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 syste ms in a variety of ways, but the mechanisms by which electric fields i nfluence cell function remain uncertain. We have investigated the effe cts of electric fields on cellular protein kinase C (PKC) activity and on the regulation of the multidrug resistance gene (MDR1), which is r esponsible for a major form of drug resistance in cancer. We found tha t exposure of H9 human leukemia cells to 60-Hz sinusoidal electric fie lds (330 or 750 mV/cm for 60 min) resulted in significantly decreased PKC activity in the cytosolic fraction, whereas electric fields at hig her (1250 and 3000 mV/cm) or lower (10 mV/cm) intensities had no effec t 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 trea tment with 25 mu M 1-beta-D-arabinofuranosylcytosine (AraC). Again, lo wer or higher field strengths;had little or no effect on the levels of AraC-induced MDR1 mRNA. Similarly, exposure of intact cells to stauro sporine (100 nM), a potent PKC inhibitor, significantly reduced cytoso lic PKC activity, but not that of the particulate fraction. Staurospor ine also prevented AraC-induced MDR1 overexpression. These data show t hat intermediate-strength electric fields inhibit cytosolic PKC and su ggest 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. (C) 1997 by Radiation Research Society.