Current Medicinal Chemistry - Volume 27, Issue 42, 2020

Nitric Oxide (NO) is internationally regarded as a signal molecule involved in several functions in the respiratory tract under physiological and pathogenic conditions. Hydrogen Sulfide (H2S) has also recently been recognized as a new gasotransmitter with a diverse range of functions similar to those of NO. Depending on their respective concentrations, both these molecules act synergistically or antagonistically as signals or damage promoters. Nevertheless, available evidence shows that the complex biological connections between NO and H2S involve multiple pathways and depend on the site of action in the respiratory tract, as well as on experimental conditions. This review will provide an update on these two gasotransmitters in physiological and pathological processes.

The imbalance between increased oxidative agents and antioxidant defence mechanisms is central in the pathogenesis of obstructive lung diseases such as asthma and COPD. In these patients, there are increased levels of reactive oxygen species. Superoxide anions (O2 -), Hydrogen Peroxide (H2O2) and hydroxyl radicals (•OH) are critical for the formation of further cytotoxic radicals in the bronchi and lung parenchyma. Chronic inflammation, partly induced by oxidative stress, can further increase the oxidant burden through activated phagocytic cells (neutrophils, eosinophils, macrophages), particularly in severer disease states. Antioxidants and anti-inflammatory genes are, in fact, frequently downregulated in diseased patients. Nrf2, which activates the Antioxidant Response Element (ARE) leading to upregulation of GPx, thiol metabolism-associated detoxifying enzymes (GSTs) and stressresponse genes (HO-1) are all downregulated in animal models and patients with asthma and COPD. An exaggerated production of Nitric Oxide (NO) in the presence of oxidative stress can promote the formation of oxidizing reactive nitrogen species, such as peroxynitrite (ONO2 -), leading to nitration and DNA damage, inhibition of mitochondrial respiration, protein dysfunction, and cell damage in the biological systems. Protein nitration also occurs by activation of myeloperoxidase and H2O2, promoting oxidation of nitrite (NO2 -). There is increased nitrotyrosine and myeloperoxidase in the bronchi of COPD patients, particularly in severe disease. The decreased peroxynitrite inhibitory activity found in induced sputum of COPD patients correlates with pulmonary function. Markers of protein nitration - 3- nitrotyrosine, 3-bromotyrosine, and 3-chlorotyrosine - are increased in the bronchoalveolar lavage of severe asthmatics. Targeting the oxidative, nitrosative stress and associated lung inflammation through the use of either denitration mechanisms or new drug delivery strategies for antioxidant administration could improve the treatment of these chronic disabling obstructive lung diseases.

Asthma is a heterogeneous disease with regard to the inflammatory pathways activated. In recent years, biologic drugs (monoclonal antibodies) directed towards specific components of type 2 inflammation have been approved for the treatment of severe asthma. Phenotyping of patients with severe asthma and evaluation of biomarkers have been recommended to help identify patients who are candidates for treatment with biologics and to monitor treatment responses. Fractional exhaled Nitric Oxide (FeNO) is a biomarker of type 2 inflammation in asthma, signaling activation of Interleukin (IL)-4/IL-13 pathway. FeNO could be useful to assess treatment response or identify candidates for a specific drug that acts on type 2 inflammation mechanisms linked to Nitric Oxide (NO) production, such as the IL-4/IL-13 pathway or upstream processes. The value of FeNO as a biomarker predictive of responses to the biologics available for treating severe asthma is discussed based on the published studies at the moment of the review.

The altered Nitric Oxide (NO) pathway in the pulmonary endothelium leads to increased vascular smooth muscle tone and vascular remodelling, and thus contributes to the development and progression of pulmonary arterial hypertension (PAH). The pulmonary NO signalling is abrogated by the decreased expression and dysfunction of the endothelial NO synthase (eNOS) and the accumulation of factors blocking eNOS functionality. The NO deficiency of the pulmonary vasculature can be assessed by detecting nitric oxide in the exhaled breath or measuring the degradation products of NO (nitrite, nitrate, S-nitrosothiol) in blood or urine. These non-invasive biomarkers might show the potential to correlate with changes in pulmonary haemodynamics and predict response to therapies. Current pharmacological therapies aim to stimulate pulmonary NO signalling by suppressing the degradation of NO (phosphodiesterase- 5 inhibitors) or increasing the formation of the endothelial cyclic guanosine monophosphate, which mediates the downstream effects of the pathway (soluble guanylate cyclase sensitizers). Recent data support that nitrite compounds and dietary supplements rich in nitrate might increase pulmonary NO availability and lessen vascular resistance. This review summarizes current knowledge on the involvement of the NO pathway in the pathomechanism of PAH, explores novel and easy-to-detect biomarkers of the pulmonary NO.

