The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

Abstract

Here evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast to normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on HPLC analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin: dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid and head and neck tumors compared to normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by clonogenic assay, Ki67 staining and 18F-deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and as a consequence nitric oxide synthase activity generates more peroxynitrite and superoxide anion than nitric oxide resulting in important tumor growth promoting and anti-apoptotic signaling properties. Implications The synthetic BH4, Kuvan®, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth.

Sepiapterin Enhances Tumor Radio- and Chemosensitivities by Promoting Vascular Normalization

“…In addition to being able to lower the dose of doxorubicin, SP has also been shown to improve cardiac function and reduce fibrosis in models of cardiac ischemia and pressure overload as well as ameliorate diabetic cardiomyopathy (Baumgardt et al, 2016). In addition to low toxicity, SP also demonstrates its own antitumor properties with MMTV-neu and other tumor models (Rabender et al, 2015).…”

“…For example, in the MMTV-neu model, the tumor BH4/BH2 ratio increases to 2.8 6 0.5 with oral administration of SP. The consequences of therapeutically increasing the BH4/BH2 ratio is the recoupling NOS activity, leading to enhanced generation of NO and causing a shift from proinflammatory/prosurvival signaling to anti-inflammatory/proapoptotic signaling resulting in the inhibition of spontaneous tumor growth (Rabender et al, 2015).…”

Oxidative stress and antioxidants in the pathophysiology of malignant melanoma

“…In contrast with normal tissues, an increase in superoxide and peroxynitrite generation associates to higher NOS activities of tumor cells (including melanoma). Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tet rahydrobiopterin:dihydrobiopterin ratio (BH4:BH2) resulting in important tumor growth promoting and anti-apoptotic signaling properties (Rabender et al, 2015). In addition, eNOS uncoupling seems to play a pivotal role in melanocyte malignant transformation induced by sustained anchorage impediment, because no malignant transformation was Brought to you by | University of California -Irvine Authenticated Download Date | 5/4/19 12:43 AM observed when L-NAME-treated melanocytes were subjected to sequential cycles of de-adhesion (Melo et al, 2011).…”

Role of Nitric Oxide Synthase in Normal Brain Function and Pathophysiology of Neural Diseases

“…However, that NOS dense status becomes sparse in the peritumoral tissues [73]. NOSs of tumour cells, opposite to the healthy cells, synthesize predominantly superoxide and peroxynitrite, which generate oxidative stress [74].…”