Nitric Oxide-Releasing Hybrid Drugs Target Cellular Processes Through S-Nitrosylation.

Nitric oxide (NO)-releasing agents such as JS-K and NO-releasing hybrids such as NO- and NONO-nonsteroidal anti-inflammatory drugs are novel agents with great potential for controlling cancer. Although studied extensively, a key question pertaining to their molecular targets and mechanism of action remains unclear: the role of NO in the overall biological effect of these agents. It has been shown that NO can directly modify sulfhydryl residues of proteins through S-nitrosylation and induce apoptosis. We showed that 3 structurally diverse NO-nonsteroidal anti-inflammatory drugs S-nitrosylated nuclear factor-κB p65 in vitro and in vivo and also showed that these agents S-nitrosylated caspase-3 in vivo. JS-K reduced nuclear β-catenin and cyclin D1 protein levels without affecting cytosolic β-catenin expression. On the basis of a time course study, S-nitrsolyation of nuclear β-catenin was determined to precede its degradation. These data provide a mechanistic role for NO and a rationale for the chemopreventive effects of these novel agents.