450:Genes, MDR; D006801:Humans; D015458:Leukemia, T-Cell; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D003561:Cytarabine; D011493:Protein Kinase C; D019311:Staurosporine