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.