S-nitroso adducts of albumin analogs: Characterization, categorization, and possible future therapeutic applications

Abstract

Nitric oxide (NO) is a ubiquitous messenger molecule that is involved in multiple cellular functions. In particular, NO has multiple important actions that contribute to the maintenance of vascular homeostasis. Thus, an inappropriate production of NO leads to a disease state. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by undesirable side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties would be highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA), and that is why we are testing whether this albumin form has the potential to be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA) which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA exerts very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In addition, we recently developed an S-nitrosated HSA dimer (SNO-HSA dimer) as a novel enhanced permeability and retention (EPR) effect enhancer. The SNO-HSA dimer increases the tumor accumulation of macromolecular antitumor drugs by a factor 3-4 and thereby their antitumor effects. In this review, we first summarize the effective factors on the S-nitrosation and S-denitrosation of HSA both in vitro and in biological systems. Finally, we propose the possibility that Poly-SNO-HSA and SNO-HSA dimer can be used as a safe and effective multifunctional antitumor agent and as a nano-EPR enhancer.