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.