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.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide [1].Epidemiology models estimate that there will be 104,610 new cases and 53,200 deaths in the U.S.among males and females in 2020 [2]
Previous studies have demonstrated that NOS1 promotes the survival of nasopharyngeal carcinoma cells and cancer-associated fibroblasts, but little has been related to colon cancer [42,43]
It has been reported that Maqui berry (MB) extracts downregulated the expression of inducible NO synthases (NOSs) (iNOS), resulting in the inhibition of nitric oxide (NO) production in human CRC cells
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide [1]. Advances in understanding colon carcinogenesis, drug discovery, and drug delivery systems contribute to novel targeting strategies for CRC prevention and therapy [5]. Nitric oxide (NO) can be synthesized in mammalian cells [6]. In various tissues, this free-radical gas is endogenously generated from L-arginine by a family of enzymes named NO synthases (NOSs), including neuronal NOS (nNOS/NOS1), inducible NOS (iNOS/NOS2), and endothelial NOS. ENOS and nNOS are constitutive, calcium-dependent isoforms with a low-output of NO, whereas inducible NOS (iNOS) is a calcium-independent and constantly inducible isoform. We discuss the conventional and innovative paradigms of NO donors and NOS chemo-inhibitors for CRC prevention and therapy
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