Na+: H+ exchange inhibition induces intracellular acidosis and differentially impairs cell growth and viability of human and rat hepatocarcinoma cells

Amiloride and its more potent analog, hexamethylene amiloride (HMA), inhibi ts Na+:H+ exchange and decreases intracellular pH in a concentration-depend ent way in two human hepatocarcinoma cell lines and in a rat hepatocarcinom a cell line that differs in its phenotypic characteristics, resembling the clinical situation encountered in human hepatocarcinomas. After 24 h of exp osure, DNA synthesis and cell protein content of the cultures decreases acc ording to the concentration of the drugs and in parallel to Na+ exchange in hibition and the drop in pH, promoted. RNA and protein syntheses are less s ensitive to its action. The above effects induced by HMA are accompanied by an abrupt decrease in cell viability and lysosomal integrity at 24 h. Thes e effects develop gradually with the exposure time as does the increase in free radical production. Decreased viability is totally or partially restor ed by N-acetylcysteine or deferoxamine, but the degree of Intracellular aci dification produced is not. These results tend to suggest that intracellula r acidification can diminish cell growth and provoke cytotoxic cell death b y diminishing reduced glutathione (GSH) levels and impairing lysosomal inte grity, reflecting the sensitivity of hepatocarcinoma cells to Na+ exchange inhibition and intracellular acidosis. (C) 1999 Elsevier Science Ireland Lt d. All rights reserved.