Pharmacological and In Silico Analysis of Oat Avenanthramides as EGFR Inhibitors: Effects on EGF-Induced Lung Cancer Cell Growth and Migration.

Avena sativa L. is a wholegrain cereal and an important edible crop. Oats possesses high nutritional and health promoting values and contains high levels of bioactive compounds, including a group of phenolic amides, named avenanthramides (Avns), exerting antioxidant, anti-inflammatory, and anticancer activities. Epidermal growth factor receptor (EGFR) represents one of the most known oncogenes and it is frequently up-regulated or mutated in human cancers. The oncogenic effects of EGFR include enhanced cell growth, angiogenesis, and metastasis, and down-regulation or inhibition of EGFR signaling has therapeutic benefit. Front-line EGFR tyrosine kinase inhibitor therapy is the standard therapy for patients with EGFR-mutated lung cancer. However, the clinical effects of EGFR inhibition may be lost after a few months of treatment due to the onset of resistance. Here, we showed the anticancer activity of Avns, focusing on EGFR activation and signaling pathway. Lung cancer cellular models have been used to evaluate the activity of Avns on tumor growth, migration, EMT, and anoikis induced by EGF. In addition, docking and molecular dynamics simulations showed that the Avns bind with high affinity to a region in the vicinity of αC-helix and the DGF motif of EGFR, jeopardizing the target biological function. Altogether, our results reveal a new pharmacological activity of Avns as EGFR tyrosine kinase inhibitors.

Phaseolus vulgaris L. var. Venanzio Grown in Tuscany: Chemical Composition and In Vitro Investigation of Potential Effects on Colorectal Cancer.

Phaseolus vulgaris L. (common bean) is a leguminous species that is an important dietary component due to its high content of proteins, unsaturated fatty acids, minerals, dietary fibers and vitamins. Due to the high content of polyphenols, several biological activities have been described for bean extracts, making it possible to include P. vulgaris among food with beneficial effects for human health. Moreover, more than 40,000 varieties of beans have been recognised with different nutraceutical properties, pointing out the importance of food biodiversity. In this work, we describe for the first time the chemical composition and biological activity of a newly recognized Italian variety of P. vulgaris grown in a restricted area of the Tuscany region and named "Fagiola di Venanzio". Fagiola di Venanzio water extract is rich in proteins, sugars and polyphenols and displays antioxidant, anti-inflammatory and antiproliferative activities in in vitro assays on colon cancer cellular models. Our data indicate that this variety of P. vulgaris appears to be a promising source of bioactive compounds and encourage more in-depth studies to better elucidate the implications of its consumption for public health.

Prostaglandin E2 and Cancer: Insight into Tumor Progression and Immunity.

The involvement of inflammation in cancer progression has been the subject of research for many years. Inflammatory milieu and immune response are associated with cancer progression and recurrence. In different types of tumors, growth and metastatic phenotype characterized by the epithelial mesenchymal transition (EMT) process, stemness, and angiogenesis, are increasingly associated with intrinsic or extrinsic inflammation. Among the inflammatory mediators, prostaglandin E2 (PGE2) supports epithelial tumor aggressiveness by several mechanisms, including growth promotion, escape from apoptosis, transactivation of tyrosine kinase growth factor receptors, and induction of angiogenesis. Moreover, PGE2 is an important player in the tumor microenvironment, where it suppresses antitumor immunity and regulates tumor immune evasion, leading to increased tumoral progression. In this review, we describe the current knowledge on the pro-tumoral activity of PGE2 focusing on its role in cancer progression and in the regulation of the tumor microenvironment.

KRIT1 as a possible new player in melanoma aggressiveness.

Krev interaction trapped protein 1 (KRIT1) is a scaffold protein known to form functional complexes with distinct proteins, including Malcavernin, PDCD10, Rap1 and others. It appears involved in several cellular signaling pathways and exerts a protective role against inflammation and oxidative stress. KRIT1 has been studied as a regulator of endothelial cell functions and represents a determinant in the pathogenesis of Cerebral Cavernous Malformation (CCM), a cerebrovascular disease characterized by the formation of clusters of abnormally dilated and leaky blood capillaries, which predispose to seizures, neurological deficits and intracerebral hemorrhage. Although KRIT1 is ubiquitously expressed, few studies have described its involvement in pathologies other than CCM including cancer. Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic propensity. Despite the numerous efforts made to define the signaling pathways activated during melanoma progression, the molecular mechanisms at the basis of melanoma growth, phenotype plasticity and resistance to therapies are still under investigation.

KRIT1 loss-mediated upregulation of NOX1 in stromal cells promotes paracrine pro-angiogenic responses.

Cerebral cavernous malformation (CCM) is a cerebrovascular disorder of proven genetic origin characterized by abnormally dilated and leaky capillaries occurring mainly in the central nervous system, with a prevalence of 0.3-0.5% in the general population. Genetic studies have identified causative mutations in three genes, CCM1/KRIT1, CCM2 and CCM3, which are involved in the maintenance of vascular homeostasis. However, distinct studies in animal models have clearly shown that CCM gene mutations alone are not sufficient to cause CCM disease, but require additional contributing factors, including stochastic events of increased oxidative stress and inflammation. Consistently, previous studies have shown that up-regulation of NADPH oxidase-mediated production of reactive oxygen species (ROS) in KRIT1 deficient endothelium contributes to the loss of microvessel barrier function. In this study, we demonstrate that KRIT1 loss-of-function in stromal cells, such as fibroblasts, causes the up-regulation of NADPH oxidase isoform 1 (NOX1) and the activation of inflammatory pathways, which in turn promote an enhanced production of proangiogenic factors, including vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2). Furthermore and importantly, we show that conditioned media from KRIT1 null fibroblasts induce proliferation, migration, matrix metalloproteinase 2 (MMP2) activation and VE-cadherin redistribution in wild type human endothelial cells. Taken together, our results demonstrate that KRIT1 loss-of-function in stromal cells affects the surrounding microenvironment through a NOX1-mediated induction and release of angiogenic factors that are able to promote paracrine proangiogenic responses in human endothelial cells, thus pointing to a novel role for endothelial cell-nonautonomous effects of KRIT1 mutations in CCM pathogenesis, and opening new perspectives for disease prevention and treatment.