Nitric oxide and cancer therapy: the emperor has NO clothes

Abstract

The role of nitric oxide (NO()) as a mediator of cancer phenotype has led researchers to investigate strategies for manipulating in vivo production and exogenous delivery of this molecule for therapeutic gain. Unfortunately, NO() serves multiple functions in cancer physiology. In some instances, NO() or nitric oxide synthase (NOS) levels correlate with tumor suppression and in other cases they are related to tumor progression and metastasis. Understanding this dichotomy has been a great challenge for researchers working in the field of NO() and cancer therapy. Due to the unique chemical and biochemical properties of NO(), it's interactions with cellular targets and the subsequent downstream signaling events can be vastly different based upon tumor heterogeneity and microenvironment. Simple explanations for the vast range of NO-correlated behaviors will continue to produce conflicting information about the relevance of NO() and cancer. Paying considerable attention to the chemical properties of NO() and the methodologies being used will remove many of the discrepancies in the field and allow for in depth understanding of when NO-based chemotherapeutics will have beneficial outcomes.

Fig. (1)

The effect of oxygen on nitric oxide releasing chemotherapeutics. Oxygen affects both the concentration of NO (y-axis) and the distance it diffuses (x-axis). The half-life of NO is a function of the oxygen concentration; low oxygen (hypoxia) increases the half-life of NO. The longer the half-life of NO, the greater its local concentration will be and the further distance it will diffuse from its point of origin. Various cellular targets (A, B, C, D) will be differentially affected by NO based simply on its local concentration. Hypoxia will extend the distance that NO diffuses and therefore allow it to interact with a greater number of targets that are a further distance away (x-axis, C and D). Hypoxia will also raise the local concentration of NO and increase the likelihood that it will activate proteins which are less sensitive to NO (y-axis, C and D). The impact of O₂ on NO concentration is an important factor that greatly influences the effect of NO-based chemotherapeutics on tumor phenotype.

Fig. (2)

All donor compounds are not created equal. A) Measurements of NO in the media of NONOate treated cells. MCF-7 cells were treated with either DEA/NO, Sper/NO or DETA/NO, and NO concentrations were determined from 100µl aliquots of medium. Samples were analyzed by chemiluminescence at the indicated time points. B) Western blot demonstrating the temporal relationship between NO exposure and HIF-1α accumulation in MCF-7 cells exposed to the three different NONOates. Cells were serum-starved overnight, treated with NONOates and harvested at the indicated time points (modified from [60]).