Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer
College of Laboratory Medicine, Jilin Medical University, Jilin 132013, China
Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA
Department of Statistics, North Dakota University, Fargo, ND 58105, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(7), 1881; https://doi.org/10.3390/cancers12071881
Received: 30 May 2020 / Revised: 10 July 2020 / Accepted: 10 July 2020 / Published: 13 July 2020
(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)
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.