MECHANISM OF POTENTIATION OF LY83585-INDUCED GROWTH-INHIBITION BY SODIUM-NITROPRUSSIDE IN HUMAN BRAIN-TUMOR CELLS

The effect of 6-anilino-5,8-quinolinedione (LY83583), an inhibitor of guanylyl cyclase (GC), on the growth of human brain tumor cells (U-373 MG astrocytoma and SK-N-MC neuroblastoma) was evaluated. LY83583 inhi bited the growth of these cells in a dose-dependent manner. This growt h inhibition was found to be the result of decreased cell viability as assessed by the trypan blue exclusion method. The LY83583-induced dec rease in cell viability was not altered by dibutyryl cyclic GMP, but s ignificantly was reversed by superoxide dismutase and catalase, indica ting that these effects of LY83583 may not be due to the inhibition of GC, but due to the formation of superoxide anion. The LY83583-induced decrease in cell viability was potentiated by cotreatment with sodium nitroprusside (SNP), a nitric oxide (NO) donor. This SNP-induced pote ntiation was significantly blocked by various scavengers for hydroxyl radicals or by intracellular Ca2+ release blockers. These results sugg est that the potentiation effects of SNP may be mediated through the g eneration of hydroxyl radicals which can be formed by the interaction of superoxide anion (from LY83583) and NO (from SNP), and that intrace llular Ca2+ release from internal stores may play an important role in the cytotoxic mechanism of hydroxyl radicals.