Role of Nitric Oxide in the Chemistry and Anticancer Activity of Etoposide (VP-16,213)

Originally identified as an innate cytotoxin, nitric oxide (·NO) formation in tumors can influence chemotherapy and exacerbate cancer progression. Here, we examined the hypothesis that ·NO generation contributes to cancer cell drug resistance toward the widely used anticancer drug Etoposide (VP-16). The UV–vis spectrum of VP-16 was not changed by exposure of VP-16 to ·NO in aqueous buffer. In contrast, reddish-orange compound(s) characteristic of o-quinone- and nitroso-VP-16 were readily generated in a hydrophobic medium (chloroform) in an oxygen-dependent manner. Similar products were also formed when the VP-16 radical, generated from VP-16 and horseradish peroxidase/H2O2, was exposed directly to ·NO in chloroform in the presence of oxygen. Separation and spectral analysis of VP-16 reaction extracts by electron spin resonance and UV–vis indicated the generation of the phenoxy radical and the o-quinone of VP-16, as well as putative nitroxide, iminoxyl, and other nitrogen oxide intermediates. Nitric oxide ...