Background: Fractional exhaled nitric oxide (FENO) concentration reliably reflects central airway inflammation, but it is not sensitive to changes in the NO dynamics in the lung periphery. By measuring FENO at several different flow rates one can estimate alveolar NO concentration (CANO), bronchial NO flux (JawNO), bronchial wall NO concentration (CawNO) and the bronchial diffusivity of NO (DawNO). Objective: We aimed to describe the current knowledge and clinical relevance of NO parameters in different pulmonary diseases. Methods: We conducted a systematic literature search to identify publications reporting NO parameters in subjects with pulmonary or systemic diseases affecting the respiratory tract. A narrative review was created for those with clinical relevance. Results: Estimation of pulmonary NO parameters allows for differentiation between central and peripheral inflammation and a more precise analysis of central airway NO output. CANO seems to be a promising marker of parenchymal inflammation in interstitial lung diseases and also a marker of tissue damage and altered gas diffusion in chronic obstructive pulmonary disease and systemic diseases affecting the lung. In asthma, CANO can detect small airway involvement left undetected by ordinary FENO measurement. Additionally, CawNO and DawNO can be used in asthma to assess if FENO is increased due to enhanced inflammatory activity (increased CawNO) or tissue changes related to bronchial remodelling (altered DawNO). Conclusion: NO parameters may be useful for diagnosis, prediction of disease progression and prediction of treatment responses in different parenchymal lung and airway diseases. Formal trials to test the added clinical value of NO parameters are needed.

Background: The widespread application of engineered nanomaterials (ENMs) and the increasing likelihood of general and occupational exposure raised concerns on their possible human health impact. ENMs, in fact, may induce alterations in different organ systems, and particularly in the respiratory tract. This makes it important to identify possible biomarkers of early lung effect in exposed workers. In this regard, the possibility to use the fractional exhaled levels of nitric oxide (FENO) in biological monitoring has attracted considerable interest. Objective: To comprehensively assess the role of FENO as a possible biomarker of lung effect in ENM exposed workers. Methods: A systematic search was performed on Pubmed, Scopus, and ISI Web of Knowledge databases according to the PRISMA guidelines. Results: Seven studies investigated FENO in workers exposed to different kinds of metal- (i.e. silver and gold), metal oxide- (titanium and silica dioxide), and carbon-based ENMs (carbon nanotubes). In general, no significant alterations were detected between exposed workers and controls. Conclusion: Definite conclusion on the function of FENO in occupational biological monitoring cannot be extrapolated due to the limited number of available studies and the small size of investigated populations. Additionally, the lack of environmental monitoring data and the fragmented knowledge on ENM modes of action prevent to establish dose-response relationships. Future research appears necessary to deeply define the possibility to employ FENO as an early biomarker of lung effects taking in consideration possible occupational exposure issues, i.e. differently characterized ENMs and work tasks, as well as individual influencing factors, i.e. smoking and atopy.

Drug repurposing is the process of developing existing or abandoned drugs for a different disease. Repurposing can circumvent higher costs and times associated with conventional drug discovery strategies because toxicity and pharmacokinetics profiles are typically already established. This brief review focuses on efforts to repurpose drugs for skin cancer and includes reuse of antihypertensives, anthelmintics and antifungals among a range of other medicines. Repurposing not only ushers promising known drugs for new indications, the process of repurposing can uncover new mechanistic insights in the pathogenesis of disease and uncover new opportunities for pharmaceutical intervention.

