Targeting Nitric Oxide: Say NO to Metastasis

Abstract

Utilizing targeted therapies capable of reducing cancer metastasis, targeting chemoresistant and self-renewing cancer stem cells, and augmenting the efficacy of systemic chemo/radiotherapies is vital to minimize cancer-associated mortality. Targeting nitric oxide synthase (NOS), a protein within the tumor microenvironment, has gained interest as a promising therapeutic strategy to reduce metastatic capacity and augment the efficacy of chemo/radiotherapies in various solid malignancies. Our review highlights the influence of nitric oxide (NO) in tumor progression and cancer metastasis, as well as promising preclinical studies that evaluated NOS inhibitors as anticancer therapies. Lastly, we highlight the prospects and outstanding challenges of using NOS inhibitors in the clinical setting.

Figure 1.

Concentration-dependent influence of NO for cancer therapy and cellular signaling. A, Intermediate–low concentrations of NO can support tumor growth and angiogenesis and have cytoprotective effects. Inhibition of NO can be of safe therapeutic benefit by sensitizing tumor cells to standard anticancer therapies. High concentrations of NO can be cytostatic/cytotoxic. Therapeutic administration of NO at sufficiently high concentrations can have anticancer effects and potentiate the efficacy of anticancer chemo/radiotherapy. Inhibition of NO as an anticancer therapeutic has shown clinical benefit in cancers, such as chemorefractory TNBC, with minimal side effects. B, Different levels of intracellular NO released from various NOS isoforms can alter signaling pathways involved in cellular proliferation, CSC maintenance, metastasis, and cell-cycle arrest/apoptosis. sGC, soluble guanylate cyclase; ERK, extracellular signaling-regulated kinase; PI3K, phosphoinositide 3-kinase; HIF, hypoxia-inducible factor; EGFR, epidermal growth factor receptor; COX, cyclooxygenase. (Adapted from an image created with BioRender.com.)

Figure 2.

Hallmarks of the influence of NO in the TME. NO derived from iNOS/eNOS at intermediate concentrations within the TME (50–300 nmol/L) is involved in (1) maintaining chemoresistant CSCs with tumor-initiating potential, (2) promoting EMT, (3) activating factors crucial for cancer cell invasion and metastasis, (4) promoting molecular events crucial for cell proliferation/survival, (5) inducing angiogenesis, and (6) modulating immune responses (protumoral and immunosuppressive events). NO, nitric oxide; iNOS, inducible nitric oxide synthase; EMT, epithelial-to-mesenchymal transition; MET, mesenchymal-to-epithelial transition; NET, neutrophil extracellular traps; MMP, matrix metalloproteinase; TIMP1, tissue inhibitor of metalloproteinase; TME, tumor microenvironment; VEGF, vascular endothelial growth factor; Mo-MDSC, monocytic myeloid-derived suppressor cells; G-MDSC, granulocyte-like myeloid-derived suppressor cells; eNOS, endothelial nitric oxide synthase; CCL2, C–C motif chemokine ligand 2; SNO, S-nitrosothiol. (Adapted from an image created with BioRender.com.)