Effects of 6-aminonicotinamide on cell growth, poly(ADP-ribose) synthesis and nucleotide metabolism

Abstract

The purpose of this study was to determine if the cytotoxic effects of 6—aminonicotinamide are solely the result of an inhibition of poly(ADP-ribose) synthesis. The effects of 6-aminonicotinamide on cell growth, poly(ADP-ribose) synthesis and nucleotide concentrations were compared with the effect of 3-aminobenzamide, a more potent inhibitor of poly(ADP-ribose) synthesis. The growth of L1210 cells was not inhibited by 1 mM 3-aminobenzamide and was only slightly inhibited by 5 mM 3-aminobenzamide even though poly(ADP-ribose) synthesis, as measured by the N-methyl N-nitrosourea induced depletion of NAD +, was inhibited substantially. In contrast, 6-aminonicotinamide was found to be a potent inhibitor of L1210 and CHO cell growth. A 5 mM concentration of 3-aminobenzamide had no effect on purine and pyrimidine ribonucleotide concentrations or on the ATP to ADP ratio, but it did cause a slight elevation of NAD +. 6-Aminonicotinamide at 0.01 mM caused a depletion of purine and pyrimidine nucleotides and NAD + as well as a reduction in the ATP to ADP ratio. 6-Aminonicotinamide at 1 mM caused a substantial inhibition of purine nucleotide synthesis from [ 14C] glycine but did not stimulate ATP breakdown. We conclude that inhibition of poly(ADP-ribose) synthesis caused little growth inhibition in itself and that the effects of 6-amininicotinamide on nucleotide metabolism were sufficient to produce an inhibition of both cell growth and DNA repair.