Albumin as a Nitric Oxide-Traffic Protein : Novel Anticancer Agent

Objective While Nitro Oxide (NO) has a wide range of biological functions, NO therapy still has problems that need to be overcome, such as its short half-life in vivo ( ~0.1 s). To accomplish this, we examined human serum... [ view full abstract ]

Objective While Nitro Oxide (NO) has a wide range of biological functions, NO therapy still has problems that need to be overcome, such as its short half-life in vivo ( ~0.1 s). To accomplish this, we examined human serum albumin (HSA) because it is the most abundant plasma protein and endogenous S-nitrosothiols in human plasma are largely associated with HSA. S-nitrosated HSA (SNO-HSA) is significantly more stable than low molecular weight S-nitrosothiols. It should also be noted that the cellular uptake of NO from HSA with one NO-moiety results in cytoprotective effects, whereas HSA with more SNO-groups induces apoptosis, an effect that is probably useful in cancer therapy. We introduced two type SNO-HSA, ca 7 conjugated SNO groups using chemical modification (Poly-SNO-HSA) and an S-nitrosated recombinant HSA dimer (SNO-AL –Dimer), as possible cancer therapeutic applications.
Results and Discussion　　The transfer of NO from Poly-SNO-HSA to cells was faster and more pronounced. Surprisingly, the inflow of NO results in apoptotic cell death by ROS induction and caspase-3 activation and not cytoprotection.
Interestingly, NO donors the such as nitroglycerin have been reported to reverse resistant to anticancer agents. Therefore, we evaluated the effect of Poly-SNO-HSA on the resistance of human myelogunous leukemic cells (K562 cells) to doxorubicin (dx). The results showed that treatment with Poly-SNO-HSA increased its accumulation in dx-resistant K562 cells (K562/dx). Furthermore, Poly-SNO-HSA enhanced the anticancer effect of dx in K562/dx mice. Poly-SNO-HSA reversed dx resistance by decreasing the expression of P-gp and HIF-1-α.
The SNO-AL-Dimer was found to specifically deliver large amounts of cytotoxic NO to tumor tissue but not to normal organs in C26 tumor-bearing mice. In this respect, the SNO-AL-Dimer is superior to SNO-HSA and GS-NO. Interestingly, S-nitrosation improved the uptake of the HSA dimer in tumor tissue through augmenting the enhanced permeability and retention (EPR) effect. The data suggest that the SNO-AL-Dimer behaves not only as an anticancer therapeutic drug but also as a potentiator of the EPR effect. Therefore, the SNO-AL-Dimer might be a very appealing carrier for utilizating the EPR effect in cancer therapeutics.