Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumorigenic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, the presence or absence of NO transduction elements, and the tumor microenvironment. Generally, there are four major categories of NO-based anticancer therapies: NO donors, phosphodiesterase inhibitors (PDE-i), soluble guanylyl cyclase (sGC) activators, and immunomodulators. Of these, NO donors are well studied, well characterized, and also the most promising. In this study, we review the current knowledge in this area, with an emphasis placed on the role of NO as an anticancer therapy and dysregulated molecular interactions during the evolution of cancer, highlighting the strategies that may aid in the targeting of cancer.

Best JC, et al. World J Mens Health. 2021 Jan;39:e12. https://doi.org/10.5534/wjmh.200192

Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.

Sustained oxidative overload in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R blockade therapy (CSF1Ri) is limited as a monotherapy. We postulated that one of the causative agents for reduced efficacy of CSF1Ri and increased oxidation in CRPC is endothelial nitric oxide syntheses (eNOS). Results showed that in high grade PCa human specimens, eNOS is positively correlated with CSF1-CSF1R signaling and remains in an un-coupled state. The uncoupling disables eNOS to generate sufficient Nitric oxide (NO) that are required for inducing effective S-nitrosylation of CSF1R molecule at specific cysteine sites (Cys 224, Cys 278 and Cys 830). We found that exogenous NO treatment (using S-nitrosoglutathione (GSNO)) is effective in not only inducing S-Nitrosylation of CSF1R molecule, but it helps in rescuing the excess oxidation in tumor regions, suppresses the tumor promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results postulated that NO therapy could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, results demonstrated that exogenous NO treatment successfully augment the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decrease the intratumoral percentage of anti-inflammatory macrophages, myeloid derived progenitor cells and increasing the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells respectively. Together, our study suggests that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restore control over TME and improve the outcomes of PCa patients.