Background: Ovary Carcinoma (OC) is the most lethal gynecological neoplasm due to the late diagnoses and to the common development of resistance to platinum-based chemotherapy. Thus, novel therapeutic approaches are urgently required. In this regard, the strategy of drug repurposing is becoming attractive. By this approach, the effectiveness of a drug originally developed for another indication is tested in a different pathology. The advantage is that data about pharmacokinetic properties and toxicity are already available. Thus, in principle, it is possible to reduce research costs and to speed up drug usage/marketing. Results: Here, some noticeable examples of repurposed drugs for OC, such as amiodarone, ruxolitinib, statins, disulfiram, ormeloxifenem, and Quinacrine, are reported. Amiodarone, an antiarrhythmic agent, has shown promising anti-OC activity, although the systemic toxicity should not be neglected. The JAK inhibitor, Ruxolitinib, may be employed particularly in coadministration with standard OC therapy as it synergistically interacts with platinum-based drugs. Particularly interesting is the use of statin which represent one of the most commonly administered drugs in aged population to treat hypercholesterolemia. Disulfiram, employed in the treatment of chronic alcoholism, has shown anti-OC properties. Ormeloxifene, commonly used for contraception, seems to be promising, especially due to the negligible side effects. Finally, Quinacrine used as an antimicrobial and anti-inflammatory drug, is able to downregulate OC cell growth and promote cell death. Conclusion: Whereas further testing in patients are necessary to better clarify the therapeutic potential of repurposed drugs for OC, it is believed that their use, better if combined with OC targeted delivery systems, can significantly contribute to the development of novel and effective anti-OC treatments.

Nanodrugs represent novel solutions to reshuffle repurposed drugs for cancer therapy. They might offer different therapeutic options by combining targeted drug delivery and imaging in unique platforms. Such nanomaterials are deemed to overcome the limitations of currently available treatments, ultimately improving patients’ life quality. However, despite these promises being made for over three decades, the poor clinical translation of nanoparticle- based therapies calls for deeper in vitro and in vivo investigations. Translational issues arise very early during the development of nanodrugs, where complex and more reliable cell models are often replaced by easily accessible and convenient 2D monocultures. This is particularly true in the field of cancer therapy. In fact, 2D monocultures provide poor information about the real impact of the nanodrugs in a complex living organism, especially given the poor mimicry of the solid Tumors Microenvironment (TME). The dense and complex extracellular matrix (ECM) of solid tumors dramatically restricts nanoparticles efficacy, impairing the successful implementation of nanodrugs in medical applications. Herein, we propose a comprehensive guideline of the 3D cell culture models currently available, including their potential and limitations for the evaluation of nanodrugs activity. Advanced culture techniques, more closely resembling the physiological conditions of the TME, might give a better prediction of the reciprocal interactions between cells and nanoparticles and eventually help reconsider the use of old drugs for new applications.

At least a proportion of patients suffering from chronic inflammatory airway diseases respond poorly to the bronchodilator and corticosteroid therapies. There is a need for the development of improved anti-inflammatory treatment. Insulin Growth Factor 1 (IGF1) and insulin participate in not only metabolism and glucose homeostasis, but also many other physiological and pathophysiological processes, including growth and inflammation. Recently, it was shown that not only the classical IGF1 and IGF1 Receptor (IGF1R), but also the other molecules in the IGF1/insulin network, including insulin, insulin-like growth factor-binding protein (IGFBP), and IGFBP protease, have roles in chronic inflammatory airway diseases. This review aims to provide a comprehensive insight into recent endeavors devoted to the role of the IGF1/insulin network in chronic inflammatory airway diseases. Its participation in airway inflammation, remodeling, and hyper-responsiveness (AHR), as well as acute exacerbation, has been conclusively demonstrated. Its possible relation to glucocorticoid insensitivity has also been indicated. A better understanding of the IGF1/insulin network by further bench-to-bedside research may provide us with rational clinical therapeutic approaches against chronic inflammatory airway diseases.

Protein Kinase Inhibitors (PKIs) and Histone Deacetylase Inhibitors (HDACIs) are two important classes of anticancer agents and have provided a variety of small molecule drugs for the treatment of various types of human cancers. However, malignant tumors are of a multifactorial nature that can hardly be “cured” by targeting a single target, and treatment of cancers hence requires modulation of multiple biological targets to restore the physiological balance and generate sufficient therapeutic efficacy. Multi-target drugs have attracted great interest because of their advantages in the treatment of complex cancers by simultaneously targeting multiple signaling pathways and possibly leading to synergistic effects. Synergistic effects have been observed in the combination of kinase inhibitors, such as imatinib, dasatinib, or sorafenib, with an array of HDACIs including vorinostat, romidepsin, or panobinostat. A considerable number of multi-target agents based on PKIs and HDACIs have been developed. In this review, we summarize the recent literature on the development of multi-target kinase-HDAC inhibitors and provide our view on the challenges and future directions on this topic.