Inhibition of iNOS as a Novel Effective Targeted Therapy Against Triple-Negative Breast Cancer

INTRODUCTION: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with no effective targeted therapy. Inducible nitric oxide synthase (iNOS) is associated with poor survival in patients with breast cancer by increasing tumor aggressiveness. This work aimed to investigate the potential of iNOS inhibitors as a targeted therapy for TNBC. We hypothesized that inhibition of endogenous iNOS would decrease TNBC aggressiveness by reducing tumor initiation and metastasis through modulation of epithelial-mesenchymal transition (EMT)-inducing factors. METHODS: iNOS protein levels were determined in 83 human TNBC tissues and correlated with clinical outcome. Proliferation, mammosphere-forming efficiency, migration, and EMT transcription factors were assessed in vitro after iNOS inhibition. Endogenous iNOS targeting was evaluated as a potential therapy in TNBC mouse models. RESULTS: High endogenous iNOS expression was associated with worse prognosis in patients with TNBC by gene expression as well as immunohistochemical analysis. Selective iNOS (1400 W) and pan-NOS (L-NMMA and L-NAME) inhibitors diminished cell proliferation, cancer stem cell self-renewal, and cell migration in vitro, together with inhibition of EMT transcription factors (Snail, Slug, Twist1, and Zeb1). Impairment of hypoxia-inducible factor 1α, endoplasmic reticulum stress (IRE1α/XBP1), and the crosstalk between activating transcription factor 3/activating transcription factor 4 and transforming growth factor β was observed. iNOS inhibition significantly reduced tumor growth, the number of lung metastases, tumor initiation, and self-renewal. CONCLUSIONS: Considering the effectiveness of L-NMMA in decreasing tumor growth and enhancing survival rate in TNBC, we propose a targeted therapeutic clinical trial by re-purposing the pan-NOS inhibitor L-NMMA, which has been extensively investigated for cardiogenic shock as an anti-cancer therapeutic

Diets based on virgin olive oil or fish oil but not on sunflower oil prevent age-related alvolar bone resorption by mitochondrial-related mechanisms

Background/Objectives: Aging enhances frequency of chronic diseases like cardiovascular diseases or periodontitis. Here we reproduced an age-dependent model of the periodontium, a fully physiological approach to periodontal conditions, to evaluate the impact of dietary fat type on gingival tissue of young (6 months old) and old (24 months old) rats.Methods/Findings: Animals were fed life-long on diets based on monounsaturated fatty acids (MUFA) as virgin olive oil, n-6 polyunsaturated fatty acids (n-6PUFA), as sunflower oil, or n-3PUFA, as fish oil. Age-related alveolar bone loss was higher in n-6PUFA fed rats, probably as a consequence of the ablation of the cell capacity to adapt to aging. Gene expression analysis suggests that MUFA or n-3PUFA allowed mitochondria to maintain an adequate turnover through induction of biogenesis, autophagy and the antioxidant systems, and avoiding mitochondrial electron transport system alterations.Conclusions: The main finding is that the enhanced alveolar bone loss associated to age may be targeted by an appropriate dietary treatment. The mechanisms involved in this phenomenon are related with an ablation of the cell capacity to adapt to aging. Thus, MUFA or n-3PUFA might allow mitochondrial maintaining turnover through biogenesis or autophagy. They might also be able to induce the corresponding antioxidant systems to counteract age-related oxidative stress, and do not inhibit mitochondrial electron transport chain. From the nutritional and clinical point of view, it is noteworthy that the potential treatments to attenuate alveolar bone loss (a feature of periodontal disease) associated to age could be similar to some of the proposed for the prevention and treatment of cardiovascular diseases, a group of pathologies recently associated with age-related periodontitis.This study was supported by I+D grants from the Spanish Ministry of Education and Science (AGL2008-01057) and the Autonomous Government of Andalusia (AGR832)

Nutraceutical therapies for atherosclerosis

Atherosclerosis is a chronic inflammatory disease affecting large and medium arteries and is considered to be a major underlying cause of cardiovascular disease (CVD). Although the development of pharmacotherapies to treat CVD has contributed to a decline in cardiac mortality in the past few decades, CVD is estimated to be the cause of one-third of deaths globally. Nutraceuticals are natural nutritional compounds that are beneficial for the prevention or treatment of disease and, therefore, are a possible therapeutic avenue for the treatment of atherosclerosis. The purpose of this Review is to highlight potential nutraceuticals for use as antiatherogenic therapies with evidence from in vitro and in vivo studies. Furthermore, the current evidence from observational and randomized clinical studies into the role of nutraceuticals in preventing atherosclerosis in humans will also be discussed

Cells electric charge analyses define specific properties for cancer cells activity

The surface electrical charge of cells is conditioned by the ionic medium in which they are immersed. This charge is specific for each cell type and is especially important in tumour cells because it determines their state of aggregation and their adhesion in the different organs. This study analyses the variations in surface charge of cells when pH, electrolytes, and their concentration are modified. The modification of these factors leads to changes in the surface charge of tumour cells; therefore, their states of aggregation and behaviour can be modified. This may even have a use in the prognosis and treatment of various tumours. Some studies conclude that the activity associated with the glycolysis process is accompanied by a change in the surface charge of cells. Notably, there is a high rate of glycolysis in tumours. Our results show that surface charge of cells strongly depends on nature of ionic medium in which they are found, with the valence of the majority ion being the most important factor. When ionic strength was high, the charge decreased dramatically. On the other hand, charge becomes zero or positive in an acidic pH, while in a basic pH, the negative charge increases.we gratefully acknowledge the support of the institutions involved: the University of Jaén for the resources used; the “Liquid Biopsy and Cancer Interception” research group of the Genomics and Oncology Research Centre (GENYO) for providing the tumour cells used; UJA Research Group 'Cardiac and Skeletal Myogenesis: Muscle Regeneration (CTS 446) for providing the normal cells used

Cells electric charge analyses define specific properties for cancer cells activity.

The surface electrical charge of cells is conditioned by the ionic medium in which they are immersed. This charge is specific for each cell type and is especially important in tumour cells because it determines their state of aggregation and their adhesion in the different organs. This study analyses the variations in surface charge of cells when pH, electrolytes, and their concentration are modified. The modification of these factors leads to changes in the surface charge of tumour cells; therefore, their states of aggregation and behaviour can be modified. This may even have a use in the prognosis and treatment of various tumours. Some studies conclude that the activity associated with the glycolysis process is accompanied by a change in the surface charge of cells. Notably, there is a high rate of glycolysis in tumours. Our results show that surface charge of cells strongly depends on nature of ionic medium in which they are found, with the valence of the majority ion being the most important factor. When ionic strength was high, the charge decreased dramatically. On the other hand, charge becomes zero or positive in an acidic pH, while in a basic pH, the negative charge increases