Cannabidiol inhibits angiogenesis by multiple mechanisms.

BACKGROUND AND PURPOSE: Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. EXPERIMENTAL APPROACH: Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. KEY RESULTS: CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. CONCLUSIONS AND IMPLICATIONS: This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.

Cell delivery of Met docking site peptides inhibit angiogenesis and vascular tumor growth.

Hepatocyte growth factor (HGF) and its receptor Met are responsible for a wide variety of cellular responses, both physiologically during embryo development and tissue homeostasis, and pathologically, particularly during tumor growth and dissemination. In cancer, Met can act as an oncogene on tumor cells, as well as a pro-angiogenic factor activating endothelial cells and inducing new vessel formation. Molecules interfering with Met activity could be valuable therapeutic agents. Here we have investigated the antiangiogenic properties of a synthetic peptide mimicking the docking site of the Met carboxyl-terminal tail, which was delivered into the cells by fusion with the internalization sequences from Antennapedia or HIV-Tat. We showed that these peptides inhibit ligand-dependent endothelial cell proliferation, motility, invasiveness and morphogenesis in vitro to an even greater extent and with much less toxicity than the Met inhibitor PHA-665752, which correlated with interference of HGF-dependent downstream signaling. In vivo, the peptides inhibited HGF-induced angiogenesis in the matrigel sponge assay and impaired xenograft tumor growth and vascularization in Kaposi's sarcoma. These data show that interference with the Met receptor intracellular sequence impairs HGF-induced angiogenesis, suggesting the use of antidocking site compounds as a therapeutic strategy to counteract angiogenesis in cancer as well as in other diseases.

[Equilibrium and orthognathodontic surgery: correlations in a group of patients undergoing treatment]. / Posturologia e chirurgia ortognatodontica. Correlazioni in un gruppo di pazienti trattati.

BACKGROUND: The aim of this study was to evaluate the main parameters provided by the static stabilometric test (mean X, mean Y, mean velocity, length of tracing, standard deviation of velocity, ellipse area) in the follow-up of patients suffering from skeletal occlusive pathology undergoing orthognathodontic surgery to confirm the re-establishment of postural equilibrium. METHODS: Fifteen patients with skeletal dysgnathia were correlated with a group of 10 healthy subjects. The same parameters were analysed in the dysgnathic subjects at 6 and 12 months after surgical correction. The patients enrolled in this study underwent surgery at the Division of Maxillofacial surgery of Turin University. Student's "t"-test and multivariate statistical analysis (Cox regression) were used for the statistical analysis of results. RESULTS: A significant variability was noted in some of the main parameters analysed (mean X, mean Y, tracing length) between the two populations (healthy and dysgnathic) compared to visual signs (eyes opened-closed). The change in stabilometric values within the group of dysgnathic patients was highly significant 6 and 12 months after surgery, not only in terms of visual signs but also the cervical component (retroflexion of the head), above all the value of mean Y (p = 0.001). CONCLUSIONS: An analysis of these results shows that static stabilometry can be a valuable aid both during the preoperative evaluation and during the follow-up in patients undergoing jaw surgery since it can quantify the improvement of body balance.

[Heavy metals: soil characteristics and methods of evaluating parameters for defining "contaminated soils"]. / Metalli pesanti: caratteristiche dei suoli e metodologie di valutazione dei parametri per la definizione di "suoli contaminati".

The excessive content of toxic elements in the human environment is associated with the etiology of a number of diseases. Soils' pollutants decontamination regards the main industrialised countries. Heavy metals represent the main problem for soil pollution characterisation. The first approach for pollution evaluation is the determination of total metal concentration; the evaluation of their bioavailability is required for a correct knowledge of the environmental risk. In the present work is shown the procedure to evaluate the sites, which require decontamination and which need the following data: knowledge of the threshold for each metal in the soil and its range, chemical analysis of the components, determination of bioavailability and soil destination. The bioavailability is easily calculated by the procedure of aimed extractions.

Angiogenesis: prognostic significance in laryngeal cancer.

The aim of this study was to evaluate the role of angiogenesis in the progression of laryngeal squamous cell carcinoma (LSCC). We correlated disease-free survival with microvessel count (MC) in the hot spot areas of 97 randomly selected caucasian males with LSCC followed for 60 to 90 months after surgery with or without radiotherapy. The results obtained indicate that: a) MC higher than 130 microvessels/mm2 is a cut-off value that distinguished patients who relapsed during the follow up period; b) multivariated analysis indicates that MC (p < 0.00001) is an independent predictor of disease free-survival; c) multivariated analysis selectively done on cases with relapse demonstrates that MC correlates with the presence of metastasis (or/and M) with local relapse (T). We suggest that MC is useful in the assessment of prognosis in LSCC and probably will permit selection of patients that could benefit from anti-angiogenic therapy associated with chemotherapy and/or radiotherapy.

[Laryngeal cancer and angiogenesis]. / Angiogenesi e cancro della laringe.

Angiogenesis is required for the growth of solid tumors which, in avascular condition, are limited to 2-3 mm3 volume. The switch to the angiogenic phenotype allows new vessels to converge upon the tumor, growth to proceed at an exponential rate and metastasis diffusion. The evaluation of tumoral angiogenesis has been proposed to be an independent prognostic marker of behaviour of some solid tumors: it has been demonstrated that, in some types of carcinoma (breast, prostate, lung, etc...), an intense vascular proliferation correlates with the aggressiveness of the disease. However in malignant melanomas and colorectal carcinomas, there are conflicting results on the correlation between angiogenesis and the progression of the cancer. There are also conflicting data on the role of microvessels count (MC) in the management of head and neck cancer. Despite a large number of studies, at the present, there are not biological or molecular markers available to predict consistently the outcome of the patients with laryngeal squamous cell carcinoma (LSCC). In fact the prognosis of this tumor has been mainly based, up to now, on a number of clinico-pathological parameters, especially localization, tumor extent and nodal involvement. The aim of this study has been to compare MC inside LSCC with disease free survival, grading, pT, pN and pathological stage. We investigated the relevance of the number of microvessels in the peritumoral stroma of 68 LSCC (only Caucasian males, age 35-70 years), classified according to UICC/1987 randomly selected (33 classified in clinical stage I e II and 35 in clinical stage III-IV). All patients have been surgically treated and pN + cases have been also submitted to radiotherapy. The follow-up was 60-84 months. The vascular density was assessed according to Horak et Al. with an immunohistochemical method using JC70 monoclonal antibody (CD31; Dako, Astrup, Denmark). Univariate analysis showed that MC, pT, pN, Pathological Stage and grading were correlated with the disease-free survival. A MC < 120/mm2 was predictive for a high survival index; in contrast a MC > 150 mm2 were associated with relapse. Furthermore, multivariate analysis demonstrated that MC was the only independent predictor for the disease free survival. Our findings demonstrate that in LSCC, MC is the first measurable biological parameter which is significant for evaluating the disease free-survival. Therefore, MC in LSCC is crucial in the prognosis and in the choice of a more aggressive management of the disease, including the possible treatment with antiangiogenic compound.