Effects of pH on the Cytotoxicity of Sodium Trioxodinitrate (Angeli's Salt)

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Abstract
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−NN−OH; 3) with concomitant azo-type homolytic fission to N2 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.