Effects of pH on the cytotoxicity of sodium trioxodinitrate (Angeli's salt)

Tumor tissues have an acidic microenvironment with a PH from 6.0 to 7.0, whereas the intra-and extracellular milieu of normal cells is 7.4. We have found that the hydrolysis of sodium trioxodinitrate (Angeli's salt; 1) to hydroxyl radical (-OH) was 10 times higher at PH = 6.0 than at PH = 7.4. It is hypothesized that the formation of -OH in solutions of 1 reflects the hydrolysis of the latter compound to nitroxyl (HNO) which dimerizes to cis-hyponitrous acid (HO-N=N-OH; 3) with concomitant azo-type homolytic fission to N-2 and -OH. In weakly acidified solutions, 1 exhibited strong toxicity to cancer cells that was inhibited by scavengers of hydroxyl radical, whereas no toxicity was observed at pH = 7.4. In a subcutaneous xenograft model of pheochromocytoma, 1 markedly inhibited tumor growth at a dose that was nontoxic to nude mice. These data suggest that the H+-amplified production of -OH from 1, and maybe other precursors of HNO, could be a selective mechanism for destruction cells with an acidic intra- or extracellular microenvironment.