Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer

Abstract

Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)—a free-radical gas—plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. Endogenous levels of NO promote colon neoplasms, whereas exogenously sustained doses lead to cytotoxic functions. Importantly, NO has been implicated as an essential mediator in many signaling pathways in CRC, such as the Wnt/β-catenin and extracellular-signal-regulated kinase (ERK) pathways, which are closely associated with cancer initiation, metastasis, inflammation, and chemo-/radio-resistance. Therefore, NO/NOS have been proposed as promising targets in the regulation of CRC carcinogenesis. Clinically relevant NO-donating agents have been developed for CRC therapy to deliver a high level of NO to tumor sites. Notably, inducible NOS (iNOS) is ubiquitously over-expressed in inflammatory-associated colon cancer. The development of iNOS inhibitors contributes to targeted therapies for CRC with clinical benefits. In this review, we summarize the multifaceted mechanisms of NO-mediated networks in several hallmarks of CRC. We review the clinical manifestation and limitations of NO donors and NOS inhibitors in clinical trials. We also discuss the possible directions of NO/NOS therapies in the immediate future.

Helicase-like transcription factor-deletion from the tumor microenvironment in a cell line-derived xenograft model of colorectal cancer reprogrammed the human transcriptome-S-nitroso-proteome to promote inflammation and redirect metastasis

“…HLTF is a zinc finger protein with a highly conserved C3HC4 ring motif (aa760-801); however, we found no evidence of human HLTF-SNO in primary tumors from Hltf +/+ TME. Collectively, these findings support ongoing efforts to find selective iNOS inhibitors as chemo-preventive agents against CRC [23].…”

“…CRC progression is accompanied by overexpression of nitric oxide (NO)—a diffusible/pleiotropic regulator of many normal cellular processes—implicated in the activation of oncogenic signaling pathways [ 22 , 23 ]. NO is endogenously generated by three different isoforms of the enzyme NO synthase (NOS) using L-arginine and molecular oxygen as substrates.…”

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

“…Previous studies reported that NOS activity modulates β -catenin posttranslational modifications to promote endothelial cell survival [ 23 ]. NO acted a mediator in colorectal cancer via Wnt/ β -catenin pathway, which was closely associated with cancer initiation and metastasis [ 24 ]. All findings indicate that iNOS might be an important regulator in OS development.…”

The Etiology and Pathophysiology Genesis of Benign Prostatic Hyperplasia and Prostate Cancer: A New Perspective

“…Nutraceuticals supplement: three supplement combinations [231][232][233][234][235][236][237][238][239][240] are necessary to ameliorate the biological processes of endothelial dysfunction (e.g., l-citrulline [241][242][243], l-arginine [244,245]), oxidative stress and inflammation [246]; publications on this topic are extensive and therefore it is not discussed here.…”