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.
Stoyanovsky
Detcho A
DA
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. stoyanovskyd@msx.upmc.edu
Schor
Nina F
NF
Nylander
Karen D
KD
Salama
Guy
G
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004578:Electron Spin Resonance Spectroscopy; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D017665:Hydroxyl Radical / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009573:Nitrites / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D009573:Nitrites; C021229:oxyhyponitrite; D017665:Hydroxyl Radical