Work

Influence of pteridines and statins on cancer: A therapeutic strategy targeting nitric oxide synthase (NOS) pathway

Year: 2026

Type: article

Abstract: • Nitric Oxide (NO), a key signaling molecule which may exhibit a dual response, indicating the apoptotic/growth arrest or cell survival pathways gets triggered when NO levels surpass a threshold which would be a therapeutic strategy for Cancer. • Tetrahydrobiopterin (BH4) is a key cofactor for the Nitric oxide synthase (NOS) pathway which will enhance the production of NO in cells. • Statins, a group of drugs to treat hypercholesterolaemia also possess pleiotropic benefits in stimulating various pathways generating NO. • The use of statins in conjunction with pharmacologic modification of BH4 levels is a promising method for controlling NO in cancer cells. • By the synergistic treatment of Pterins and Statins may trigger various apoptotic pathways by the slow increase in NO concentration in cancer cells, including p53 phosphorylation, NF-kB inhibition, guanylyl cyclase activation, PDE inhibition, ROS activation, and more. • This approach may create a huge impact on the drug repurposing strategies in combating Cancer with minimal side effects. A family of enzymes known as nitric oxide synthases (NOS) produces nitric oxide (NO), a tiny, unstable, and potentially hazardous gas that is highly diffusible across cell membranes. NO and NO metabolites, such as nitrite, nitrate, S-nitrosothiols, nitrosamines, and peroxynitrite, mediate a variety of cytotoxic and genotoxic effects, such as inhibition of mitochondrial respiration, protein and DNA damage that leads to gene mutation, loss of protein function, necrosis, and apoptosis. Through a variety of apoptotic mechanisms, abnormally elevated NO generation by NOS II/iNOS may cause cytotoxicity of cancer cells. Tetrahydrobiopterin (BH4) is required by all NOS isoforms for NO production. Another way mammalian cells can create BH4 is by the "salvage pathway," which uses sepiapterin reductase and dihydrofolate reductase to convert sepiapterin to BH4. Better apoptotic effects on cancer cells may result from boosting BH4 levels by treating cells with sepiapterin, 7-8-dihydropterin, or pterin derivatives, which work in concert to improve NO levels. Another common medication used to treat and prevent hypercholesterolaemia and related cardiovascular disorders is statins, which lower serum cholesterol. They are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, the enzyme that limits the rate at which cholesterol is produced. Statins also improve cardiovascular and endothelial function by increasing the generation of nitric oxide (NO) by endothelial cells. They also have an impact on a variety of molecules and signaling pathways that govern the synthesis of apoptotic proteins and raise nitric oxide (NO) levels. Therefore, the NO-mediated route may be used to induce apoptosis due to the synergistic potency of statins and pterin derivatives. This review focusses on the effectiveness of statins and pterin derivatives, as well as their ability to influence the production of nitric oxide, which intensifies the effect on cancer cells.

Source: Advances in Redox Research

DOI: 10.1016/j.arres.2026.100152