Poly-S-Nitrosated Albumin as a Safe and Effective Multifunctional Antitumor Agent: Characterization, Biochemistry and Possible Future Therapeutic Applications

Figure 6

Mechanisms of Poly-SNO-HSA as a safe and strong multiple antitumor agent. Fast and pronounced transfer of NO from Poly-SNO-HSA into the cell mainly takes place via cell-surface protein disulfide isomerase (PDI) and to a minor extent via 60 kDa glycoprotein (gp60). Within the cell, a high concentration of NO induces apoptosis by the mechanisms mentioned, and perhaps by other means not yet identified. NO also reverts dx resistance partly by activating a cGMP dependent pathway. Finally, NO reverts drug resistance by decreasing the efflux of the drug. The latter effect is brought about by decreasing the expression of hypoxia-inducible factor-1α (HIF-1α) and P-glycoprotein (P-gp). In addition, Poly-SNO-HSA inhibits hypoxia-induced autophagy via downregulation of the cell signaling factors LC3-II/LC3-I and Beclin-1. The green and red arrows represent increasing and decreasing effects, respectively.